FSD1L

Inheritance Pattern: AR

Disease ID:MONDO:0100038

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0100038

Submitter: LiferaOmics

Genetic evidence – Published: PMID: 41720098 reports 6 unrelated families (14 affected individuals, including fetuses) with biallelic FSD1L variants in an autosomal recessive model presenting with congenital hydrocephalus, ventriculomegaly, and neurodevelopmental involvement overlapping with L1 syndrome. Family A: Two affected individuals from a consanguineous family. Case-level (biallelic predicted loss-of-function in AR model; homozygous scored once; −0.5 consanguinity deduction applied) = 1.0; segregation (affected sibling counted as segregation) = 0.5; case-control = 0. Total=1.5 Family B: Three affected fetuses from a consanguineous family. Case-level (biallelic predicted null in AR model; homozygous scored once; −0.5 consanguinity deduction applied) = 1.0; segregation (two additional affected fetuses counted as segregation) = 0.5; case-control = 0. Total = 1.5 Family C: Two affected individuals from a non-consanguineous family with homozygous variants (c.1228T>G [missense] and c.1251_1252insTAA [truncating each evaluated independently]). Case-level (biallelic predicted loss-of-function in AR model; homozygous scored once; no consanguinity deduction applied) = 1.5+0.1; segregation (affected sibling counted as segregation) = 0.5; case-control = 0. Total =2.1 Family D: Two affected individuals from a consanguineous family. Case-level (biallelic non-LOF in AR model; homozygous scored once; −0.5 consanguinity deduction applied) = 0.5; segregation (affected sibling counted as segregation) = 0.5; case-control = 0. Total = 1.5 Family E: One affected individual from a consanguineous family. Case-level (biallelic non-LOF in AR model; homozygous scored once; −0.5 consanguinity deduction applied) = 0.5; segregation = 0; case-control = 0. Total = 1. Family F: Four affected fetuses from a consanguineous family. Case-level (biallelic predicted null in AR model; homozygous scored once; −0.5 consanguinity deduction applied) = 1.0; segregation (three additional affected fetuses counted as segregation) = 0.5; case-control = 0. Total = 1.5 Published genetic evidence total = 9.6/12 Genetic evidence – our cases: One consanguineous family with a homozygous predicted loss-of-function variant in FSD1L (NM_001145313.2:c.1260G>A; p.Trp420*) and phenotype consistent with congenital hydrocephalus spectrum (severe ventriculomegaly, aqueductal stenosis, macrocephaly, neonatal respiratory distress). Case-level (biallelic predicted null in AR model; homozygous scored once; −0.5 consanguinity deduction applied) = 1.0; segregation = 0 (previous affected fetus without genotype confirmation not scored); case-control = 0. Current case contribution = 1.0/12 Total genetic evidence (published + our case) = 10.6/12 Experimental evidence – Published: FSD1L demonstrates moderate loss-of-function constraint (LOEUF = 0.84, gnomAD), consistent with an autosomal recessive LoF mechanism = 0.5. Missense variants (c.1228T>G; c.1366G>C) show altered structural stability and long-range interaction changes in molecular dynamics simulations = 0.5. RNA studies in patient-derived fibroblasts and fetal brain tissue demonstrate aberrant splicing, frameshift formation, and nonsense-mediated mRNA decay for c.409T>G and c.1411C>T, confirming a loss-of-function mechanism = 1.5. No rescue models currently reported. Experimental evidence total = 2.5/6 Overall score = 13.1/18