• Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top EDTA tube (K2EDTA or K3EDTA)
  • Alternate specimens:
    Saliva, assisted saliva, buccal swab and gDNA
  • Sample requirements
  • Request a sample kit




Associated disorders

The GPC3 gene is associated with X-linked recessive Simpson-Golabi-Behmel syndrome (MedGen UID: 162917).

An estimated 40%-70% of Simpson-Golabi-Behmel syndrome is caused by pathogenic variants identified in the GPC3 gene.

The GPC3 gene encodes a cell-surface protein that can both positively (stabilize interactions) and negatively (prevent interactions) to regulate cellular growth signaling pathways, such as Wnt and Hedgehog. These pathways are important in development.

GPC3 Simpson-Golabi-Behmel
MedGen UID: 162917

Clinical condition
The GPC3 gene is a well established cause of Simpson-Golabi-Behmel syndrome (SGBS). SGBS is a congenital genetic overgrowth syndrome with highly variable clinical features including characteristic facies, cognitive impairment, pre- and postnatal overgrowth, macrosomia, and skeletal, genitourinary, cardiac and renal anomalies. There is additionally an increased risk for certain cancers (PMID: 20301398, 25238977, 23606591).

Head, ears, eyes, nose, throat
Cystic hygroma, macrosomia, esotropia, cataracts, optic disc coloboma, ocular nerve palsies, strabismus, hypertelorism, preauricular ear tags, fistulas, ear lobule creases, and helical dimples are features of SGBS. Clefting and conductive hearing loss has been described (PMID: 20301398, 25238977, 23606591).

Skeletal anomalies include advanced bone age, vertebral fusion, scoliosis, pectus excavatum, rib anomalies, winged scapula, congenital hip dislocation, small sciatic notches, and flared iliac wings. Digital anomalies include large hands, broad thumbs, brachydactyly, syndactyly, clinodactyly, and postaxial polydactyly. Striking index finger hypoplasia with congenital abnormalities of the proximal phalanx has been reported. Nail dysplasia, hypoplasia, and hypoconvexity are common (PMID: 20301398, 25238977, 23606591).

GI anomalies include pyloric ring, Meckel’s diverticulum, intestinal malrotation, hepatosplenomegaly, pancreatic hyperplasia of islets of Langerhans, choledochal cysts of the pancreatic duct, and polysplenia (PMID: 20301398, 25238977, 23606591).

Nephromegaly, multicystic kidneys, hydronephrosis, hydroureter, duplicated ureters, hypospadias, bifid scrotum, cryptorchidism, hydrocele, and inguinal and diaphragmatic hernia are described (PMID: 20301398, 25238977, 23606591).

Thoracoabdominal wall
Supernumerary nipples, diastasis recti, and umbilical hernias are features (PMID: 20301398, 25238977, 23606591).

Congenital heart defects are variable and include pulmonic stenosis, aortic coarctation, transposition of the great vessels, patent ductus arteriosus, and patent foramen ovale. Cardiac conduction defects and arrhythmias are also reported in affected individuals (PMID: 20301398, 25238977, 23606591).

Central nervous system
The incidence of developmental delay is unclear. Most affected individuals have low-to-normal IQ scores, although intelligence can range from normal to moderate cognitive impairment with language delay being very common. There is a possible association between SGBS and behavioral problems including attention deficit hyperactivity disorder (ADHD) (PMID: 26692054, 10424824, 18619000). Hypotonia, absent primitive reflexes, a neonatal high-pitched cry, seizures, and EEG abnormalities have been reported. Neuroradiologic findings are variable and include agenesis of the corpus callosum, Chiari malformation, hydrocephalus, and aplasia of the cerebellar vermis (PMID: 20301398, 25238977, 23606591).

While specific risk figures are not yet well established, SGBS is associated with the development of embryonal tumors such as Wilms, gonadoblastoma, hepatoblastoma, and hepatocellular carcinoma (PMID: 11477610, 20301398, 23606591).

There is also preliminary evidence suggesting an association between GPC3 pathogenic variants and neuroblastoma, and GPC3 is therefore available as a “preliminary evidence” gene on Invitae’s Nervous System/Brain Cancer panel (PMID: 22893378, 16010678, 1605222). Preliminary evidence genes are selected from an extensive review of the literature and expert recommendations, but the association between the gene and the specific condition has not been completely established. This uncertainty may be resolved as new information becomes available and therefore clinicians may continue to order these preliminary evidence genes.

Gene information
The GPC3 gene encodes a cell-surface protein that can both positively and negatively regulate cellular growth signaling pathways, such as Wnt and Hedgehog. These pathways are important in development (PMID: 18505598). If there is a pathogenic variant in this gene that prevents it from normally functioning, there may be an increased risk to develop certain types of cancers.

The GPC3 gene, which causes SGBS, is located on the X chromosome. Females have two copies of the X chromosome, while males have one X and one Y. Because SGBS is an X-linked condition, all males are expected to have features of the condition; however, there is variability in the clinical severity. A female who inherits a pathogenic variant in GPC3 may or may not have symptoms of SGBS because females have a second X chromosome that may compensate. Due to skewed inactivation of the X chromosome, some females may manifest symptoms (PMID: 25238977). Regardless, women who carry this variant can pass it on to their children. Daughters of a carrier female have a 50% chance of inheriting the variant (making them a carrier like their mother). Sons of carrier females have a 50% chance of inheriting the pathogenic variant and having SGBS. Affected males cannot pass the condition on to their sons (because they must pass on the Y chromosome to have a male child), but all daughters of an affected male will be carriers.

Medical management guidelines and surveillance recommendations
Management of SGBS in the neonatal period includes evaluations for hypoglycemia, airway and feeding problems, abdominal ultrasounds of liver, adrenals, and kidneys, and appropriate surgical management as needed.

To establish the extent of disease and needs of an individual diagnosed with SGBS, the following evaluations are recommended (PMID: 20301398, 25238977):

  • assessment of neonates for hypoglycemia with prompt treatment as needed
  • assessment for upper airway sufficiency if macroglossia, micrognathia, and/or glossoptosis is present with prompt treatment as appropriate
  • evaluation of young children with hypotonia and macroglossia for sleep apnea
  • baseline hearing and eye examinations
  • baseline cardiac evaluation for structural defects and conduction abnormalities including chest radiograph, electrocardiogram, and echocardiogram
  • renal ultrasound examination to evaluate for genitourinary malformations
  • abdominal/pelvic ultrasound examination to evaluate for intra-abdominal tumors and visceral anomalies; further studies (e.g., MRI) if findings are suspicious, abdominal ultrasound every three to four months from birth until age 7 or 8 years to assess for Wilms tumor and hepatic tumors
  • measurement of alpha-fetoprotein levels until age 3 to detect hepatocellular carcinoma at the following intervals:
    • every four months until age four years
    • every six months between ages four and seven years
    • annually after age seven years
  • physical examinations to monitor for tumor risk:
    • every three months until age four years
    • every four months from age four to seven years
    • biannually after age seven years
  • examination for evidence of skeletal anomalies requiring intervention (e.g., scoliosis during period of rapid growth rate) with radiographs as needed
  • development assessment including speech and language assessment
    • if development appears to be normal on initial assessment, routine monitoring of social and intellectual development
  • referral of children to the following pediatric specialists as needed:
    • craniofacial team for management of cleft lip and/or palate, or macroglossia and related feeding difficulties
    • audiologist, otolaryngologist, and speech therapy for management of hearing loss
    • ophthalmologist for management of vision problems
    • cardiologist for management of congenital heart defects and/or cardiac conduction defects
    • routine pre- and post-surgical preparation and monitoring for individuals with congenital heart disease and/or conduction defects
    • orthopedist for the treatment of vertebral malformations and scoliosis
    • urologist for surgical correction of anomalies such as hypospadias and cryptorchidism
    • monitoring of renal function if renal anomalies are present
    • neurologist and brain MRI if seizures are present
    • oncologist if a tumor is identified
    • neurodevelopmental follow up for individual treatment plan that may include special education, occupational therapy, and physical therapy

An individual’s cancer risk and medical management are not determined by genetic test results alone. Overall cancer risk assessment incorporates additional factors including personal medical history, family history as well as available genetic information that may result in a personalized plan for cancer prevention and surveillance.

It is advantageous to know if a GPC3 pathogenic variant is present as medical management recommendations can be implemented. At-risk relatives can be identified, allowing pursuit of a diagnostic evaluation. In addition, the available information regarding hereditary cancer susceptibility genes is constantly evolving and more clinically relevant GPC3 data is likely to become available in the near future. Awareness of this cancer predisposition allows patients and their providers to be vigilant in maintaining close and regular contact with their local genetics clinic in anticipation of new information, inform at-risk family members, and diligently follow condition-specific screening protocols.

Review date: August 2016

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
GPC3 NM_004484.3