EHBP1L1

Inheritance Pattern: AR

Disease ID:MONDO:0009369

Submitter: LiferaOmics

Genetic evidence – Published: The primary AR report supporting EHBP1L1-related multiple congenital anomalies syndrome with non-immune hydrops fetalis (NIHF) describes two unrelated consanguineous families with biallelic pLOF EHBP1L1 variants (frameshift and canonical splice with aberrant splicing shown), consistent with an autosomal recessive model (PMID: 34645488). Additional published observations include a homozygous c.4004-1G>A case with heterozygous parents (PMID: 31130284) and a severe NIHF/neonatal failure presentation homozygous for the recurrent frameshift c.3333_3346del (PMID: 37644014); to avoid potential overlap/double counting across reports/alleles, these are treated as supportive context only and not scored as additional independent probands here. Case-level (biallelic predicted null in AR model; homozygous scored once; −0.5 consanguinity deduction applied) = 1.0 per family ×2 = 2.0; segregation = 1.0 (reported recurrent affected pregnancies/affected sibs counted as segregation, not independent probands; conservative); case-control = 0. Published genetic evidence total = 3.0/12. Genetic evidence – our cases: Four unrelated families with EHBP1L1 variants and overlapping NIHF/multiple congenital anomalies spectrum. (Conservative/consistent segregation approach: genotyped family members contribute 0.5 per family when supportive; affected siblings/fetal cases are not counted as independent probands.) • Family 1: 1 proband; pLOF variant; AR inheritance; parents consanguineous; one additional affected fetus/stillbirth homozygous for the variant (counts as segregation only); no case-control data. Case-level (biallelic predicted null; homozygous scored once; −0.5 consanguinity deduction applied) = 1.0. Segregation (supportive genotyped affected relative; conservative) = 0.5. Case-control = 0 • Family 2: 1 proband; pLOF (canonical splice) variant; AR inheritance; parents consanguineous; one affected sibling homozygous (segregation only); no case-control data. Case-level (biallelic predicted null; homozygous scored once; −0.5 consanguinity deduction applied) = 1.0. Segregation (affected sibling; conservative) = 0.5. Case-control = 0. • Family 3: 1 proband; non-pLOF (missense) variant; AR inheritance; consanguinity not specified; no additional genotyped affected relatives; no segregation or case-control data. Because the allele is non-pLOF (missense), case-level points were assigned using the AR “other variant” default = 1.0. Segregation = 0; case-control = 0. • Family 4: 1 proband; non-pLOF (missense) variant; AR inheritance; parents consanguineous; no additional genotyped affected relatives; no segregation or case-control data. Because the allele is non-pLOF (missense), case-level points were assigned using the AR “other variant” default = 1.0, with −0.5 consanguinity deduction = 0.5. Segregation = 0; case-control = 0 Current case contribution = case-level (1.0 + 1.0 + 1.0 + 0.5 = 3.5) + segregation (0.5 + 0.5 = 1.0) = 4.5/12. Total genetic evidence (published + our cases) = 3.0/12 + 4.5/12 = 7.5/12. Experimental evidence – Published: EHBP1L1 has relevant vesicle trafficking/apical transport function (biochemical function) = 0.5. The splice variant report demonstrates aberrant splicing by RT-PCR (functional alteration) = 1.0. Reported/compiled model system evidence consistent with lethality/edema/cardiac findings in loss-of-function contexts = 2.0. Experimental evidence total = 3.5/6. Overall score = 11.0

Inheritance Pattern: AR

Disease ID:MONDO:0009369

Submitter: PanelApp Australia