TELO2‐related syndrome (You‐Hoover‐Fong syndrome): Description of 14 new affected individuals and review of the literature

You‐Hoover‐Fong syndrome (YHFS) is an autosomal recessive condition caused by pathogenic variants in the TELO2 gene. Affected individuals were reported to have global developmental delay, intellectual disability, microcephaly, dysmorphic facial features, ocular involvement including cortical visual impairment, strabismus, cataract and rotatory nystagmus, movement disorder, hypertonia and spasticity, balance disturbance and ataxia, and abnormal sleep pattern. Other features reported include poor growth, cleft palate, cardiac malformations, epilepsy, scoliosis, and hearing loss. To date, 12 individuals with YHFS have been reported in the literature. Here we describe 14 new individuals with YHFS from 10 families. Their clinical presentation provides additional support of the phenotype recognized previously and delineates the clinical spectrum associated with YHFS syndrome. In addition, we present a review of the literature including follow‐up data on four previously reported individuals with YHFS.

K E Y W O R D S developmental delay, microcephaly, syndromic intellectual disabilities, TELO2, YHFS, You-Hoover-Fong syndrome

| INTRODUCTION
You-Hoover-Fong syndrome (YHFS) is an autosomal recessive condition caused by pathogenic variants in the TELO2 gene, which has a critical role in checkpoint responses to cellular stress. The protein product of TELO2 also interacts with each of the six-mammalian phosphatidylinositol-3-kinase-related kinase (PIKK) genes (ATM, ATR, DNA-PKcs, mTOR, SMG1, TRRAP) and prevents their rapid degradation.
All of the affected individuals with TELO2-related syndrome recognized thus far have been observed to have global developmental delay, intellectual disabilities, and microcephaly. Other common features include facial dysmorphism, ocular involvement including strabismus, cortical visual impairment, cataracts and rotatory nystagmus, sleep disorder, movement disorders, hypertonia and spasticity, balance disturbance, and ataxia. Some other features have been occasionally reported include poor growth, cleft palate, scoliosis, cardiac malformations, epilepsy, and hearing loss. As whole-exome sequencing (WES) becomes more widely used, more individuals are being diagnosed with this condition thus providing more opportunity to understand the natural history of YHFS. Here we describe the clinical and molecular features of 14 new individuals from 10 families diagnosed with YHFS. In addition, we present a review of the literature including follow-up data on four previously reported individuals with YHFS.

| Human subjects research and data collection and management
This study was approved by the Institutional Review Board of Johns Hopkins University and was conducted in accordance with institutional standards. Families included in this research study provided oral consent for participating in the study and written consent to review the clinical medical records. The study participants included the clinical individuals diagnosed with YHFS and seen for initial or ongoing care within the medical genetics clinic at Johns Hopkins and individuals referred by their physicians from other institutions in the United States and other countries. Further recruitment was done through GeneDx, a large commercial laboratory, which contacted the submitters of samples found to harbor pathogenic variants TELO2 and connected us with the physicians/families who were interested to be part of the study. Later, we included affected individuals whose families learned about the study through peer recruiting and were interested to be part of the research study. Inclusion criteria for this study required the presence of biallelic pathogenic variants in TELO2 for individuals at any age who were diagnosed with YHFS.
The study is a retrospective and cross-sectional description of the phenotype. The clinical information was collected by interviewing families and reviewing the clinical medical records of the individuals.
We designed our own comprehensive data collection form (available upon request from the authors) and we collected and stored the data in a REDCAP database administered by the Data Informatics Services Core (DISC) of the Johns Hopkins Biostatistics Center (Harris et al., 2009 (Frankenburg, 1992(Frankenburg, & 1992. Regarding growth, we used Pedi-Tools based on the WHO child growth standards to determine the Z-score of length/height, weight and head circumference (Chou et al., 2020).

| Molecular analysis
We identified nine novel pathogenic variants in TELO2 in our cohort from the previously unreported 14 individuals from 10 families, bringing the total to 19 pathogenic variants in TELO2 gene ( Figure 1). We identified biallelic TELO2 variants in all individuals diagnosed with YHFS ( Figure 1 and Table S1). These variants were mostly missense and scattered throughout the gene. The most frequent variant in our cohort is p.Gly131Asp present in six individuals (12% of the total variants  Table S1 and Appendix S1.

| Pregnancy and perinatal period
Pregnancy and perinatal complications have not been clearly described previously for YHFS. Prenatal complications were an almost constant finding in this cohort (16/18). Intrauterine growth restriction was the most frequent complication (n = 8) during pregnancy, followed by decreased fetal movements and preeclampsia (n = 4) each, and oligohydramnios (n = 3). Prematurity was identified in six individuals with gestational age range from 34 to 36 weeks. Seventy-two percent were delivered vaginally and 28% had caesarean section; 60% of these due to fetal distress. APGAR scores were reportedly below 7 in 6 of 14. Birth weight ranged from 1.59 kg (delivered at 38 weeks) to 3.71 kg, with an average birth weight of 2.46 kg in 18 individuals.
The mean birth weight Z-score was À1.9 ± 1.36 (À4.6 to 1) with 44% within 0 to À2 standard deviations (SD), 28% within À2 to À3 SD, and 22% below À3 SD of the mean birth weight of a 40-week (term) gestation newborn. Nine individuals required neonatal intensive care unit admission for a range of 1 day to 6 weeks. The most common reason for prolonged newborn hospitalization were feeding issues (7/9), hypoxia with need for oxygen therapy (5/9), hypotonia (3/9), and birth defects such cleft lip/palate, cardiac and vascular anomalies (3/9). Less common were seizures, jaundice, and infection in one individual each.
Out of 17, 14 individuals passed their newborn hearing screening.
Seventy-eight percent of the parents had concerns about prolonged poor feeding since birth, which was associated with hypotonia in 43% of the time. However, further investigations were initiated at age of 6 months in 50% of the individuals, while the rest of the affected individuals had delayed work-up until the age between 9 months and 2.5 years.

| Neurologic complications and brain imaging
The most commonly reported neurological abnormalities were hypoto- and height (10th-17th percentile) around 10 years of age.
In our cohort, out of 16 individuals who underwent neuroimaging, 12 individuals reported some form of brain abnormalities identified by MRI or CT including white matter abnormality (n = 11), thin or hypoplastic corpus callosum (n = 7), and prominent ventricles or ventriculomegaly (n = 9). Other brain abnormalities including hypoplasia of the bilateral optic nerves, diminished pituitary gland volume, and maldevelopment of the left cochlea and vestibular canal along with empty sella were identified in one individual each.

| Development
The parents were asked about the age when their child/children achieved specific developmental milestones (

| Musculoskeletal
Musculoskeletal problems were observed in the majority of our cohort (15/18) including kyphosis/scoliosis (39%), pectus deformities, torticollis, and pes planus (17% each). Joint laxity was observed frequently in our cohort (50%) and joint contractures were also noted in 28%. Other minor anomalies included syndactyly and small hands/feet (28% each), brachydactyly (22%), clinodactyly (17%), and broad thumbs (11%). Less common musculoskeletal problems include femoral anteversion in two individuals, and bilateral acetabular dysplasia in one individual. In one individual (P6), muscle biopsy showed lipid overload in muscular fibers, and decreased activity of complex I in the mitochondrial respiratory chain.

| Immunology and hematology
In 12

| Endocrine
The endocrine features in our individuals (

| Other features
Cardiac and vascular involvement have been described in early case series. We had no report of major cardiac or vascular anomalies observed in our new individuals affected with YHFS. Minor cardiac anomalies were identified including patent foramen ovale and mitral valve prolapse. Dental problems were identified in eight individuals (47%) including multiple cavities in four individuals and overcrowded teeth in two individuals. Other problems identified in one individual each included multiple enamel fractures, front teeth nerves damaged, loss of some of the permanent teeth, and congenitally missing teeth.
Renal and genitourinary problems were not commonly reported in our cohort and previous reports. In our cohort, small kidneys were reported in three individuals, and hypogenitalism (i.e., small penis) was reported in two individuals. One individual each had cryptorchidism, hypospadias, and bilateral hydrocele. Audiological evaluation indicated hearing loss in three individuals; one with sensorineural hearing loss, and one with mixed hearing loss.
In addition to the previously described features, our cohort expands  Table S1 and Appendix S1.) All individuals with YHFS recognized in our cohort and in the litera- Melatonin alone or combined with either gabapentin or risperidone was used to treat sleeping problems in five individuals. The clinical outcome was satisfactory, and parents reported improve in the quality of their sleep in 80% of the individuals. Further, behavioral therapy was beneficial when initiated in three individuals. These finding support that neuropsychology assessment in older children is warranted.
In our cohort, one individual had a seizure disorder, which is a feature reported previously in three individuals with YHFS (Moosa et al., 2017;You et al., 2016) suggesting that seizures may be more Another relevant finding in our cohort involved poor growth which is commonly noted in the neonatal period and persists through childhood. Aside from feeding issues, intrauterine growth restriction was reported frequently (44%) in pregnancy which implies that growth deficiency may begin prenatally in these children. Interestingly, diet modification in three individuals showed objective improvement in behaviors, developmental status, and abnormal movement.
The parent of two siblings noted improvement in the behaviors and resolution of abnormal movement and ataxia when gluten, soy, sugar, and high carbohydrate foods are eliminated from their diet along with starting mitochondrial supplements. In the third individual, use of maldextrin-containing formula led to worsening GI symptoms and he developed abnormal somatic movements. Once this formula was discontinued, parents noted improvement in the child's behavior and energy status, and he began to acquire new milestones. These observations from our cohort were measured objectively by the parents and no cell-line studies were done to support these observations. However, the metabolism of glucose supply carbons to the TCA cycle utilized by mitochondria to generate energy is directly regulated by mTORC1. Studies have suggested that the disassembled and inhibited Tel2-Tti1-Tti2 (TTT)-RUVBL1/2 complex could block mTORC1 activation leading to ATP depletion (Kim et al., 2013). We propose the need for close monitoring by dietitian especially after any diet modification in individuals with YHFS to detect any worsening symptoms while ensuring adequate caloric intake.
The clinical and laboratory data from our cohort suggest that immunological problems could be a part of the YHFS. The immune pathophysiology could be due to the role of the TTT complex to control protein stability of PIKKs, including the interaction with mTOR gene that plays a role in various cellular processes including Tlymphocyte activation and differentiation (Delgoffe et al., 2009), (Delgoffe et al., 2011). For that, children with YHFS who suffered from recurrent infection may benefit from an assessment by an immunologist. Further study is needed to define the extent and prevalence of immunopathology in individuals with YHFS.
Our study has expanded the phenotype and genotypes recog- The table content is statement of opinion based on the clinical findings from the patients from the cohort and literature.