| Domain | Key facts | Suggested ontology terms | Key evidence |
|---|---|---|---|
| Identifiers / synonyms | Simpson-Golabi-Behmel syndrome type 1 (SGBS1) is a rare congenital overgrowth-malformation syndrome caused by GPC3 loss of function; OMIM disease identifier **#312870**; Open Targets disease identifier **MONDO:0020602**. Common names/synonyms in the literature: Simpson-Golabi-Behmel syndrome, SGBS, SGBS1. Evidence is largely from aggregated disease-level reviews/guidelines plus published case reports/series, not EHR cohorts. | MONDO:0020602 | (pqac-00000001, pqac-00000003, pqac-00000004) |
| Causal gene / inheritance | Primary causal gene: **GPC3** (glypican 3), Xq26.3; OMIM gene **#300037**; Open Targets target **ENSG00000147257**. Inheritance is **X-linked**; males typically show full penetrance, while female carriers are often asymptomatic or mildly affected, though clinically significant affected females have been reported. | HGNC:4451; SO:0001483 loss_of_function_variant | (pqac-00000001, pqac-00000003, pqac-00000004) |
| Variant spectrum | Review data identified **86 distinct GPC3 variants** in **120 unrelated families** involving **152 male patients**. Reported classes: **large deletions 34.9%**, **frameshift 24.4%**, **nonsense 16.3%**, **missense 8.1%**, **large duplications 8.1%**, **splice-site 4.7%**, **translocations 2.3%**, **in-frame indels 1.2%**. Variants are predominantly germline **loss-of-function** defects; only **18%** were reported as de novo in the mutation update. | SO:0000159 deletion; SO:0001589 frameshift_variant; SO:0001587 stop_gained; SO:0001629 splice_site_variant; SO:1000032 chromosomal_duplication | (pqac-00000003, pqac-00000007, pqac-00000008) |
| Hallmark phenotypes | Core phenotype includes **fetal macrosomia/pre- and postnatal overgrowth**, **macrocephaly**, **organomegaly**, **coarse/distinctive facies**, **extremity abnormalities**, **supernumerary nipples**, and variable **cardiac, skeletal, gastrointestinal, genitourinary malformations**; **learning difficulties/intellectual disability** occur variably. Typical presentation is **from birth/congenital**. Suggested HPO terms: overgrowth **HP:0001548**, fetal macrosomia **HP:0001524**, macrocephaly **HP:0000256**, organomegaly **HP:0002742**, coarse facial features **HP:0000280**, supernumerary nipple **HP:0100807**, congenital heart defect **HP:0001627**, skeletal abnormality **HP:0000924**, cryptorchidism **HP:0000028**, intellectual disability **HP:0001249**. | HPO terms listed in cell | (pqac-00000001, pqac-00000003, pqac-00000006, pqac-00000008) |
| Tumor predisposition | Documented tumor predisposition is an established component of SGBS1, with emphasis on **Wilms tumor** and **liver tumors/hepatoblastoma**; **gonadoblastoma** surveillance is also recommended in guidance. Exact tumor incidence was not available in the gathered evidence set, so risk should be described qualitatively rather than numerically here. | HP:0002669 Neoplasm; NCIT:C3434 Wilms Tumor; NCIT:C3728 Hepatoblastoma; NCIT:C3088 Gonadoblastoma | (pqac-00000002, pqac-00000006, pqac-00000007, pqac-00000008) |
| Diagnosis | Diagnosis combines clinical recognition with molecular confirmation. Reported methods include **PCR/direct sequencing (Sanger)** and **MLPA** on peripheral-blood genomic DNA; analytical sensitivity/specificity for coding-exon and flanking-intron variant detection was described as **nearly 100%** in the clinical utility guideline. Prenatal diagnosis has been reported using ultrasound findings plus molecular testing, including detection of partial **GPC3** deletions. | NCIT:C16444 Sanger Sequencing; NCIT:C111298 Multiplex Ligation-dependent Probe Amplification | (pqac-00000001, pqac-00000003, pqac-00000005) |
| Management / surveillance | Management is **multidisciplinary and largely symptomatic**: neonatal hypoglycemia treatment, surgery for congenital malformations, specialist management for arrhythmia/conduction disease, and developmental supports (e.g., speech/learning services). Guidance recommends screening in affected males and symptomatic carrier females for **Wilms tumors, liver tumors, and gonadoblastoma**, plus **regular cardiac follow-up**. Prenatal molecular diagnosis can be offered to at-risk pregnancies of known female carriers. | NCIT:C51932 Supportive Care; NCIT:C17428 Surgical Procedure; NCIT:C15709 Genetic Counseling; NCIT:C47891 Ultrasound | (pqac-00000002, pqac-00000005) |
| Mechanism | Causal chain: **GPC3 loss-of-function** leads to defective cell-surface glypican regulation of morphogen signaling, which leads to dysregulated developmental growth control and organ patterning, resulting in overgrowth, congenital malformations, and tumor susceptibility. The gathered evidence supports dysregulation of **WNT**, **Hedgehog**, **FGF**, and **BMP** pathways; Hedgehog hyperactivation with elevated Sonic/Indian Hedgehog proteins has been reported in GPC3-null models. Some downstream links to specific human phenotypes remain inferred from model systems rather than directly demonstrated in patient tissues. | GO:0060070 canonical Wnt signaling pathway; GO:0007224 smoothened signaling pathway; GO:0008543 fibroblast growth factor receptor signaling pathway; GO:0030509 BMP signaling pathway | (pqac-00000006, pqac-00000007) |
| Model organisms | **Gpc3-targeted/deletion mouse models** recapitulate major developmental features, including **developmental overgrowth**, **perinatal death**, **renal dysplasia**, **accessory spleens**, **impaired lung development**, **polydactyly**, and **placentomegaly**. These models support an upstream developmental-regulatory role for GPC3 and are useful for mechanism studies, but they do not fully quantify human neurodevelopmental or tumor outcomes. | NCBITaxon:10090; CL/GO not disease-specific here | (pqac-00000007) |
| Epidemiology / prognosis | **Prevalence is unknown** and the disorder is likely **underdiagnosed**. Prognosis is **generally favorable in many cases**, but can be **life-threatening at birth or in infancy** because of major congenital malformations, especially severe diaphragmatic or other structural defects; otherwise many patients may have near-normal life expectancy, tempered by cardiac and tumor risks and by variable neurodevelopmental burden. | Orphan disease epidemiology not firmly established in gathered evidence | (pqac-00000001, pqac-00000002, pqac-00000003) |
| Recent developments / evidence gaps | 2021-2023 literature expanded **prenatal diagnosis**, **familial female expression**, and unusual presentations (e.g., disorders of sex development), while 2024 search results indicate continuing phenotype-spectrum work. No **SGBS1-specific disease-modifying therapy** or **interventional trial** was identified in the gathered evidence. Important gaps remain in **robust prevalence/incidence**, **tumor-risk quantification**, **standardized surveillance intervals/ages**, **natural-history cohorts**, and **omics-based biomarkers**. Oncology trials targeting **GPC3** in cancer should **not** be interpreted as treatments for germline GPC3 deficiency. | NCIT:C16084 Clinical Trial; NCIT:C15220 Biomarker | (pqac-00000002, pqac-00000004, pqac-00000007) |


*Table: This table condenses the highest-yield disease knowledge-base fields for Simpson-Golabi-Behmel syndrome type 1, including identifiers, genetics, phenotype, mechanism, management, and evidence gaps. It is aligned to the gathered evidence and highlights the key quantitative variant data needed for structured curation.*