FAT1

Inheritance Pattern: AR

Disease ID:MONDO:0002254

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0100313

Submitter: ClinGen

FAT1 was first reported in relation to autosomal recessive glomerulotubular nephropathy in 2016 (Gee et al., PMID: 26905694). This condition is syndromic, characterized by renal failure and podocyte foot process effacement, as well as cancer, vision anomalies, and brain structural issues. 10 variants (missense, nonsense, frameshift) that have been reported in 14 probands in 4 publications (PMIDs: 26905694, 31831576, 30862798, 34013115) are included in this curation. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by experimental evidence (expression-level evidence, mouse models). Data shows high expression in the kidney (Humphrey's Lab), and mouse models replicate the kidney and eye components of the phenotype (PMIDs: 12724416, 26905694). In summary, there is definitive evidence supporting the relationship between FAT1 and autosomal recessive glomerulotubular nephropathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Glomerulopathy GCEP on the meeting date [11/13/2023] (SOP Version #9).

Inheritance Pattern: AR

Disease ID:MONDO:0016073

Submitter: LiferaOmics

Genetic evidence – Published PMID: 30862798 (2019) – Identified homozygous frameshift (pLOF) FAT1 variants in 10 affected individuals from 5 unrelated consanguineous families, with a syndromic spectrum including colobomatous microphthalmia/coloboma, ptosis, syndactyly, and variable renal involvement. • Case-level: 5 homozygous probands (AR predicted/proven null; homozygous scored once; −0.5 consanguinity deduction applied) = 5 × 1.0 = 5.0 • Segregation: pedigrees show affected counts per family (3, 3, 2, 1, 1) = 5 additional affected relatives beyond the 5 probands. The paper confirms recessive segregation with parental confirmation where available, but does not provide an explicit meioses/LOD summary in the main text; therefore scored conservatively = 2.0. • Case-control: 0 PMID 30862798 total = 7.0 PMID: 34013115 (2021) – Reports 4 patients from 3 families: 3 patients with homozygous truncating (pLOF) variants (two are affected siblings in one family; one is a single affected individual in a second family), and 1 patient with compound heterozygous missense (non-LoF) variants. Ocular findings and renal disease are present across the cohort; the paper notes that the “hallmark” combination including feet syndactyly is more typical of truncating variants, consistent with a spectrum. • Case-level (truncating pLOF families): o Family A (patients 1 & 2; one proband scored, homozygous truncating; consanguinity = yes) = 1.5 − 0.5 = 1.0 o Family B (patient 3; homozygous truncating; consanguinity = yes) = 1.5 − 0.5 = 1.0 Truncating subtotal = 2.0 • Case-level (missense family): Patient 4, compound heterozygous missense (non-LoF): start at 0.1 each, score independently and sum = 0.1 + 0.1 = 0.2 (no consanguinity deduction). • Total case-level (PMID 34013115) = 0.2 + 0.2 = 0.4 • Segregation: affected sibling in Family A = 0.5 (siblings counted as segregation, not independent probands). • Case-control: 0 PMID 34013115 total = 2.9 A novel frameshift homozygous mutation in FAT1 gene causes ptosis, nephropathy, and syndactyly in an Emirati family: case report and literature review ( https://doi.org/10.24911/JBCGenetics/183-1645370249 ) – Reports 1 consanguineous family (3 affected individuals) with homozygous frameshift (pLOF) FAT1 and syndromic features including ptosis and syndactyly with variable renal involvement. • Case-level: 1 homozygous pLOF proband; consanguinity stated → 1.5 − 0.5 = 1.0 • Segregation: additional affected relatives (conservative) = 0.5 • Case-control: 0 2022 report total = 1.5 PMID: 36951427 (2023) – Reports 1 individual with a homozygous frameshift FAT1 variant and bilateral coloboma + renal disease, supporting the ocular–renal spectrum. (Consanguinity not clearly specified in the accessible abstract-level information.) • Case-level: homozygous predicted/proven null; no consanguinity deduction applied = 1.5 • Segregation: 0 • Case-control: 0 PMID 36951427 total = 1.5 PMID: 40976965 (2025) – Reports 1 individual with homozygous frameshift FAT1 and syndromic findings including ptosis and foot syndactyly with renal disease, supporting the spectrum. (Consanguinity not specified in abstract-level information.) • Case-level: homozygous predicted/proven null; no consanguinity deduction applied = 1.5 • Segregation: 0 • Case-control: 0 PMID 40976965 total = 1.5 Published genetic evidence total • Case-level total = 5.0 + 2.9 + 1.0 + 1.5 + 1.5 = 11.9 • Segregation total = 2.0 + 0.5 + 0.5 = 3.0 • Case-control = 0 Published genetic evidence total = 14.9 → capped at 12/12 Genetic evidence – our case Family 1: – 1 proband; homozygous nonsense (NM_005245.3:c.10198C>T; p.Arg3400Ter); AR; consanguinity present. • Case-level: AR predicted/proven null; homozygous scored once; −0.5 consanguinity deduction applied = 1.0 • Segregation: 0 (no affected siblings scored; parental carrier confirmation not provided in the scoring inputs) • Case-control: 0 Family 1 contribution = 1.0 Family 2 :1 proband; homozygous nonsense (same variant); AR; consanguinity present. • Case-level: AR predicted/proven null; homozygous scored once; −0.5 consanguinity deduction applied = 1.0 • Segregation: 0 • Case-control: 0 Family 2 contribution = 1.0 Current cases total = 2.0/12 Total genetic evidence Total genetic evidence (published + our cases) = 12/12 (capped) Experimental evidence – Published PMID: 30862798 (2019) – Experimental support consistent with FAT1 loss-of-function causing the ocular phenotype: • Model systems: Fat1 knockout mouse and truncating zebrafish models show coloboma consistent with optic fissure closure defects = 2.0 • Functional/expression support in relevant context: supportive localization/expression data consistent with developmental mechanism = 1.0 Experimental evidence total = 3.0/6 Overall score = Genetic 12/12 + Experimental 3.0/6 = 15.0 First report (2019) Subsequent supporting publications: (2021, 2022, 2023, 2025)