Simpson Golabi Behmel Syndrome Type 1

A rare, X-linked inherited syndrome caused by mutations in the GPC3 and GPC4 genes. It is characterized by pre-and postnatal overgrowth, coarse facial features, macrocephaly, macroglossia, congenital heart defects, and intellectual disability.


Diagnosis/testing
The diagnosis of SGBS1 is established in a male proband with suggestive findings and/or a hemizygous pathogenic variant in GPC3, an intragenic or whole-gene deletion of GPC3 that may include part or all of GPC4, or a large multiexon duplication of GPC4 identified by molecular genetic testing.The diagnosis is usually established in a female proband who has suggestive findings and a heterozygous pathogenic variant in GPC3, an intragenic or whole-gene deletion of GPC3 that may include part or all of GPC4, or a large multiexon duplication of GPC4 identified by molecular genetic testing.

Management
Treatment of manifestations: Prompt treatment of neonatal hypoglycemia and airway obstruction resulting from micrognathia and glossoptosis.Treatment of cleft lip and/or cleft palate or macroglossia and related feeding difficulties, obstructive sleep apnea, ophthalmologic issues, hearing loss, heart defects, urogenital abnormalities, skeletal abnormalities, and seizures in a standard fashion by appropriate pediatric specialists.Speech therapy as needed.Neurodevelopmental assessment to determine the need for special education, occupational therapy, and/or physical therapy.
Surveillance: Screening for Wilms tumor and hepatoblastoma with abdominal ultrasound and serum AFP level every three months from time of diagnosis until age four years; renal ultrasound every three months from age four to seven years; no specific tumor screening protocol has been established for neuroblastoma, gonadoblastoma, or medulloblastoma.Annual (or as indicated) ophthalmologic and audiologic evaluations in childhood; sleep study if there are concerns about sleep disturbance or sleep apnea; routine monitoring of renal function if renal anomalies are present; evaluation for scoliosis at least annually or during periods of rapid growth; monitoring of serum glucose level in the neonatal period; monitoring of developmental progress at each visit through adolescence.
Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual by molecular genetic testing of the GPC3 or GCP4 pathogenic variant in the family in order to identify as early as possible those who would benefit from preventive measures, such as tumor surveillance in males.

Genetic counseling
Simpson-Golabi-Behmel syndrome type 1 is inherited in an X-linked manner.If the mother of the proband has a pathogenic variant, the chance of transmitting the pathogenic variant in each pregnancy is 50%.Males who inherit the pathogenic variant will be affected.Females who inherit the pathogenic variant will be carriers, although due to X-chromosome inactivation, carrier females may have manifestations of SGBS1.Males with SGBS1 will pass the pathogenic variant to all of their daughters and none of their sons.Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible for families in which the pathogenic variant has been identified.

Diagnosis
Consensus clinical diagnostic criteria for Simpson-Golabi-Behmel syndrome type 1 (SGBS1) have not been established.

Suggestive Findings
The diagnosis of SGBS1 should be suspected in males with the following findings: • Macrosomia (weight or length ≥95th percentile) • Characteristic facial features ⚬ Widely spaced eyes, epicanthal folds, and downslanted palpebral fissures ⚬ Redundant, furrowed skin over the glabella ⚬ Wide nasal bridge and anteverted nares in infants; broad nose and coarsening of facial features in older individuals ⚬ Macrocephaly with or without a prominent forehead ⚬ Macrostomia (abnormally large mouth) ⚬ Macroglossia (abnormally large tongue) with or without a midline groove in the lower lip and/or deep furrow in the middle of the tongue ⚬ Cleft lip and/or submucous cleft palate (with a bifid uvula); high and narrow palate ⚬ Small mandible (micrognathia) in neonates; macrognathia in older individuals

Establishing the Diagnosis
Male proband.The diagnosis of SGBS1 is established in a male proband with suggestive findings and/or a hemizygous pathogenic variant in GPC3, an intragenic or whole-gene deletion of GPC3 that may include part or all of GPC4, or a large multiexon duplication of GPC4 identified by molecular genetic testing (see Table 1).
Female proband.The diagnosis of SGBS1 is usually established in a female proband with suggestive findings and a heterozygous pathogenic variant in GPC3, an intragenic or whole-gene deletion of GPC3 that may include part or all of GPC4, or a large multiexon duplication of GPC4 identified by molecular genetic testing (see Table 1).
Note: (1) Intragenic pathogenic GPC4 variants have not been described in isolation and are usually an extension of a deletion that includes GPC3 [Vuillaume et al 2018]; however, duplication of exons 1-9 in GPC4 without deletion or mutation of GPC3 was found in the original family described by Golabi & Rosen [1984] in which no GPC3 pathogenic variant had been identified [Waterson et al 2010].
(2) There are currently no reports of a female proband with biallelic pathogenic variants in either GPC3 or GPC4.
Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, concurrent or serial single-gene testing, multigene panel) and comprehensive genomic testing (chromosomal microarray analysis, exome sequencing, exome array, genome sequencing) depending on the phenotype.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not.Because the phenotype of SGBS1 is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of SGBS1 has not been considered are more likely to be diagnosed using genomic testing (see Option 2).Any molecular findings must be interpreted in the context of the affected individual's clinical presentation [Vuillaume et al 2018].

Option 1
When the phenotypic and laboratory findings suggest the diagnosis of SGBS1, molecular genetic testing approaches can include serial single-gene testing, chromosomal microarray, or use of a multigene panel.
Serial single-gene testing.Sequence analysis of GPC3 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants.Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications.Note: Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis.
• Sequence analysis of GPC3 is performed first, followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.
• If no pathogenic variant is found, chromosomal microarray analysis (CMA), which uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including GPC3 and GPC4) that cannot be detected by sequence analysis, may be considered next.

Note:
(1) CMA cannot determine the location or orientation of a duplication.
(2) If a deletion or duplication is of sufficient size, fluorescence in situ hybridization (FISH) can be used to test parental samples for inheritance of the deletion or duplication.
A multigene panel that includes GPC3, GPC4, and other genes of interest (see Differential Diagnosis) may also be considered.A multigene panel may identify the genetic cause of the condition at a reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype.Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time.
(2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview.
(3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician.(4) Methods used in a panel may include sequence analysis, deletion/ duplication analysis, and/or other non-sequencing-based tests.For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).
For an introduction to multigene panels click here.More detailed information for clinicians ordering genetic tests can be found here.

Option 2
When the diagnosis of SGBS1 is not considered because an individual has atypical phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option.Exome sequencing is the most commonly used genomic testing method; genome sequencing is also possible.
If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.
For an introduction to comprehensive genomic testing click here.More detailed information for clinicians ordering genomic testing can be found here.9. Gene-targeted methods will detect single-exon up to whole-gene deletions; however, breakpoints of large deletions and/or deletion of adjacent genes may not be determined.CMA testing is appropriate to define breakpoints of large deletions.10.A contiguous deletion of GPC3 and GPC4 has been identified in one family with SGBS1 [Veugelers et al 1998].
11. Two females reported [Punnett 1994, Pilia et al 1996] 12. Intragenic pathogenic GPC4 variants have not been described in isolation and are usually an extension of a deletion that includes GPC3 [Spencer et al 2016].
13. Duplication of exons 1-9 in GPC4 without deletion or mutation of GPC3 was found in the original family described by Golabi & Rosen [1984] in which no GPC3 pathogenic variant had been identified [Waterson et al 2010].
Macrosomia.Virtually all persons with SGBS1 have pre-and postnatal overgrowth.As with other macrosomic syndromes, hypoglycemia may be present in the neonatal period.
Eyes.Esotropia, cataracts, and coloboma of the optic disc [Golabi & Rosen 1984] have been noted.Ocular nerve palsies and strabismus can occur.
Oropharynx.Macroglossia is a characteristic feature.Other anomalies include various degrees of palatal clefting (including submucous cleft and bifid uvula), laryngeal cleft, and laryngeal web.Obstructive sleep apnea may be present.Silent aspiration leading to chronic respiratory infections and bronchiectasis has also been described [Glamuzina et al 2009, Tenorio et al 2014].
Thoracoabdominal wall.Supernumerary nipples are common, either one or multiple, unilateral or bilateral.Diastasis recti and umbilical hernias are observed frequently; however, true omphalocele is rare.
Cardiothoracic.Congenital heart defects are variable; septal defects are common.Pulmonic stenosis, aortic coarctation, transposition of the great vessels, and patent ductus arteriosus or patent foramen ovale have been reported.
Conduction defects and arrhythmias have frequently been described [Lin et al 1999].Transient QT interval prolongation has also been reported [Gertsch et al 2010].
Lungs.Abnormal branching of the bronchi and an abnormal lower airway pit have been described in one affected individual [Glamuzina et al 2009].
Hand anomalies such as large hands, broad thumbs, and brachydactyly are common.Other findings include syndactyly, clinodactyly, and postaxial polydactyly.Striking index finger hypoplasia with congenital abnormalities of the proximal phalanx have been reported [Day & Fryer 2005].Nail dysplasia, hypoplasia (particularly of the index finger), and hypoconvexity are common.
Advanced bone age, including presence of ossified carpal bones in a newborn, has been described [Chen et al 1993].
Central nervous system (CNS).Normal intelligence has been described, but mild to severe intellectual disability is common, with language delay being the most characteristic finding.
Neurologic manifestations are perhaps the most varied findings.Hypotonia and absent primitive reflexes, a high-pitched cry in neonates, seizures, and abnormal EEG have all been described.Hydrocephalus, epilepsy, and attention-deficit/hyperactivity disorder may also be present [Tenorio et al 2014].
CNS malformations include agenesis of the corpus callosum, Chiari malformation and hydrocephalus [Young et al 2006], and aplasia of the cerebellar vermis.
Neoplasia.An absolute incidence and relative risk for tumors has not been established; the embryonic tumor frequency in persons with SGBS1 is likely between 5% and 10%; however, these numbers are based on case reports [Lapunzina et al 1998, Lin et al 1999].At least six tumor types have been described [Lapunzina et al 1998, Li et al 2001, Lapunzina 2005, Thomas et al 2012].

Heterozygous Females
Due to skewed X-chromosome inactivation, carrier females can have manifestations of SBGS including macrosomia, macrocephaly, widely spaced eyes, broad and upturned nasal tip with prominent columella, macrostomia, prominent chin, hypoplastic fingernails, coccygeal skin tag and bony appendage, extra lumbar and thoracic vertebrae, and accessory nipples [Golabi & Rosen 1984].Tall stature, coarse facial features, and developmental delay have also been reported [Gertsch et al 2010].
Two females with a heterozygous GPC3 pathogenic variant were reported to have two different types of cancer: one had a sero-papilliferous cystoadenoma, a low-grade ovarian carcinoma; the other had breast cancer [Gurrieri et al 2011].Information was not sufficient to exclude other possible genetic causes for breast/ovarian cancer in the family.

Genotype-Phenotype Correlations
In a study of genotype-phenotype correlations, Mariani et al [2003] determined that all deletions and singlenucleotide variants occurring in the eight GPC3 exons result in loss of function with no phenotypic distinctions based on size or position of a deletion or single-nucleotide variant.

Penetrance
Penetrance in heterozygous females is unknown, but mildly affected females have been reported.All males reported with a GPC3 pathogenic variant have had clinical findings of SGBS1.
Terms no longer in use for SGBS: • Gigantism-dysplasia syndrome

Prevalence
The prevalence of SGBS1 is unknown; however, it is believed to be underdiagnosed due to the wide spectrum of clinical severity.

Genetically Related (Allelic) Disorders
No other phenotypes are known to be associated with pathogenic variants in GPC3 and GPC4.• Hydrocephalus • Micro-/retrognathia AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; XL = X-linked 1. Fauth et al [2016] 2. Tenorio et al [2014] 3. BWS is associated with abnormal regulation of gene transcription through methylation at one or both imprinted domains on chromosome 11p15.5.Most alterations are postzygotic, but rare cases are due to deletions, duplications, or chromosome rearrangements affecting 11p15.5.Most individuals with BWS have no family history of BWS; approximately 5%-10% have a family history consistent with parent-of-origin autosomal dominant transmission.4. Baujat et al [2005] Other syndromes that may share overlapping features:

Differential Diagnosis
• Perlman syndrome (OMIM 267000), a rare autosomal recessive condition caused by biallelic pathogenic variants in DIS3L2, includes macrosomia and a high incidence of Wilms tumor; facial features are distinctive and neonatal mortality is high.• Nevo syndrome, an autosomal recessive condition that shares vertebral anomalies, ear malformations, cryptorchidism, overgrowth, and intellectual disability with SGBS1.Nevo syndrome manifestations further include accelerated osseous maturation, large extremities, and hypotonia.This condition is caused by pathogenic variants in exon 9 of PLOD1 [Giunta et al 2005].(See Ehlers-Danlos Syndrome, Kyphoscoliotic Form.) • Marshall-Smith syndrome (OMIM 602535), which shares advanced bone age and intellectual disability with SGBS1; differences include facial features and predisposition to fractures.This condition is caused by a heterozygous pathogenic variant in NFIX and frequently occurs de novo.

Management Evaluations Following Initial Diagnosis
To establish the extent of disease and needs of an individual diagnosed with Simpson-Golabi-Behmel syndrome type 1 (SGBS1), the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Feeding difficulties
Milder feeding issues may be managed w/special nipples or nasogastric feeding in consultation w/ specialist.
Limited data are available on treatment of feeding difficulties in individuals w/SGBS1.Gastrostomy tube may be considered in those w/ severe feeding issues.

Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
Ages 0-3 years.Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy.In the US, early intervention is a federally funded program available in all states.
Ages 3-5 years.In the US, developmental preschool through the local public school district is recommended.Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed.
Ages 5-21 years All ages.Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies and to support parents in maximizing quality of life.
Consideration of private supportive therapies based on the affected individual's needs is recommended.Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
In the US: • Developmental Disabilities Administration (DDA) enrollment is recommended.DDA is a public agency that provides services and support to qualified individuals.Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
• Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.

Motor Dysfunction
Gross motor dysfunction.Physical therapy is recommended to maximize mobility.

Fine motor dysfunction.
Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.

Oral motor dysfunction.
Assuming that the individual is safe to eat by mouth, feeding therapy -typically from an occupational or speech therapist -is recommended for affected individuals who have difficulty feeding due to poor oral motor control.Little information on tumor risk in heterozygous females is available; there are currently only two reports of tumors in females with SGBS1 (see Clinical Description, Heterozygous Females).However, screening can be considered in affected females.

Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual by molecular genetic testing of the GPC3 or GCP4 pathogenic variant in the family in order to identify as early as possible those who would benefit from preventive measures, such as tumor surveillance in males.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.Note: There may not be clinical trials for this disorder.

Genetic Counseling
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions.The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members.This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional.-ED.

Mode of Inheritance
Simpson-Golabi-Behmel syndrome type 1 (SGBS1) is inherited in an X-linked manner.

Risk to Family Members
Parents of a male proband • The father of an affected male will not have the disorder nor will he be hemizygous for the SBGS1-causing pathogenic variant; therefore, he does not require further testing.• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote and may demonstrate some features of the condition.Note: If a woman has more than one affected child and no other affected relatives, and if the pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism [Romanelli et al 2007].The frequency of germline mosaicism is currently unknown.• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote or the affected male may have either a de novo hemizygous pathogenic variant in GPC3, a de novo intragenic or whole-gene deletion of GPC3 that may include part or all of GPC4, or a de novo large multiexon duplication of GPC4, in which case the mother is not a heterozygote.The frequency of de novo pathogenic variants is about 20%-30% [Tenorio et al 2014].

Parents of a female proband
• A female proband may have inherited the pathogenic variant from either her mother (who may or may not have manifestations of SBGS1) or her father [Støve et al 2017], or the pathogenic variant may be de novo.• Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a de novo pathogenic variant from those with an inherited pathogenic variant.Molecular genetic testing of the mother (and possibly the father, or subsequently the father) may help determine whether the pathogenic variant was inherited.
Sibs of a male proband.The risk to sibs depends on the genetic status of the mother: • If the mother of the proband has a pathogenic variant, the chance of transmitting the pathogenic variant in each pregnancy is 50%.Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes and may be affected, as heterozygous females with features of SGBS1 have been reported (see Clinical Description, Heterozygous Females).• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the possibility of maternal germline mosaicism.Maternal germline mosaicism has been reported [Romanelli et al 2007].
Sibs of a female proband.The risk to sibs depends on the genetic status of the parents: • If the mother of the proband has a SGBS1-causing pathogenic variant, the chance of transmitting it in each pregnancy is 50%.Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes and may be affected; heterozygous females with features of SGBS1 have been reported (see Clinical Description, Heterozygous Females).• If the father of the proband has a pathogenic variant, he will transmit it to all of his daughters and none of his sons.To date, one case of transmission from an affected father to his affected daughter has been reported [Støve el al 2017].• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the pathogenic variant cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the possibility of parental germline mosaicism (both maternal and paternal germline mosaicism have been reported in SGBS1 [Romanelli et al 2007, Agatep et al 2014]).
Offspring of a male proband.To date, only one affected male has been reported to reproduce; the affected male was only diagnosed after the fetal demise of the affected child [Støve et al 2017].
Affected males transmit the pathogenic variant to: • All of their daughters, who will be heterozygotes and may be affected; heterozygous females with features of SGBS1 have been reported (see Clinical Description, Heterozygous Females).• None of their sons.
Offspring of a female proband.Women with a pathogenic variant have a 50% chance of transmitting the pathogenic variant to each child: • Males who inherit the pathogenic variant will be affected.
• Females who inherit the pathogenic variant will be heterozygotes (carriers) and may be affected; heterozygous females with features of SGBS1 have been reported (see Clinical Description, Heterozygous Females).
Other family members.The proband's maternal aunts may be at risk of being heterozygotes for the GPC3 and/or GPC4 pathogenic variant, and the aunts' offspring may be at risk of being having the pathogenic variant and being affected.
Note: Molecular genetic testing may be able to identify the family member in whom a de novo pathogenic variant arose, information that could help determine genetic risk status of the extended family.

Heterozygote Detection
Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the pathogenic variant has been identified in the proband.
Note: (1) Females who are heterozygous for this X-linked disorder may be affected; heterozygous females with features of SGBS1 have been reported (see Clinical Description, Heterozygous Females).( 2) Identification of female heterozygotes requires either (a) prior identification of the pathogenic variant in the family or, (b) if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and if no pathogenic variant is identified, by gene-targeted deletion/duplication analysis.
If the pathogenic variant has not been identified in the family, physical examination of at-risk female relatives and X-chromosome inactivation studies to determine if skewing of X-chromosome inactivation is present may identify some possible heterozygotes [Author, personal observation].

Related Genetic Counseling Issues
See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning
• The optimal time for determination of genetic risk, clarification of carrier status of at-risk females, and discussion of the availability of prenatal testing is before pregnancy.• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or are heterozygotes, or are at risk of being heterozygotes.
DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use.Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis
Once the SGBS1-causing pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.
In pregnancies in which SGBS1 is suspected because of fetal overgrowth or congenital anomalies, the use of genomic testing (including chromosomal microarray and exome sequencing) can aid in diagnosis [Kehrer et al 2016].
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis.While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources
GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families.GeneReviews is not responsible for the information provided by other organizations.For information on selection criteria, click here.
• National Library of Medicine Genetics Home Reference Simpson-Golabi-Behmel syndrome

Molecular Genetics
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information.-ED.

GPC3
Gene structure.GPC3 comprises eight exons that span more than 500 kb.For a detailed summary of gene and protein information, see Table A, Gene.
Pathogenic variants.All eight exons of GPC3 have been found to harbor deletions, duplications, or singlenucleotide variants that lead to the Simpson-Golabi-Behmel syndrome type 1 (SGBS1) phenotype.The majority of SGBS1 cases are attributable to GPC3.
Approximately 50% of GPC3 deletions involve exon 8 [Veugelers et al 2000].Single-nucleotide variants have been described in all exons; as expected, most occur in exon 3, the largest exon.
Abnormal gene product.The mechanism by which a pathogenic loss-of-function GPC3 variant leads to the SGBS1 phenotype is unknown.Yano et al [2011] reported that at least 43% loss of functional GPC3 protein is required to develop the SGBS1 phenotype in heterozygous females (total detection rate is unknown) [Yano et al 2011].

GPC4
Gene structure.GPC4 is adjacent to the 3' end of GPC3 and comprises nine exons.For a detailed summary of gene and protein information, see Table A, Gene.
Pathogenic variants.Duplication of exons 1-9 of GPC4 without a GPC3 pathogenic variant also leads to the SGBS1 phenotype [Waterson et al 2010].Note: Loss-of-function variants in GPC4 are not associated with SGBS1 [Veugelers et al 2000].
Abnormal gene product.The mechanism by which duplication of GPC4 leads to the SGBS1 phenotype is unknown.Duplication.Males and female carriers with complex GPC3 and GPC4 duplications have been reported [Schirwani et al 2019].Additional atypical SGBS1 features, such as brain malformations, have been noted in these patients with the dual duplication, suggesting that the new features may be associated with the GPC4 duplication [Mujezinović et al 2016].Mujezinović et al [2016] suggest that the GPC4 duplication could cause a greater disruption of GPC3 expression, altering the phenotypic expression [Mujezinović et al 2016].

GPC3/GPC4
The mechanism by which duplication of GPC3 and GPC4 leads to the SGBS1 phenotype is unknown.Schirwani et al [2019] reported two heterozygous females with 45%-56% of the active X-chromosome-containing complex GPC3/GPC4 duplications.These females manifested mild SGBS1 features including intellectual disability and developmental delay [Schirwani et al 2019].
Complex Deletions and Duplications Deletion.DiMaio et al [2017] reported a familial case of SGBS1 caused by deletion of GPC3, TFDP3, and GPC4.TFDP3 (OMIM 300772) encodes a member of the DP family of transcription factors, but has no known disease association [DiMaio et al 2017].

Table 2 .
Disorders to Consider in the Differential Diagnosis of SGBS1Table 2. continued from previous page.Table 2. continued from previous page.

Table 3 .
Recommended Evaluations Following Initial Diagnosis in Individuals with Simpson-Golabi-Behmel Syndrome Type 1

Table 4 .
Treatment of Manifestations in Individuals with Simpson-Golabi-Behmel Syndrome Type 1

Table 4 .
continued from previous page.
• In the US, an IEP based on the individual's level of function should be developed by the local public school district.Affected children are permitted to remain in the public school district until age 21. • Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years.Developmental pediatricians can provide assistance with transition to adulthood.

Table 5 .
Communication issues.Consider evaluation for alternative means of communication (e.g., Augmentative and Alternative Communication [AAC]) for individuals who have expressive language difficulties.Recommended Surveillance for Males with Simpson-Golabi-Behmel Syndrome Type 1

Table B .
Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt.For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.OMIM Entries for Simpson-Golabi-Behmel Syndrome Type 1 (View All in OMIM)IntroductionGPC3 and GPC4 both encode glycosylphosphatidylinositol-linked cell surface heparan sulfate proteoglycans, which belong to the glypican family.Heparan sulfate proteoglycans bind and regulate the activities of a variety of extracellular ligands essential to cellular functions.Glypicans have a role in cell growth and cell division.Abnormal glypican function may affect pathways such as Wnt signaling, Hedgehog pathway, BMP signaling, and FGF signaling [Paine-Saunders et al 2000, Song et al 2005, Ng et al 2009].