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Phenotypic variability to medication management: an update on fragile X syndrome

Human Genomics volume 17, Article number: 60 (2023) Cite this article

Abstract

This review discusses the discovery, epidemiology, pathophysiology, genetic etiology, molecular diagnosis, and medication-based management of fragile X syndrome (FXS). It also highlights the syndrome’s variable expressivity and common comorbid and overlapping conditions. FXS is an X-linked dominant disorder associated with a wide spectrum of clinical features, including but not limited to intellectual disability, autism spectrum disorder, language deficits, macroorchidism, seizures, and anxiety. Its prevalence in the general population is approximately 1 in 5000–7000 men and 1 in 4000–6000 women worldwide. FXS is associated with the fragile X messenger ribonucleoprotein 1 (FMR1) gene located at locus Xq27.3 and encodes the fragile X messenger ribonucleoprotein (FMRP). Most individuals with FXS have an FMR1 allele with > 200 CGG repeats (full mutation) and hypermethylation of the CpG island proximal to the repeats, which silences the gene’s promoter. Some individuals have mosaicism in the size of the CGG repeats or in hypermethylation of the CpG island, both produce some FMRP and give rise to milder cognitive and behavioral deficits than in non-mosaic individuals with FXS. As in several monogenic disorders, modifier genes influence the penetrance of FMR1 mutations and FXS’s variable expressivity by regulating the pathophysiological mechanisms related to the syndrome’s behavioral features. Although there is no cure for FXS, prenatal molecular diagnostic testing is recommended to facilitate early diagnosis. Pharmacologic agents can reduce some behavioral features of FXS, and researchers are investigating whether gene editing can be used to demethylate the FMR1 promoter region to improve patient outcomes. Moreover, clustered regularly interspaced palindromic repeats (CRISPR)/Cas9 and developed nuclease defective Cas9 (dCas9) strategies have promised options of genome editing in gain-of-function mutations to rewrite new genetic information into a specified DNA site, are also being studied.

Background

Fragile X syndrome (FXS, MIM 300624) is an X-linked dominant disorder affecting approximately 1 in 5000–7000 men and 1 in 4000–6000 women worldwide [1]. Currently, it is the second leading cause of intellectual disability (ID) (2.4% of all ID cases), surpassed only by Down syndrome, the leading cause of inherited ID, and the leading cause of ID in male individuals [1,2,3].

FXS is caused by a CGG trinucleotide repeat expansion in the FMR1 (MIM 309550). The typical number of CGG repeats in the FMR1 gene ranges from 5 to 44. Individuals with > 200 CGG repeats are considered to have a full FMR1 mutation, also known as a fragile site [4]. More than 99% of individuals diagnosed with FXS have the full mutation [5]. The presence of 55–200 repeats is considered an FMR1 premutation, which is associated with fragile X-associated tremor/ataxia syndrome (FXTAS, MIM 300623) [6, 7] and, in female individuals, with fragile X-associated premature ovarian insufficiency (FXPOI; MIM 311360) [8, 9]. Several reports have shown that AGG interruptions within the FMR1 gene also contribute to FXS [10]. The number of AGG interruptions and the length of uninterrupted CGG repeats at the 3' end of FMR1 have correlated with repeat instability during transmission from parent to a child [11]. Maternal alleles with no AGG interruptions confer the greatest risk for unstable transmission of the CGG repeats [11].

The FMR1 gene encodes the fragile X messenger ribonucleoprotein (FMRP), commonly found in the brain and essential for normal cognitive development and female reproductive function. FMRP can bind to ribosomes and regulate the translation of many mRNAs in postsynaptic neurons, which is critical for neurological development and function [12,13,14,15]. It has also been shown to bind to multiple ion channels to regulate their activity [16].

In mammals, cytosine methylation frequently occurs in the linear DNA sequence where DNA methyltransferases (DNMT) add methyl groups to a cytosine adjacent to guanine in a 5'-3' direction (a CpG island). DNA demethylation causes the replacement of 5-methylcytosine (5mC) in a DNA sequence by cytosine (C). DNA methylation is a major epigenetic modification that regulates transcription [17], and hypermethylation of this CpG island silences transcription of the FMR1 gene [18]. The full FXS mutation is associated with hypermethylation of a CpG island, proximal to the CGG repeat, in the promoter of the FMR1 gene. As a consequence, FMRP is not produced, and the absence or low expression of FMRP leads to FXS [19].

FXS is molecularly diagnosed based on relevant X chromosome abnormalities and alterations in the FMR1 gene and is clinically diagnosed based on a wide spectrum of the physical, central nervous system, and neuropsychiatric/developmental features. Most male individuals with FXS cannot perform basic activities of daily living, e.g., feeding, ambulating, toileting, maintaining personal hygiene/grooming, and dressing. Female patients are often more self-reliant but frequently exhibit learning difficulties [20]. Although there is no recognized cure for FXS, psychosocial interventions, educational interventions, and drug treatment can help manage some aspects of the disorder [21,22,23].

The early history of FXS

FXS, also known as Martin–Bell syndrome, was first described in 1943 by Martin and Bell as a form of ID following an X-linked pattern of inheritance [24]. Martin and Bell suggested X-linked inheritance because they observed that male children were more severely affected than their female counterparts. A family case study also suggested that FXS impaired brain development (likely the prefrontal cortex) since most patients had speech difficulty and ID [24]. Lubs first reported a fragile site at Chromosome Xq27.3 that segregated with ID in the late 1960s [25]. The association between this fragile site (FRAXA) and X-linked ID was confirmed two decades later [4]. Around the same time as Lub's discovery, Escalante et al. [26] noted the association of macroorchidism with X-linked mental retardation. Molecular analysis of 105 simplexes and 18 multiplex families later revealed no association between FRAXA and autism, ruling out Xq27.3 as a candidate region for autism [27]. Gross et al., however, have reported that the distinctive behavioral phenotypes of FXS-linked synaptic plasticity are consistent with autism spectrum disorder (ASD), self-injurious and stereotypic behavior, aggression, anxiety, impulsivity, hyperactivity, and attention deficit [28].

Epidemiology

In Europe and North America, the prevalence of the full FXS mutation estimates at approximately 1/5000 male and 1/4000–8000 female individuals in the general population [14, 29,30,31]. Differences in haplotype frequencies and founder effects among different racial and ethnic populations can also affect the prevalence of FXS [32]. Newborn screening of 36,124 boys in the United States identified the full mutation in every 1 in 5,161 of the boys [30]; similarly, screening of 24,449 neonates in Québec, Canada, identified the full mutation in 1 in 6,209 boys [31]. The prevalence of the full mutation in male individuals is higher in Hispanic countries such as Chile (6.7%) [33], Spain (6.4%) [34,35,36], and Colombia (4.82%) [37]. Among 574 developmentally disabled French individuals, the prevalence of FXS was 1.9% (11/574) overall and 2.5% (10/403) in male individuals; only one case of FXS was detected among the 171 girls tested (0.6%) [38]. In 504 mentally disabled Iranian patients, full FMR1 mutations were found in 19 (15.3%) of 124 unrelated families and in 13 (3.4%) of 384 consanguineous families [39]. Zhang et al. [40] have found a lower prevalence of FXS in a large-scale screening of 51,661 Chinese newborns (1/9,371 in males and 1/2,943 in females) than in Caucasians [1, 14, 29]. In the same study, they also found 33 children cohort of 33 children diagnosed with developmental delay. Among 237 Thai boys with a developmental delay of unknown cause in Southern Asia, 16 (6.8%) were found to have a full FMR1 mutation, and four were reported to have a premutation [41]. The prevalence of FXS in Indonesia ranged from 0.9% to 1.9% among the ID population and was higher (6.15%) among the ASD population [42]. In Malaysia, with 2108 children with developmental disabilities from mixed ethnicities, the FXS full mutation was reported as 70 (3.6%) in males and 3 (2.4%) in females [43]. The prevalence of FXS in Pakistan was estimated to be 19/1,000 children for severe ID and 65/1000 children for mild ID [44]. In Northern Africa, the prevalence of FXS was 7.6% in 200 Tunisian boys with ID [45].

A global meta-analysis found that the prevalence of the FMR1 premutation ranges from 1 in 250–813 male individuals to 1 in 110–270 female individuals [1], much higher than the prevalence of the full mutation. In one study of male newborn screening in Spain, the prevalence of the premutation (1 in 1,233 male infants) was about ten times higher than the prevalence of the full mutation (1 in 2,466 male infants) [34]. It is noteworthy that the prevalence of the premutation is highest in Colombia and Israel (1 in 100 female individuals) and lowest in Japan (1 in 1,674 female individuals) [46]. In Saudi Arabia, screening of 94 cases with undiagnosed mental retardation found an even higher prevalence of the premutation: 6.4 in 100 female individuals and 7.86 in 100 male individuals [47]. In Egyptian males with ID, autistic-like features, and behavioral difficulties (n = 92), Rafeat et al. [48] found a prevalence of 37%, 0.03%, and 0.07% in premutation, gray zone (45–55 CGG repeats), and full mutation, respectively.

Clinical characteristics of FXS

At birth, the physical features associated with FXS are usually not apparent and affect children's height, weight, and head circumference within normal ranges [49]. Neonates show no clinical signs except for hypotonia, which is common among the general population [50]. Many of the major clinical characteristics of boys with FXS, summarized in Table 1 [51,52,53,54], become clearer during the first year of life, and diagnosis is often made around 2–3 years of life, particularly alongside the development of language delays [54, 55]. Figure 1 shows the most prominent clinical characteristics of the condition at each stage of life, from infancy to old age.

Table 1 Major clinical characteristics of boys with FXS
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Fig. 1
figure 1

Clinical characteristics of fragile X syndrome A specific to infancy and early childhood and B spanning from infancy to old age. Adapted from [14]

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The clinical presentation of FXS varies, as some primary and secondary clinical characteristics are more common than others (Table 1). The presentation also differs between girls and boys. For example, 85% of male patients but only 60% of female patients have ID [49]. In males, the characteristic phenotype also includes post-pubertal macroorchidism (i.e., enlarged testes), a prominent lower jaw, a narrow-elongated face, and large anteverted ears [49, 57]. Notably, however, 25% of male adults diagnosed with FXS do not have the distinctive facial characteristics associated with the condition [52]. Both girls and boys diagnosed with FXS tend to have connective tissue anomalies that can lead to heart disease (e.g., mitral valve prolapses) and are atypically short but otherwise have a normal physical appearance. Overall, the clinical presentation of FXS is less observable and more variable in female individuals than in their male counterparts [58].

Brain imaging abnormalities

Almost 74% of FXS patients have been shown to have electroencephalogram (EEG) abnormalities, such as focal spikes originating from several anatomic parts. However, 35% of children with FXS report remission of EEG abnormalities by age 7 or 8 [59]. Additionally, patients with FXS have abnormal brain MRI scans. Notable defects include elevated cortical complexity, increased whole lobar and cortical thickness volume, and diffuse atrophy [60]. The anomalies can be associated with an undeveloped spine, increased spine length and density, and reduced pruning. Moreover, patients with FXS are at high risk of developing mesial temporal sclerosis, enlarged fourth ventricles, and hippocampal complications [61]. MRI abnormalities are also negatively associated with cognitive performance among children diagnosed with FXS [62].

Comorbid and overlapping conditions

Autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) are commonly comorbid conditions in individuals with FXS. Research has shown that about 60% of boys with the full FMR1 mutation are co-diagnosed with ASD or ADHD [14, 63,64,65]. Furthermore, compared to boys without FXS, boys diagnosed with FXS have higher rates of ASD, ADHD, and anxiety [66]. Additional research suggests that ASD symptoms appear during early childhood in 50–60% of male FXS patients and 20% of female FXS patients [67, 68]. Although FXS and ASD affect overlapping neurobiological pathways, clinical trials have shown that the two disorders do not respond equally to the same treatment, suggesting different molecular mechanisms underlying the shared symptomatology [69].

The co-occurrence of FXS with other genetic conditions has been occasionally reported; the full FMR1 mutation was described in a few Down syndrome cases [3] and in five female fetuses with mosaic Turner syndrome (45,X0/46,XX) [70]. Also, an autistic ID was found to be affected by FXS while having pathological MED12 variants of X-linked MED12 (MIM 300188) [71]. However, the autistic features in FXS are not due to a double genetic cause but can instead be attributed to the variable phenotypic spectrum of the syndrome. Although the co-occurrence of Duchenne muscular dystrophy (DMD) with non-contiguous genetic entities' mutational events is extremely rare, an unrecognized association of X-linked DMD (MIM 310200) with ASD was previously reported [72]. The dystrophin protein 71 (Dp71) is widely expressed in the brain, and learning difficulties and cognitive impairments are also prevalent in DMD patients [73, 74]. Moreover, the MYT1L gene (MIM 616521) is associated with obesity, epilepsy, speech delay, and aggression, and PPP2R5D (MIM 601646) gene is correlated with neurodevelopmental disorder. Therefore, Tabolacci et al. [75] have recently described three unrelated cases of FXS co-occurrence with DMD, PPP2R5D, and MYT1L genetic conditions.

FMR1 gene interactions of FMR1 and co-expressed genes

We analyzed the potential protein–protein interaction (PPI) network to predict functional interactions between proteins using the STRING database (https://string-db.org). Figure 2 presents the FMR1 protein network interactions with STRING software. The FMRP protein network showed significantly more interactions among themselves (P value = 8.68e−10) than would be expected for random proteins of the same size and degree of distribution drawn from the genome. Such an enrichment indicates that the proteins are partially biologically connected.

Fig. 2 
figure 2

Protein–protein interactions predicted by STRING (https://string-db.org/). Strong interactions were predicted between FMR1 and ten co-expressed proteins. Colored nodes (n = 11) represent proteins and the first shell of interactors (average node degree = 6.91). Edges represent specific and meaningful protein–protein associations (n = 38) (i.e., proteins jointly contribute to a shared function)

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Functional enrichment analysis

Table 2 highlights the functional enrichment of FMRP and related proteins in biological processes, including the regulation of translation and modulation of synaptic transmission (GO:0099578) and regulation of gene silencing by miRNAs (GO:2000637), cellular components, including dendritic filopodium, and dendritic spine neck (GO:1902737/Dendritic spine neck), and cytoplasmic stress granule (GO:0010494). Furthermore, KEGG pathway analysis revealed the RNA transport (hsa03013), and protein domains revealed the fragile-X 1 protein core C-terminal (PF12235) (Table 2).

Table 2 Functional enrichment in FMR1 protein-coding gene loci network
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Molecular and phenotypic variability

Mutations in the FMR1 gene due to the CGG repetition can result in several conditions, e.g., ID, FXPOI, FXTAS, autism, Parkinson’s disease, developmental delays, other cognitive deficits, and even fragile X-associated neuropsychiatric disorders (FXAND) [53, 76, 77]. So, FXAND refers to the neuropsychiatric problems that typically occur at an earlier age than FXTAS. Hence, the FMR1 premutation would exhibit variable expressivity and be associated with a wide spectrum of clinical phenotypes [78].

Mosaicism

Mosaicism has been reported as a source of phenotypic variability in FXS patients of both sexes, with a higher frequency in male patients [78]. The prevalence of mosaicism in male FXS patients varies greatly, from 12 to 41% in the general population [79]. Notably, in individuals with FXS, mosaicism can be either in the size of the CGG repeat expansion or in hypermethylation of the CpG island [80]. A recent study has evaluated alterations in FMR1 function due to both types of mosaicism [78]. Because mosaic individuals with FXS produce some FMRP, they have milder cognitive and behavioral deficits than non-mosaic individuals with FXS [81, 82].

Mosaicism of size

Mosaicism of size is described as the presence of both the full FMR1 mutation and the FMR1 premutation in some cells [79]. Approximately 50% of individuals with FXS are estimated to have this type of mosaicism [83]. FXS patients with mosaicism of size have higher IQ scores than those without mosaicism [84]. Although decreases in the number of CGG repeats (from full mutation to premutation and from premutation to normal size) are widely reported between generations, a retraction from full mutation to normal size appears to be sporadic [79, 85, 86]. In these cases, shortening of the CGG repeat expansion occurs post-zygotically due to the excision of many trinucleotides, giving rise to some alleles of normal size [86]. Baker et al. [87] reported that FXS patients with mosaicism of size had less aggressive behavior than FXS patients without this type of mosaicism. Mosaicism of size has also been associated with a higher risk of developing FXTAS [18].

Mosaicism of hypermethylation

Epigenetic silencing of the FMR1 gene in individuals with the full FMRI mutation is characterized by DNA methylation of the promoter region and modification of histones [88]. FMR1 silencing takes place at about 11 weeks of gestation and seems related to histone H3 dimethylation, which is mediated by DNA-RNA duplex formation between the CGG repeat region of FMR1 and its mRNA counterpart [89]. In mosaicism of hypermethylation, some cells exhibit hypermethylation, and others do not. In cells in which fully mutated or premutated alleles are not methylated, the FMR1 gene is transcriptionally active and can be expressed [90,91,92,93,94,95]. In male individuals, the most frequent presentation of mosaicism is non-methylation of alleles with partial mutations and either methylation or non-methylation of alleles with full mutations (i.e., a combination of mosaicism of size and mosaicism of methylation) [14].

Modifier genes

In several monogenic disorders, modifier genes have an important effect on the pathophysiological mechanisms regulating penetrance and expressivity [96]. A genetic variant can modify the phenotypic effects of other variants in many ways, including through epistasis and genetic interactions [97, 98]. Several studies have investigated modifier genes and their relationship with behavioral features of the FXS phenotype (e.g., epilepsy, aggression, autistic features) [99,100,101,102,103]. One study found that the Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene may lessen the epilepsy phenotype in FXS patients, as this polymorphism can affect cerebral anatomy [104] and fragile X-associated neuropsychiatric disorders (FXAND) [99,100,101,102,103,104,105,106,107]. Evidence has been conflicting on whether variations in genes such as SLC6A4 (MIM 182138), MAOA (MIM 309850), and COMT (MIM 116790) genes affect the severity of aggression, self-injury, and stereotypic behaviors in males with FXS [108]. However, Crawford et al. [103] recently reported that only COMT, and not SLC6A4 or MAOA, can affect dopamine levels in the brain, contributing to variability in challenging and repetitive behaviors in male FXS patients.

Molecular diagnostic testing

Although most parents notice some developmental delay during an affected child’s first year, FXS diagnosis may be delayed to 36 months. Diagnostic testing previously focused on karyotyping peripheral blood lymphocytes to determine if the X chromosome contained FRAXA [64, 109]. However, the test required advanced technical skills, and the results were challenging to interpret. Fluorescence in situ hybridization (FISH) later became the standard cytogenetic test for diagnosing FXS, given its high accuracy and reliability, but this has been replaced today by FMR1 DNA test. The American Academy of Pediatrics (https://www.aap.org/) recommends testing all individuals with ID, global developmental delay, or a family history of the full FMR1 mutation or the FMR1 premutation (Table 3).

Table 3 Clinical checklist to identify patients for molecular diagnostic testing
Full size table

Many additional molecular diagnostic techniques have recently been developed for FXS [110]. Low-cost PCR using asymmetric oligonucleotide primers that anneal to the CGG motif in FMR1 can screen individuals at high risk of FXS [35, 37, 111], and Southern blotting can be used as a confirmatory test [112]. Triplet repeat-primed PCR has also been recently introduced, allowing real-time magnification of the CGG repeats and full-length FMR1 alleles [113], and DNA methylation analysis can be used to determine methylation patterns in some male patients [112]. To help determine which patients might benefit from molecular diagnostic testing for FXS, Lubala et al. [114] have developed an evidence-based clinical checklist for physicians (Table 3).

For prenatal molecular diagnosis, PCR-based FMR1 testing is available using amniotic fluid samples (i.e., amniocytes) or chorionic villi samples. Current guidelines from the American College of Obstetricians and Gynecologists (ACOG) and the American College of Medical Genetics and Genomics (ACMG) encourage couples to have FMR1 prenatal testing to facilitate early diagnosis. Notably, women with a personal history of isolated cognitive impairment, developmental delay, inexplicable ID, autism, elevated levels of the follicle-stimulating hormone after 40 years of age, idiopathic familial primary ovarian failure, isolated cerebellar ataxia accompanied with tremor, or FXS-related disorders are encouraged to have FMR1 prenatal testing [13]. Importantly, there is also a need to perform AGG trinucleotide repeat genotyping [51], which can establish the magnitude of AGG interruptions within FMR1 CGG repeats. This is especially important among women with a small premutation or borderline allele [52], as maternal alleles with no AGG repeats are at the greatest risk for FMR1 CGG repeat instability and transmission [11]. Preconception is an ideal time for potential parents to request FXS testing or screening to make reasonable and evidence-based decisions about their reproductive health.

Current and emerging therapeutic approaches

FXS currently has no cure, as no genetic manipulation, medical intervention, or medication has been shown to reverse the full impact of a lack of FMRP during fetal development [115]. However, pharmacological treatment aims to improve behavioral symptoms linked to FXS [115, 116], with sympatholytics, stimulants, antipsychotics, anxiolytics, and antidepressants being some of the most effective medications used for this purpose. Table 4 presents pharmacologic agents commonly used to treat some FXS phenotypes or have shown promise in recent clinical studies.

Table 4 Pharmacological agents commonly used to treat fragile X syndrome
Full size table

Metformin

Metformin, a biguanide antidiabetic agent, is a safe and effective therapy for type 2 diabetes and weight loss worldwide. Preclinical studies found metformin to be a modulator of the mGluR/mTORC1-ERK cascade in animal models of FXS [118, 120]. Metformin could correct social deficits, repetitive behaviors, macroorchidism, aberrant dendritic spine morphology, and exaggerated long-term depression of synaptic transmission in the adult FXS mice model (fmr1-/y mice) [120, 121]. Moreover, Dy and colleagues reported the first clinical data demonstrating metformin’s effectiveness in treating seven children with FXS for at least six months [118]. The FXS patients had improved weight and eating behaviors and experienced positive behavioral changes in irritability, social avoidance, and aggression [118].

Sertraline

Sertraline, a selective serotonin reuptake inhibitor (SSRI), was the first antidepressant to treat anxiety in patients with FXS, including those as young as 2–3 years old starting in 2–3 years of life [69, 122]. SSRIs are described to stimulate neurogenesis, increase BDNF in FXS [123], and enhance dopamine levels in the striatum [124]. Both of these strengths can be very important for young children with FXS who have evidence of oxidative stress [125]. Metabolomic studies demonstrate the downregulation of the enzymes leading to serotonin production from tryptophan in the blood of patients with idiopathic ASD, including those with FXS [126, 127].

Minocycline

Minocycline, a tetracycline antibiotic used to treat acne in adolescence, has been reported to decrease matrix metallopeptidase-9 (MMP9) level that is too high in FXS [128, 129]. MMP9 regulates synaptic formation (GSK3β, Arc, STEP, Map1B, αCaMKII), central nervous system development, and neural plasticity [130]. The cross between an MMP9 knockout mouse with an fmr1 knockout mouse led to the rescue of the FXS phenotype in the offspring emphasizing the importance of the MMP9 pathway in the phenotype of FXS [127, 131].

Lovastatin

Lovastatin, a 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitor (also known as a statin), inhibits the RAS-MAPK-ERK1/2 activation pathway. In the FMR1 knockout mouse model, this has been shown to normalize the excess protein synthesis and prevent epileptogenesis, a functional consequence of increased protein synthesis in FXS [132]. In addition, they rescued the seizure phenotype in the live knockout mouse. These studies have encouraged clinical trials of lovastatin (10–40 mg/day) combined with a treatment of a parent-implemented language intervention in youth with FXS aged 10 to 17 years [133].

Acamprosate

Acamprosate is a drug approved for maintaining abstinence in adults from alcohol. However, acamprosate has recently been focused on due to its potential pleiotropic effects impacting glutamate and GABA neurotransmission. A 10-week acamprosate clinical trial in 12 children with FXS ages 6 to 17 years showed improvements in social behavior and inattention/hyperactivity in 75% (9 children) of the study participants [134]. A multicenter controlled trial of acamprosate was carried out in individuals with FXS (http://www.clinicaltrials.gov; NCT01911455).

Cannabidiol

Cannabidiol (CBD), an herbal drug supplement extracted from cannabis plants, is mainly related to anxiety, cognition, movement disorders, and pain. In 2018, CBD was approved by the United States Food and Drug Administration to treat two epilepsy disorders. CBD represents a promising treatment to address comorbidities in FXS, e.g., epilepsy and cognitive impairment [135]. In humans, no clinical improvement with Huntington’s disease was shown [136], while clinical neuroprotection of CBD in general Parkinson’s was observed with no psychiatric comorbidity [137]. The transdermal gel of CBD was applied to children with FXS and showed efficacy in reducing anxiety and improving other behavioral measures [138]. Palumbo et al. [119] have recently reviewed the potential mechanisms for benefit from CBD treatment. Thus, the drug affects DNA methylation, serotonin 5HT-1A signal transduction, gamma-aminobutyric acid receptor signaling, and dopamine D2/D3 receptor signaling, which may help restore synaptic homeostasis in patients with FXS [119]. In many countries, CBD is legally sold at marijuana stores or online and is thus available for clinical use.

Other therapeutic approaches

Several supplements, additional medications, and a gene editing approach have also been used or proposed to be used as a treatment for various clinical and molecular characteristics of FXS. Folic acid is an important micronutrient that facilitates the hydroxylation and methylation of neurotransmitters. Its therapeutic effects include improved speech, language, and motor coordination among patients with FXS [139]. L-acetylcarnitine has been used alongside methylphenidate or mixed amphetamine salts to treat co-morbid ADHD in FXS patients [140]. Treatment of fmr1KO mice with the metabotropic glutamate receptor (mGluR) antagonist ‘2-methyl-6-(phenylethynyl) pyridine’ resulted in suppression of the audiogenic seizure phenotype [141] and rescue of dendritic spine morphology in the fmr1KO mouse [142]. Moreover, mGluR antagonists can target features of macroorchidism, hippocampus atrophy, protein synthesis, and dendritic spine morphology [143]. Despite their promise, mGluR antagonists are still experimental drugs that must be comprehensively investigated in clinical trials to establish their efficacy [144].

CRISPR/Cas9 gene therapy

Epigenetic modifying drugs can only transiently and modestly induce FMR1 reactivation in the presence of the expanded CGG repeat. Thus, gene replacements in gene therapy approaches are the most suitable option for those disorders caused by loss-of-function (LoF) mutations. In contrast, the gene replacement approach is not an option in gain-of-function (GoF) mutations to reduce the gene expression of the mutant target genes [145, 146]. The recent discovery of clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 strategies [147,148,149,150,151] has been developed to correct disease-causing mutations mammalian genome of living organisms [89, 152,153,154,155,156].

CRISPR/Cas9 system has been applied for genome editing in both GoF and LoF mutations by inducing double-stranded DNA (dsDNA) at specific loci. Cas9 can inactivate alleles with GoF mutations by inserting indels at sites associated with a single guide RNA (sgRNA) to form double-stranded breaks [157,158,159,160,161]. Thus, CRISPR/Cas9 has been applied to efficiently and directly demethylate the FMR1 triplet expansions [113]. A great development of nuclease defective Cas9 (dCas9) has been implemented to allow its binding to target genomic DNA sequences, creating steric hindrance that prevents the activity of other DNA-binding proteins such as endogenous transcription factors and RNA polymerase II and therefore interfering with gene expression (CRISPR interference) [162]. Thus, dCas9 has been fused to the catalytic domain of DNMT3A [163, 164] and ten-eleven translocation (TET) proteins to methylate and demethylate DNA [165]. Finally, dCas9 fusion to an engineered reverse transcriptase makes it possible to rewrite new genetic information into a specified DNA site.

Conclusion

This review discussed the discovery, epidemiology, pathophysiology, genetic etiology, molecular diagnosis, and medication-based management of FXS. It also highlights the molecular mechanisms underlying the syndrome’s variable expressivity and summarizes several emerging, promising therapeutic strategies. Importantly, the content of this review can inform future public health studies on FXS and provide clinicians with evidence-based information about FXS and its genetic and clinical implications for patients and their primary caregivers.

Availability of data and materials

The data sets analyzed during the current study are available from the corresponding author.

Abbreviations

ACMG:

American College of Medical Genetics and Genomics

ACOG:

American College of Obstetricians and Gynecologists

ADHD:

Attention Deficit Hyperactive Disorder

ADHD:

Attention deficit hyperactivity disorder

ASD:

Autism spectrum disorder

CBD:

Cannabidiol

COMT:

Catechol-o-methyltransferase

CRISPR:

Clustered regularly interspaced short palindromic repeats

dCas9:

Nuclear defective Cas9

DMD:

Duchenne muscular dystrophy

DNMT:

DNA methyltransferase

EEG:

Electroencephalogram

FDR:

False discovery rate

FMR1:

Fragile X mental retardation 1 gene

FMRP:

Fragile X messenger ribonucleoprotein

Fragile X-A:

FRAXA

FSH:

Follicle-stimulating hormone

FXAND:

Fragile X associated psychiatric disorders

FXPOI:

Fragile X-associated premature ovarian insufficiency

FXS:

Fragile X syndrome

FXTAS:

Fragile X-associated tremor/ataxia syndrome

GO:

Gene ontology

GoF:

Gain-of-function

ID:

Intellectual disability

KEGG:

Kyoto Encyclopedia of Genes and Genomes

LoF:

Loss of function

5-mC:

5-Methylcytosine

MAOA:

Monoamine oxidase

mGluR:

Metabotropic glutamate receptor

MRI:

Magnetic resonance image

MYT1L :

Myelin transcription factor 1-like

PPI:

Protein–protein interaction

PPP2R5D:

Protein phosphatase 2, regulatory subunit B (B56) delta

sgRNA:

Single guide RNA

SLC6A4:

Solute carrier family 6 (neurotransmitter transporter), member 4

TET:

Ten-eleven translocation

References

  1. Hunter J, Rivero-Arias O, Angelov A, Kim E, Fotheringham I, Leal J. Epidemiology of fragile X syndrome: a systematic review and meta-analysis. Am J Med Genet A. 2014;164A(7):1648–58.

    Article  PubMed  Google Scholar 

  2. Hagerman RJ. Fragile X syndrome: diagnosis, treatment and research. In: Hagerman RJ, Hagerman PJ (eds) 3–109 (Johns Hopkins Univ. Press, 2002).

  3. Saldarriaga W, Ruiz FA, Tassone F, Hagerman R. Down syndrome and fragile X syndrome in a Colombian woman: case report. J Appl Res Intellect Disabil. 2017;30(5):970–4.

    Article  PubMed  Google Scholar 

  4. Verkerk AJ, Pieretti M, Sutcliffe JS, Fu YH, Kuhl DP, Pizzuti A, Reiner O, Richards S, Victoria MF, Zhang FP, et al. Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell. 1991;65(5):905–14.

    Article  CAS  PubMed  Google Scholar 

  5. Bagni C, Tassone F, Neri G, Hagerman R. Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics. J Clin Invest. 2012;122(12):4314–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Cabal-Herrera AM, Tassanakijpanich N, Salcedo-Arellano MJ, Hagerman RJ. Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS): pathophysiology and clinical implications. Int J Mol Sci. 2020;21(12).

  7. Higuchi Y, Ando M, Yoshimura A, Hakotani S, Koba Y, Sakiyama Y, Hiramatsu Y, Tashiro Y, Maki Y, Hashiguchi A, et al. Prevalence of fragile X-associated tremor/ataxia syndrome in patients with cerebellar ataxia in Japan. Cerebellum. 2022;21(5):851–60.

    Article  PubMed  Google Scholar 

  8. Sherman SL, Curnow EC, Easley CA, Jin P, Hukema RK, Tejada MI, Willemsen R, Usdin K. Use of model systems to understand the etiology of fragile X-associated primary ovarian insufficiency (FXPOI). J Neurodev Disord. 2014;6(1):26.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Roberts JE, McCary LM, Shinkareva SV, Bailey DB Jr. Infant development in fragile X syndrome: cross-syndrome comparisons. J Autism Dev Disord. 2016;46(6):2088–99.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Yrigollen CM, Tassone F, Durbin-Johnson B, Tassone F. The role of AGG interruptions in the transcription of FMR1 premutation alleles. PLoS ONE. 2011;6(7):e21728.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Nolin SL, Sah S, Glicksman A, Sherman SL, Allen E, Berry-Kravis E, Tassone F, Yrigollen C, Cronister A, Jodah M, et al. Fragile X AGG analysis provides new risk predictions for 45–69 repeat alleles. Am J Med Genet A. 2013;161A(4):771–8.

    Article  PubMed  Google Scholar 

  12. Tassone F, Iong KP, Tong TH, Lo J, Gane LW, Berry-Kravis E, Nguyen D, Mu LY, Laffin J, Bailey DB, et al. FMR1 CGG allele size and prevalence ascertained through newborn screening in the United States. Genome Med. 2012;4(12):100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ligsay A, Hagerman RJ. Review of targeted treatments in fragile X syndrome. Intractable Rare Dis Res. 2016;5(3):158–67.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Hagerman RJ, Berry-Kravis E, Hazlett HC, Bailey DB Jr, Moine H, Kooy RF, Tassone F, Gantois I, Sonenberg N, Mandel JL, et al. Fragile X syndrome. Nat Rev Dis Primers. 2017;3:17065.

    Article  PubMed  Google Scholar 

  15. Salcedo-Arellano MJ, Dufour B, McLennan Y, Martinez-Cerdeno V, Hagerman R. Fragile X syndrome and associated disorders: Clinical aspects and pathology. Neurobiol Dis. 2020;136:104740.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Deng PY, Klyachko VA. Channelopathies in fragile X syndrome. Nat Rev Neurosci. 2021;22(5):275–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kim M, Costello J. DNA methylation: an epigenetic mark of cellular memory. Exp Mol Med. 2017;49(4):e322.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kraan CM, Godler DE, Amor DJ. Epigenetics of fragile X syndrome and fragile X-related disorders. Dev Med Child Neurol. 2019;61(2):121–7.

    Article  PubMed  Google Scholar 

  19. Pieretti M, Zhang FP, Fu YH, Warren ST, Oostra BA, Caskey CT, Nelson DL. Absence of expression of the FMR-1 gene in fragile X syndrome. Cell. 1991;66(4):817–22.

    Article  CAS  PubMed  Google Scholar 

  20. Musumeci SA, Hagerman RJ, Ferri R, Bosco P, Dalla Bernardina B, Tassinari CA, De Sarro GB, Elia M. Epilepsy and EEG findings in males with fragile X syndrome. Epilepsia. 1999;40(8):1092–9.

    Article  CAS  PubMed  Google Scholar 

  21. Tassone F. Newborn screening for fragile X syndrome. JAMA Neurol. 2014;71(3):355–9.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Jalnapurkar I, Cochran DM, Frazier JA. New therapeutic options for fragile X syndrome. Curr Treat Options Neurol. 2019;21(3):12.

    Article  PubMed  Google Scholar 

  23. Montanaro FAM, Alfieri P, Vicari S. "Corp-Osa-Mente", a Combined psychosocial-neuropsychological intervention for adolescents and young adults with fragile X syndrome: an explorative study. Brain Sci. 2023;13(2).

  24. Martin JP, Bell J. A pedigree of mental defect showing sex-linkage. J Neurol Psychiatry. 1943;6(3–4):154–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Lubs HA. A marker X chromosome. Am J Hum Genet. 1969;21(3):231–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Escalante JA, Grunspun H, Frota-Pessoa O. Severe sex-linked mental retardation. J Genet Hum. 1971;19(2):137–40.

    Google Scholar 

  27. Klauck SM, Munstermann E, Bieber-Martig B, Ruhl D, Lisch S, Schmotzer G, Poustka A, Poustka F. Molecular genetic analysis of the FMR-1 gene in a large collection of autistic patients. Hum Genet. 1997;100(2):224–9.

    Article  CAS  PubMed  Google Scholar 

  28. Gross C, Hoffmann A, Bassell GJ, Berry-Kravis EM. Therapeutic strategies in fragile X syndrome: from bench to bedside and back. Neurotherapeutics. 2015;12(3):584–608.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Dombrowski C, Levesque S, Morel ML, Rouillard P, Morgan K, Rousseau F. Premutation and intermediate-size FMR1 alleles in 10572 males from the general population: loss of an AGG interruption is a late event in the generation of fragile X syndrome alleles. Hum Mol Genet. 2002;11(4):371–8.

    Article  CAS  PubMed  Google Scholar 

  30. Coffee B, Keith K, Albizua I, Malone T, Mowrey J, Sherman SL, Warren ST. Incidence of fragile X syndrome by newborn screening for methylated FMR1 DNA. Am J Hum Genet. 2009;85(4):503–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Levesque S, Dombrowski C, Morel ML, Rehel R, Cote JS, Bussieres J, Morgan K, Rousseau F. Screening and instability of FMR1 alleles in a prospective sample of 24,449 mother-newborn pairs from the general population. Clin Genet. 2009;76(6):511–23.

    Article  CAS  PubMed  Google Scholar 

  32. Maia N, Loureiro JR, Oliveira B, Marques I, Santos R, Jorge P, Martins S. Contraction of fully expanded FMR1 alleles to the normal range: predisposing haplotype or rare events? J Hum Genet. 2017;62(2):269–75.

    Article  CAS  PubMed  Google Scholar 

  33. Santa Maria L, Aliaga S, Faundes V, Morales P, Pugin A, Curotto B, Soto P, Pena MI, Salas I, Alliende MA. FMR1 gene mutations in patients with fragile X syndrome and obligate carriers: 30 years of experience in Chile. Genet Res (Camb). 2016;98: e11.

    Article  PubMed  Google Scholar 

  34. Rife M, Badenas C, Mallolas J, Jimenez L, Cervera R, Maya A, Glover G, Rivera F, Mila M. Incidence of fragile X in 5,000 consecutive newborn males. Genet Test. 2003;7(4):339–43.

    Article  CAS  PubMed  Google Scholar 

  35. Fernandez-Carvajal I, Walichiewicz P, Xiaosen X, Pan R, Hagerman PJ, Tassone F. Screening for expanded alleles of the FMR1 gene in blood spots from newborn males in a Spanish population. J Mol Diagn. 2009;11(4):324–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Tejada MI, Glover G, Martinez F, Guitart M, de Diego-Otero Y, Fernandez-Carvajal I, Ramos FJ, Hernandez-Chico C, Pintado E, Rosell J, et al. Molecular testing for fragile X: analysis of 5062 tests from 1105 fragile X families–performed in 12 clinical laboratories in Spain. Biomed Res Int. 2014;2014:195793.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Saldarriaga W, Forero-Forero JV, Gonzalez-Teshima LY, Fandino-Losada A, Isaza C, Tovar-Cuevas JR, Silva M, Choudhary NS, Tang HT, Aguilar-Gaxiola S, et al. Genetic cluster of fragile X syndrome in a Colombian district. J Hum Genet. 2018;63(4):509–16.

    Article  CAS  PubMed  Google Scholar 

  38. Gerard B, Le Heuzey MF, Brunie G, Lewine P, Saiag MC, Cacheux V, Da Silva F, Dugas M, Mouren-Simeoni MC, Elion J, et al. Systematic screening for fragile X syndrome in a cohort of 574 mentally retarded children. Ann Genet. 1997;40(3):139–44.

    CAS  PubMed  Google Scholar 

  39. Pouya AR, Abedini SS, Mansoorian N, Behjati F, Nikzat N, Mohseni M, Nieh SE, Abbasi Moheb L, Darvish H, Monajemi GB, et al. Fragile X syndrome screening of families with consanguineous and non-consanguineous parents in the Iranian population. Eur J Med Genet. 2009;52(4):170–3.

    Article  PubMed  Google Scholar 

  40. Zhang JY, Wu DW, Yang RL, Zhu L, Jiang MY, Wang WJ, Li XK, Jiang XL, Tong F, Shu Q. FMR1 allele frequencies in 51,000 newborns: a large-scale population study in China. World J Pediatr. 2021;17(6):653–8.

    Article  CAS  PubMed  Google Scholar 

  41. Limprasert P, Ruangdaraganon N, Sura T, Vasiknanonte P, Jinorose U. Molecular screening for fragile X syndrome in Thailand. Southeast Asian J Trop Med Public Health. 1999;30(Suppl 2):114–8.

    PubMed  Google Scholar 

  42. Sihombing NRB, Winarni TI, Utari A, van Bokhoven H, Hagerman RJ, Faradz SM. Surveillance and prevalence of fragile X syndrome in Indonesia. Intractable Rare Dis Res. 2021;10(1):11–6.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Ali EZ, Yakob Y, Md Desa N, Ishak T, Zakaria Z, Ngu LK, Keng WT. Molecular analysis of fragile X syndrome (FXS) among Malaysian patients with developmental disability. Malays J Pathol. 2017;39(2):99–106.

    CAS  PubMed  Google Scholar 

  44. Mirza I, Tareen A, Davidson LL, Rahman A. Community management of intellectual disabilities in Pakistan: a mixed methods study. J Intellect Disabil Res. 2009;53(6):559–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Ben Jemaa L, Khemir S, Maazoul F, Richard L, Beldjord C, Chaabouni M, Chaabouni H. Molecular diagnosis of fragile X syndrome. Tunis Med. 2008;86(11):973–7.

    PubMed  Google Scholar 

  46. Man L, Lekovich J, Rosenwaks Z, Gerhardt J. Fragile X-associated diminished ovarian reserve and primary ovarian insufficiency from molecular mechanisms to clinical manifestations. Front Mol Neurosci. 2017;10:290.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Al Husain M, Salih MA, Zaki OK, Al Othman L, Al Nasser MN. A clinical study of mentally retarded children with fragile X syndrome in Saudi Arabia. Ann Saudi Med. 2000;20(1):16–9.

    Article  CAS  PubMed  Google Scholar 

  48. Refeat MM, El Saied MM, Abdel Raouf ER. Diagnostic value of molecular approach in screening for fragile X premutation cases. Ir J Med Sci. 2022.

  49. Lachiewicz AM, Dawson DV, Spiridigliozzi GA. Physical characteristics of young boys with fragile X syndrome: reasons for difficulties in making a diagnosis in young males. Am J Med Genet. 2000;92(4):229–36.

    Article  CAS  PubMed  Google Scholar 

  50. Hagerman RJ, Hagerman PJ. Fragile X syndrome and premutation disorders. London: Mac Keith Press; 2020.

    Google Scholar 

  51. Heulens I, Suttie M, Postnov A, De Clerck N, Perrotta CS, Mattina T, Faravelli F, Forzano F, Kooy RF, Hammond P. Craniofacial characteristics of fragile X syndrome in mouse and man. Eur J Hum Genet. 2013;21(8):816–23.

    Article  PubMed  Google Scholar 

  52. Charalsawadi C, Wirojanan J, Jaruratanasirikul S, Ruangdaraganon N, Geater A, Limprasert P. Common clinical characteristics and rare medical problems of fragile X syndrome in Thai patients and review of the literature. Int J Pediatr. 2017;2017:9318346.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Ciaccio C, Fontana L, Milani D, Tabano S, Miozzo M, Esposito S. Fragile X syndrome: a review of clinical and molecular diagnoses. Ital J Pediatr. 2017;43(1):39.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Salcedo-Arellano MJ, Hagerman RJ, Martinez-Cerdeno V. Fragile X syndrome: clinical presentation, pathology and treatment. Gac Med Mex. 2020;156(1):60–6.

    PubMed  Google Scholar 

  55. Bailey DB Jr, Raspa M, Bishop E, Holiday D. No change in the age of diagnosis for fragile x syndrome: findings from a national parent survey. Pediatrics. 2009;124(2):527–33.

    Article  PubMed  Google Scholar 

  56. Roberts JE, Bradshaw J, Will E, Hogan AL, McQuillin S, Hills K. Emergence and rate of autism in fragile X syndrome across the first years of life. Dev Psychopathol. 2020;32(4):1335–52.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Kaufmann WE, Abrams MT, Chen W, Reiss AL. Genotype, molecular phenotype, and cognitive phenotype: correlations in fragile X syndrome. Am J Med Genet. 1999;83(4):286–95.

    Article  CAS  PubMed  Google Scholar 

  58. Rajaratnam A, Shergill J, Salcedo-Arellano M, Saldarriaga W, Duan X, Hagerman R. Fragile X syndrome and fragile X-associated disorders. F1000Res. 2017;6:2112.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Heard TT, Ramgopal S, Picker J, Lincoln SA, Rotenberg A, Kothare SV. EEG abnormalities and seizures in genetically diagnosed Fragile X syndrome. Int J Dev Neurosci. 2014;38:155–60.

    Article  PubMed  Google Scholar 

  60. Lozano R, Azarang A, Wilaisakditipakorn T, Hagerman RJ. Fragile X syndrome: A review of clinical management. Intractable Rare Dis Res. 2016;5(3):145–57.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Dahlhaus R. Of men and mice: modeling the fragile X syndrome. Front Mol Neurosci. 2018;11:41.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Meguid NA, Fahim C, Sami R, Nashaat NH, Yoon U, Anwar M, El-Dessouky HM, Shahine EA, Ibrahim AS, Mancini-Marie A, et al. Cognition and lobar morphology in full mutation boys with fragile X syndrome. Brain Cogn. 2012;78(1):74–84.

    PubMed  Google Scholar 

  63. Budimirovic DB, Kaufmann WE. What can we learn about autism from studying fragile X syndrome? Dev Neurosci. 2011;33(5):379–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Budimirovic DB, Berry-Kravis E, Erickson CA, Hall SS, Hessl D, Reiss AL, King MK, Abbeduto L, Kaufmann WE. Updated report on tools to measure outcomes of clinical trials in fragile X syndrome. J Neurodev Disord. 2017;9:14.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Kaufmann WE, Kidd SA, Andrews HF, Budimirovic DB, Esler A, Haas-Givler B, Stackhouse T, Riley C, Peacock G, Sherman SL, et al. Autism spectrum disorder in fragile X syndrome: cooccurring conditions and current treatment. Pediatrics. 2017;139(Suppl 3):S194–206.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Thurman AJ, McDuffie A, Hagerman R, Abbeduto L. Psychiatric symptoms in boys with fragile X syndrome: a comparison with nonsyndromic autism spectrum disorder. Res Dev Disabil. 2014;35(5):1072–86.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Sherman SL, Kidd SA, Riley C, Berry-Kravis E, Andrews HF, Miller RM, Lincoln S, Swanson M, Kaufmann WE, Brown WT. FORWARD: A registry and longitudinal clinical database to study fragile X syndrome. Pediatrics. 2017;139(Suppl 3):S183–93.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Saldarriaga W, Payan-Gomez C, Gonzalez-Teshima LY, Rosa L, Tassone F, Hagerman RJ. Double genetic hit: fragile X syndrome and partial deletion of protein patched homolog 1 antisense as cause of severe autism spectrum disorder. J Dev Behav Pediatr. 2020;41(9):724–8.

    Article  PubMed  Google Scholar 

  69. Greiss Hess L, Fitzpatrick SE, Nguyen DV, Chen Y, Gaul KN, Schneider A, Lemons Chitwood K, Eldeeb MA, Polussa J, Hessl D, et al. A randomized, double-blind, placebo-controlled trial of low-dose sertraline in young children with fragile X syndrome. J Dev Behav Pediatr. 2016;37(8):619–28.

    Article  PubMed  Google Scholar 

  70. Dobkin C, Radu G, Ding X-H, Brown WT, Nolin SL. Fragile X prenatal analyses show full mutation females at high risk for mosaic Turner syndrome: Fragile X leads to chromosome loss. Am J Med Genet Part A. 2009;149A(10):2152–7.

    Article  CAS  PubMed  Google Scholar 

  71. Lahbib S, Trabelsi M, Dallali H, Sakka R, Bourourou R, Kefi R, Mrad R, Abdelhak S, Gaddour N. Novel MED12 variant in a multiplex Fragile X syndrome family: dual molecular etiology of two X-linked intellectual disabilities with autism in the same family. Mol Biol Rep. 2019;46(4):4185–93.

    Article  CAS  PubMed  Google Scholar 

  72. Wu JY, Kuban KC, Allred E, Shapiro F, Darras BT. Association of Duchenne muscular dystrophy with autism spectrum disorder. J Child Neurol. 2005;20(10):790–5.

    Article  PubMed  Google Scholar 

  73. Elhawary NA, Jiffri EH, Jambi S, Mufti AH, Dannoun A, Kordi H, Khogeer A, Jiffri OH, Elhawary AN, Tayeb MT. Molecular characterization of exonic rearrangements and frame shifts in the dystrophin gene in Duchenne muscular dystrophy patients in a Saudi community. Hum Genom. 2018;12(1):18.

    Article  Google Scholar 

  74. Naidoo M, Anthony K. Dystrophin Dp71 and the neuropathophysiology of Duchenne muscular dystrophy. Mol Neurobiol. 2020;57(3):1748–67.

    Article  CAS  PubMed  Google Scholar 

  75. Tabolacci E, Pomponi MG, Remondini L, Pietrobono R, Orteschi D, Nobile V, Pucci C, Musto E, Pane M, Mercuri EM, et al. Co-occurrence of fragile X syndrome with a second genetic condition: three independent cases of double diagnosis. Genes (Basel). 2021;12(12).

  76. Debrey SM, Leehey MA, Klepitskaya O, Filley CM, Shah RC, Kluger B, Berry-Kravis E, Spector E, Tassone F, Hall DA. Clinical phenotype of adult fragile X gray zone allele carriers: a case series. Cerebellum. 2016;15(5):623–31.

    Article  PubMed  Google Scholar 

  77. Hagerman RJ, Protic D, Rajaratnam A, Salcedo-Arellano MJ, Aydin EY, Schneider A. Fragile X-associated neuropsychiatric disorders (FXAND). Front Psychiatry. 2018;9:564.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Payan-Gomez C, Ramirez-Cheyne J, Saldarriaga W. Variable expressivity in fragile X syndrome: towards the identification of molecular characteristics that modify the phenotype. Appl Clin Genet. 2021;14:305–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Nolin SL, Glicksman A, Houck GE Jr, Brown WT, Dobkin CS. Mosaicism in fragile X affected males. Am J Med Genet. 1994;51(4):509–12.

    Article  CAS  PubMed  Google Scholar 

  80. Stöger R, Genereux DP, Hagerman RJ, Hagerman PJ, Tassone F, Laird CD. Testing the FMR1 promoter for mosaicism in DNA methylation among CpG sites, strands, and cells in FMR1-expressing males with fragile X syndrome. PLoS ONE. 2011;6(8):e23648.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Myrick LK, Nakamoto-Kinoshita M, Lindor NM, Kirmani S, Cheng X, Warren ST. Fragile X syndrome due to a missense mutation. Eur J Hum Genet. 2014;22(10):1185–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Quartier A, Poquet H, Gilbert-Dussardier B, Rossi M, Casteleyn AS, Portes VD, Feger C, Nourisson E, Kuentz P, Redin C, et al. Intragenic FMR1 disease-causing variants: a significant mutational mechanism leading to Fragile-X syndrome. Eur J Hum Genet. 2017;25(4):423–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Budimirovic DB, Schlageter A, Filipovic-Sadic S, Protic DD, Bram E, Mahone EM, Nicholson K, Culp K, Javanmardi K, Kemppainen J, et al. A Genotype-phenotype study of high-resolution FMR1 nucleic acid and protein analyses in Fragile X patients with neurobehavioral aAssessments. Brain Sci. 2020;10(10).

  84. Schneider A, Seritan A, Tassone F, Rivera SM, Hagerman R, Hessl D. Psychiatric features in high-functioning adult brothers with fragile x spectrum disorders. Prim Care Companion CNS Disord. 2013;15(2).

  85. Schmucker B, Seidel J. Mosaicism for a full mutation and a normal size allele in two fragile X males. Am J Med Genet. 1999;84(3):221–5.

    Article  CAS  PubMed  Google Scholar 

  86. Stark Z, Francis D, Gaffney L, Greenberg J, Hills L, Li X, Godler DE, Slater HR. Prenatal diagnosis of fragile X syndrome complicated by full mutation retraction. Am J Med Genet A. 2015;167A(10):2485–7.

    Article  PubMed  Google Scholar 

  87. Baker EK, Arpone M, Vera SA, Bretherton L, Ure A, Kraan CM, Bui M, Ling L, Francis D, Hunter MF, et al. Intellectual functioning and behavioural features associated with mosaicism in fragile X syndrome. J Neurodev Disord. 2019;11(1):41.

    Article  PubMed  PubMed Central  Google Scholar 

  88. Nelson CE, Hakim CH, Ousterout DG, Thakore PI, Moreb EA, Castellanos Rivera RM, Madhavan S, Pan X, Ran FA, Yan WX, et al. In vivo genome editing improves muscle function in a mouse model of Duchenne muscular dystrophy. Science. 2016;351(6271):403–7.

    Article  CAS  PubMed  Google Scholar 

  89. Colak D, Zaninovic N, Cohen MS, Rosenwaks Z, Yang WY, Gerhardt J, Disney MD, Jaffrey SR. Promoter-bound trinucleotide repeat mRNA drives epigenetic silencing in fragile X syndrome. Science. 2014;343(6174):1002–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Tassone F, Hagerman RJ, Loesch DZ, Lachiewicz A, Taylor AK, Hagerman PJ. Fragile X males with unmethylated, full mutation trinucleotide repeat expansions have elevated levels of FMR1 messenger RNA. Am J Med Genet. 2000;94(3):232–6.

    Article  CAS  PubMed  Google Scholar 

  91. Primerano B, Tassone F, Hagerman RJ, Hagerman P, Amaldi F, Bagni C. Reduced FMR1 mRNA translation efficiency in fragile X patients with premutations. RNA. 2002;8(12):1482–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Dolskiy AA, Yarushkin AA, Grishchenko IV, Lemskaya NA, Pindyurin AV, Boldyreva LV, Pustylnyak VO, Yudkin DV. miRNA expression and interaction with the 3’UTR of FMR1 in FRAXopathy pathogenesis. Noncoding RNA Res. 2021;6(1):1–7.

    Article  CAS  PubMed  Google Scholar 

  93. Pretto DI, Mendoza-Morales G, Lo J, Cao R, Hadd A, Latham GJ, Durbin-Johnson B, Hagerman R, Tassone F. CGG allele size somatic mosaicism and methylation in FMR1 premutation alleles. J Med Genet. 2014;51(5):309–18.

    Article  CAS  PubMed  Google Scholar 

  94. Jiraanont P, Kumar M, Tang HT, Espinal G, Hagerman PJ, Hagerman RJ, Chutabhakdikul N, Tassone F. Size and methylation mosaicism in males with Fragile X syndrome. Expert Rev Mol Diagn. 2017;17(11):1023–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Baker EK, Arpone M, Bui M, Kraan CM, Ling L, Francis D, Hunter MF, Rogers C, Field MJ, Santa Maria L, et al. Tissue mosaicism, FMR1 expression and intellectual functioning in males with fragile X syndrome. Am J Med Genet A. 2023;191(2):357–69.

    Article  CAS  PubMed  Google Scholar 

  96. Elhawary NA, AlJahdali IA, Abumansour IS, Elhawary EN, Gaboon N, Dandini M, Madkhali A, Alosaimi W, Alzahrani A, Aljohani F, et al. Genetic etiology and clinical challenges of phenylketonuria. Hum Genomics. 2022;16(1):22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Dipple KM, McCabe ER. Phenotypes of patients with “simple” Mendelian disorders are complex traits: thresholds, modifiers, and systems dynamics. Am J Hum Genet. 2000;66(6):1729–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Schaffer AA. Digenic inheritance in medical genetics. J Med Genet. 2013;50(10):641–52.

    Article  CAS  PubMed  Google Scholar 

  99. Louhivuori V, Arvio M, Soronen P, Oksanen V, Paunio T, Castren ML. The Val66Met polymorphism in the BDNF gene is associated with epilepsy in fragile X syndrome. Epilepsy Res. 2009;85(1):114–7.

    Article  CAS  PubMed  Google Scholar 

  100. Stepniak B, Kastner A, Poggi G, Mitjans M, Begemann M, Hartmann A, Van der Auwera S, Sananbenesi F, Krueger-Burg D, Matuszko G, et al. Accumulated common variants in the broader fragile X gene family modulate autistic phenotypes. EMBO Mol Med. 2015;7(12):1565–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Tondo M, Poo P, Naudo M, Ferrando T, Genoves J, Molero M, Martorell L. Predisposition to epilepsy in fragile X syndrome: does the Val66Met polymorphism in the BDNF gene play a role? Epilepsy Behav. 2011;22(3):581–3.

    Article  PubMed  Google Scholar 

  102. Wassink TH, Hazlett HC, Davis LK, Reiss AL, Piven J. Testing for association of the monoamine oxidase A promoter polymorphism with brain structure volumes in both autism and the fragile X syndrome. J Neurodev Disord. 2014;6(1):6.

    Article  PubMed  PubMed Central  Google Scholar 

  103. Crawford H, Scerif G, Wilde L, Beggs A, Stockton J, Sandhu P, Shelley L, Oliver C, McCleery J. Genetic modifiers in rare disorders: the case of fragile X syndrome. Eur J Hum Genet. 2021;29(1):173–83.

    Article  CAS  PubMed  Google Scholar 

  104. Szeszko PR, Lipsky R, Mentschel C, Robinson D, Gunduz-Bruce H, Sevy S, Ashtari M, Napolitano B, Bilder RM, Kane JM, et al. Brain-derived neurotrophic factor val66met polymorphism and volume of the hippocampal formation. Mol Psychiatry. 2005;10(7):631–6.

    Article  CAS  PubMed  Google Scholar 

  105. Chen ZY, Jing D, Bath KG, Ieraci A, Khan T, Siao CJ, Herrera DG, Toth M, Yang C, McEwen BS, et al. Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior. Science. 2006;314(5796):140–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Gratacos M, Gonzalez JR, Mercader JM, de Cid R, Urretavizcaya M, Estivill X. Brain-derived neurotrophic factor Val66Met and psychiatric disorders: meta-analysis of case-control studies confirm association to substance-related disorders, eating disorders, and schizophrenia. Biol Psychiatry. 2007;61(7):911–22.

    Article  CAS  PubMed  Google Scholar 

  107. Arab AH, Elhawary NA. Methylenetetrahydrofolate reductase gene variants confer potential vulnerability to Autism Spectrum Disorder in a Saudi Community. Neuropsychiatr Dis Treat. 2019;15:3569–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Hessl D, Tassone F, Cordeiro L, Koldewyn K, McCormick C, Green C, Wegelin J, Yuhas J, Hagerman RJ. Brief report: aggression and stereotypic behavior in males with fragile X syndrome–moderating secondary genes in a “single gene” disorder. J Autism Dev Disord. 2008;38(1):184–9.

    Article  PubMed  Google Scholar 

  109. Lee AW, Ventola P, Budimirovic D, Berry-Kravis E, Visootsak J. Clinical development of targeted fragile X syndrome treatments: an industry perspective. Brain Sci. 2018;8(12).

  110. Hayward BE, Kumari D, Usdin K. Recent advances in assays for the fragile X-related disorders. Hum Genet. 2017;136(10):1313–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Tassone F, Pan R, Amiri K, Taylor AK, Hagerman PJ. A rapid polymerase chain reaction-based screening method for identification of all expanded alleles of the fragile X (FMR1) gene in newborn and high-risk populations. J Mol Diagn. 2008;10(1):43–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Schenkel LC, Schwartz C, Skinner C, Rodenhiser DI, Ainsworth PJ, Pare G, Sadikovic B. Clinical validation of Fragile X syndrome screening by DNA methylation array. J Mol Diagn. 2016;18(6):834–41.

    Article  CAS  PubMed  Google Scholar 

  113. Liu XS, Wu H, Krzisch M, Wu X, Graef J, Muffat J, Hnisz D, Li CH, Yuan B, Xu C, et al. Rescue of fragile X syndrome neurons by DNA methylation editing of the FMR1 gene. Cell. 2018;172(5):979-92 e6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Lubala TK, Lumaka A, Kanteng G, Mutesa L, Mukuku O, Wembonyama S, Hagerman R, Luboya ON, Lukusa TP. Fragile X checklists: A meta-analysis and development of a simplified universal clinical checklist. Mol Genet Genom Med. 2018;6(4):526–32.

    Article  CAS  Google Scholar 

  115. Castagnola S, Bardoni B, Maurin T. The Search for an effective therapy to treat fragile X syndrome: Dream or reality? Front Synaptic Neurosci. 2017;9:15.

    Article  PubMed  PubMed Central  Google Scholar 

  116. Berry-Kravis E, Hagerman R, Budimirovic D, Erickson C, Heussler H, Tartaglia N, et al. A randomized, controlled trial of ZYN002 cannabidiol transdermal gel in children and adolescents with fragile X syndrome (CONNECT-FX). J Neurodev Disord. 2022;14(1):56.

    Article  PubMed  PubMed Central  Google Scholar 

  117. Erickson CA, Ray B, Maloney B, Wink LK, Bowers K, Schaefer TL, McDougle CJ, Sokol DK, Lahiri DK. Impact of acamprosate on plasma amyloid-beta precursor protein in youth: a pilot analysis in fragile X syndrome-associated and idiopathic autism spectrum disorder suggests a pharmacodynamic protein marker. J Psychiatr Res. 2014;59:220–8.

    Article  PubMed  PubMed Central  Google Scholar 

  118. Dy ABC, Tassone F, Eldeeb M, Salcedo-Arellano MJ, Tartaglia N, Hagerman R. Metformin as targeted treatment in fragile X syndrome. Clin Genet. 2018;93(2):216–22.

    Article  CAS  PubMed  Google Scholar 

  119. Palumbo JM, Thomas BF, Budimirovic D, Siegel S, Tassone F, Hagerman R, Faulk C, O’Quinn S, Sebree T. Role of the endocannabinoid system in fragile X syndrome: potential mechanisms for benefit from cannabidiol treatment. J Neurodev Disord. 2023;15(1):1.

    Article  PubMed  PubMed Central  Google Scholar 

  120. Gantois I, Khoutorsky A, Popic J, Aguilar-Valles A, Freemantle E, Cao R, Sharma V, Pooters T, Nagpal A, Skalecka A, et al. Metformin ameliorates core deficits in a mouse model of fragile X syndrome. Nat Med. 2017;23(6):674–7.

    Article  CAS  PubMed  Google Scholar 

  121. Wood H. Neurodevelopmental disorders: Metformin - a therapeutic option for fragile X syndrome? Nat Rev Neurol. 2017;13(7):384–5.

    Article  PubMed  Google Scholar 

  122. Rajaratnam A, Potter LA, Biag HMB, Schneider A, Petrasic IC, Hagerman RJ. Review of autism profiles and response to sertraline in fragile x syndrome-associated autism vs. non-syndromic autism; Next steps for targeted treatment. Front Neurol. 2020;11:581429.

    Article  PubMed  PubMed Central  Google Scholar 

  123. Erickson CA, Wink LK, Early MC, Stiegelmeyer E, Mathieu-Frasier L, Patrick V, McDougle CJ. Brief report: Pilot single-blind placebo lead-in study of acamprosate in youth with autistic disorder. J Autism Dev Disord. 2014;44(4):981–7.

    Article  PubMed  Google Scholar 

  124. Kitaichi Y, Inoue T, Nakagawa S, Boku S, Kakuta A, Izumi T, Koyama T. Sertraline increases extracellular levels not only of serotonin, but also of dopamine in the nucleus accumbens and striatum of rats. Eur J Pharmacol. 2010;647(1–3):90–6.

    Article  CAS  PubMed  Google Scholar 

  125. Hagerman RJ, Polussa J. Treatment of the psychiatric problems associated with fragile X syndrome. Curr Opin Psychiatry. 2015;28(2):107–12.

    Article  PubMed  PubMed Central  Google Scholar 

  126. Boccuto L, Chen CF, Pittman AR, Skinner CD, McCartney HJ, Jones K, Bochner BR, Stevenson RE, Schwartz CE. Decreased tryptophan metabolism in patients with autism spectrum disorders. Mol Autism. 2013;4(1):16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Hanson AC, Hagerman RJ. Serotonin dysregulation in Fragile X Syndrome: implications for treatment. Intractable Rare Dis Res. 2014;3(4):110–7.

    Article  PubMed  PubMed Central  Google Scholar 

  128. Ethell IM, Ethell DW. Matrix metalloproteinases in brain development and remodeling: synaptic functions and targets. J Neurosci Res. 2007;85(13):2813–23.

    Article  CAS  PubMed  Google Scholar 

  129. Dziembowska M, Pretto DI, Janusz A, Kaczmarek L, Leigh MJ, Gabriel N, Durbin-Johnson B, Hagerman RJ, Tassone F. High MMP-9 activity levels in fragile X syndrome are lowered by minocycline. Am J Med Genet A. 2013;161A(8):1897–903.

    Article  PubMed  Google Scholar 

  130. Darnell JC, Klann E. The translation of translational control by FMRP: therapeutic targets for FXS. Nat Neurosci. 2013;16(11):1530–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Sidhu H, Dansie LE, Hickmott PW, Ethell DW, Ethell IM. Genetic removal of matrix metalloproteinase 9 rescues the symptoms of fragile X syndrome in a mouse model. J Neurosci. 2014;34(30):9867–79.

    Article  PubMed  PubMed Central  Google Scholar 

  132. Osterweil EK, Chuang SC, Chubykin AA, Sidorov M, Bianchi R, Wong RK, Bear MF. Lovastatin corrects excess protein synthesis and prevents epileptogenesis in a mouse model of fragile X syndrome. Neuron. 2013;77(2):243–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Thurman AJ, Potter LA, Kim K, Tassone F, Banasik A, Potter SN, et al. Controlled trial of lovastatin combined with an open-label treatment of a parent-implemented language intervention in youth with fragile X syndrome. J Neurodev Disord. 2020;12(1):12.

    Article  PubMed  PubMed Central  Google Scholar 

  134. Erickson CA, Early M, Stigler KA, Wink LK, Mullett JE, McDougle CJ. An open-label naturalistic pilot study of acamprosate in youth with autistic disorder. J Child Adolesc Psychopharmacol. 2011;21(6):565–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Protic D, Salcedo-Arellano MJ, Dy JB, Potter LA, Hagerman RJ. New targeted treatments for fragile X syndrome. Curr Pediatr Rev. 2019;15(4):251–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Lopez-Sendon Moreno JL, Garcia Caldentey J, Trigo Cubillo P, Ruiz Romero C, Garcia Ribas G, Alonso Arias MA, Garcia de Yebenes MJ, Tolon RM, Galve-Roperh I, Sagredo O, et al. A double-blind, randomized, cross-over, placebo-controlled, pilot trial with Sativex in Huntington’s disease. J Neurol. 2016;263(7):1390–400.

    Article  CAS  PubMed  Google Scholar 

  137. Crippa JA, Guimaraes FS, Campos AC, Zuardi AW. Translational investigation of the therapeutic potential of Cannabidiol (CBD): toward a new age. Front Immunol. 2018;9:2009.

    Article  PubMed  PubMed Central  Google Scholar 

  138. Kwan Cheung KA, Mitchell MD, Heussler HS. Cannabidiol and neurodevelopmental disorders in children. Front Psychiatry. 2021;12:643442.

    Article  PubMed  PubMed Central  Google Scholar 

  139. Rueda JR, Ballesteros J, Tejada MI. Systematic review of pharmacological treatments in fragile X syndrome. BMC Neurol. 2009;9:53.

    Article  PubMed  PubMed Central  Google Scholar 

  140. Torrioli MG, Vernacotola S, Peruzzi L, Tabolacci E, Mila M, Militerni R, Musumeci S, Ramos FJ, Frontera M, Sorge G, et al. A double-blind, parallel, multicenter comparison of L-acetylcarnitine with placebo on the attention deficit hyperactivity disorder in fragile X syndrome boys. Am J Med Genet A. 2008;146A(7):803–12.

    Article  PubMed  Google Scholar 

  141. Yan QJ, Rammal M, Tranfaglia M, Bauchwitz RP. Suppression of two major fragile X syndrome mouse model phenotypes by the mGluR5 antagonist MPEP. Neuropharmacology. 2005;49(7):1053–66.

    Article  CAS  PubMed  Google Scholar 

  142. Su T, Fan HX, Jiang T, Sun WW, Den WY, Gao MM, Chen SQ, Zhao QH, Yi YH. Early continuous inhibition of group 1 mGlu signaling partially rescues dendritic spine abnormalities in the Fmr1 knockout mouse model for fragile X syndrome. Psychopharmacology. 2011;215(2):291–300.

    Article  CAS  PubMed  Google Scholar 

  143. Oakes A, Thurman AJ, McDuffie A, Bullard LM, Hagerman RJ, Abbeduto L. Characterising repetitive behaviours in young boys with fragile X syndrome. J Intellect Disabil Res. 2016;60(1):54–67.

    Article  CAS  PubMed  Google Scholar 

  144. Bear MF. Therapeutic implications of the mGluR theory of fragile X mental retardation. Genes Brain Behav. 2005;4(6):393–8.

    Article  CAS  PubMed  Google Scholar 

  145. Rinaldi C, Wood MJA. Antisense oligonucleotides: the next frontier for treatment of neurological disorders. Nat Rev Neurol. 2018;14(1):9–21.

    Article  CAS  PubMed  Google Scholar 

  146. Setten RL, Rossi JJ, Han SP. The current state and future directions of RNAi-based therapeutics. Nat Rev Drug Discov. 2019;18(6):421–46.

    Article  CAS  PubMed  Google Scholar 

  147. Cong L, Ran FA, Cox D, Lin S, Barretto R, Habib N, Hsu PD, Wu X, Jiang W, Marraffini LA, et al. Multiplex genome engineering using CRISPR/Cas systems. Science. 2013;339(6121):819–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Mali P, Yang L, Esvelt KM, Aach J, Guell M, DiCarlo JE, Norville JE, Church GM. RNA-guided human genome engineering via Cas9. Science. 2013;339(6121):823–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Gilbert LA, Horlbeck MA, Adamson B, Villalta JE, Chen Y, Whitehead EH, Guimaraes C, Panning B, Ploegh HL, Bassik MC, et al. Genome-scale CRISPR-mediated control of gene repression and activation. Cell. 2014;159(3):647–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Jinek M, Chylinski K, Fonfara I, Hauer M, Doudna JA, Charpentier E. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science. 2012;337(6096):816–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Komor AC, Badran AH, Liu DR. CRISPR-based technologies for the manipulation of eukaryotic genomes. Cell. 2017;168(1–2):20–36.

    Article  CAS  PubMed  Google Scholar 

  152. Park CY, Kim DH, Son JS, Sung JJ, Lee J, Bae S, Kim JH, Kim DW, Kim JS. Functional correction of large factor viii gene chromosomal inversions in hemophilia A patient-derived iPSCs using CRISPR-Cas9. Cell Stem Cell. 2015;17(2):213–20.

    Article  CAS  PubMed  Google Scholar 

  153. Long C, Amoasii L, Mireault AA, McAnally JR, Li H, Sanchez-Ortiz E, Bhattacharyya S, Shelton JM, Bassel-Duby R, Olson EN. Postnatal genome editing partially restores dystrophin expression in a mouse model of muscular dystrophy. Science. 2016;351(6271):400–3.

    Article  CAS  PubMed  Google Scholar 

  154. Tabebordbar M, Zhu K, Cheng JKW, Chew WL, Widrick JJ, Yan WX, Maesner C, Wu EY, Xiao R, Ran FA, et al. In vivo gene editing in dystrophic mouse muscle and muscle stem cells. Science. 2016;351(6271):407–11.

    Article  CAS  PubMed  Google Scholar 

  155. Huai C, Jia C, Sun R, Xu P, Min T, Wang Q, Zheng C, Chen H, Lu D. CRISPR/Cas9-mediated somatic and germline gene correction to restore hemostasis in hemophilia B mice. Hum Genet. 2017;136(7):875–83.

    Article  CAS  PubMed  Google Scholar 

  156. Oh HS, Diaz FM, Zhou C, Carpenter N, Knipe DM. CRISPR-Cas9 Expressed in Stably Transduced Cell Lines Promotes Recombination and Selects for Herpes Simplex Virus Recombinants. Curr Res Virol Sci. 2022;3.

  157. Dai WJ, Zhu LY, Yan ZY, Xu Y, Wang QL, Lu XJ. CRISPR-Cas9 for in vivo gene therapy: promise and hurdles. Mol Ther Nucleic Acids. 2016;5(8):e349.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Gao X, Tao Y, Lamas V, Huang M, Yeh WH, Pan B, Hu YJ, Hu JH, Thompson DB, Shu Y, et al. Treatment of autosomal dominant hearing loss by in vivo delivery of genome editing agents. Nature. 2018;553(7687):217–21.

    Article  CAS  PubMed  Google Scholar 

  159. Pawelczak KS, Gavande NS, VanderVere-Carozza PS, Turchi JJ. Modulating DNA repair pathways to improve precision genome engineering. ACS Chem Biol. 2018;13(2):389–96.

    Article  CAS  PubMed  Google Scholar 

  160. Christie KA, Robertson LJ, Conway C, Blighe K, DeDionisio LA, Chao-Shern C, Kowalczyk AM, Marshall J, Turnbull D, Nesbit MA, et al. Mutation-independent allele-specific editing by CRISPR-Cas9, a Novel approach to treat autosomal dominant disease. Mol Ther. 2020;28(8):1846–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Wang D, Zhang F, Gao G. CRISPR-based therapeutic genome editing: strategies and in vivo delivery by AAV Vectors. Cell. 2020;181(1):136–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Qi LS, Larson MH, Gilbert LA, Doudna JA, Weissman JS, Arkin AP, Lim WA. Repurposing CRISPR as an RNA-guided platform for sequence-specific control of gene expression. Cell. 2013;152(5):1173–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Amabile A, Migliara A, Capasso P, Biffi M, Cittaro D, Naldini L, Lombardo A. Inheritable silencing of endogenous genes by hit-and-run targeted epigenetic editing. Cell. 2016;167(1):219-32 e14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Xiong T, Meister GE, Workman RE, Kato NC, Spellberg MJ, Turker F, Timp W, Ostermeier M, Novina CD. Targeted DNA methylation in human cells using engineered dCas9-methyltransferases. Sci Rep. 2017;7(1):6732.

    Article  PubMed  PubMed Central  Google Scholar 

  165. Morita S, Noguchi H, Horii T, Nakabayashi K, Kimura M, Okamura K, Sakai A, Nakashima H, Hata K, Nakashima K, et al. Targeted DNA demethylation in vivo using dCas9-peptide repeat and scFv-TET1 catalytic domain fusions. Nat Biotechnol. 2016;34(10):1060–5.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors are grateful to the Batterjee Medical College, Jeddah, Saudi Arabia, for the technical and financial support to publish this work. The authors would like to thank the Saudi Digital Library, Umm Al-Qura University for providing the updated scientific periodicals to achieve this work.

Funding

This work was technically and financially supported by the Batterjee Medical College, Jeddah, Saudi Arabia for publishing this work.

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Authors and Affiliations

  1. Department of Medical Genetics, College of Medicine, Umm Al-Qura University, Mecca, 21955, Saudi Arabia

    Nasser A. Elhawary, Iman S. Abumansour, Zohor A. Azher & Ghydda Alghamdi

  2. Department of Community Medicine, College of Medicine, Umm Al-Qura University, Mecca, Saudi Arabia

    Imad A. AlJahdali

  3. Department of Pharmacology and Toxicology, College of Medicine, Umm Al-Qura University, Mecca, 24382, Saudi Arabia

    Alaa H. Falemban

  4. Department of Hematology and Immunology, Faculty of Medicine, Umm Al-Qura University, Mecca, Saudi Arabia

    Wefaq M. Madani

  5. Department of Hematology, Maternity and Children Hospital, Mecca, Saudi Arabia

    Wafaa Alosaimi

  6. Department of Biology, Faculty of Science, King Abdulaziz University, Jeddah, 21589, Saudi Arabia

    Ikhlas A. Sindi

  7. Preparatory Year Program, Batterjee Medical College, Jeddah, 21442, Saudi Arabia

    Ikhlas A. Sindi

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  1. Nasser A. Elhawary
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  2. Imad A. AlJahdali
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Contributions

The study conception and design were initiated by NAE. Material preparation, data collection, and analysis were performed by NAE, IAA, ISA, ZAA, AHF, IAS, WA, WMM, and GA. Protein–protein interactions and functional enrichment analysis were done by NAE. Current and therapeutic approaches were reviewed by NAE, and AHF. Figures and tables were prepared by NAE, WA, WMM, and GA. The first draft of the review article was written by NAE, ISA, WA, ZAA, and AHF. All authors reviewed and approved the final version of the manuscript.

Corresponding author

Correspondence to Nasser A. Elhawary.

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Ethics approval and consent to participate

This work was approved by the Institutional Biomedical Ethics Committee of Umm Al-Qura University under the declaration of the National Committee of Biomedical Ethics at King Abdulaziz City for Sciences and Technology (KACST) (http://bioethics.kacst.edu.sa/About.aspx?lang=en-US).

Consent for publication

Written informed consent was obtained from the parents of all study participants to publish the results.

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The authors declare that they have no competing interests.

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Elhawary, N.A., AlJahdali, I.A., Abumansour, I.S. et al. Phenotypic variability to medication management: an update on fragile X syndrome. Hum Genomics 17, 60 (2023). https://doi.org/10.1186/s40246-023-00507-2

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Keywords

Human Genomics

ISSN: 1479-7364