Submission Details

The TMEM94 gene is located on chromosome 17 at 17q25.1 and encodes transmembrane protein 94 which is involved in transport of magnesium ions into the endoplasmic reticulum . TMEM94 was first reported in relation to autosomal recessive intellectual developmental disorder with cardiac defects and dysmorphic facies (IDDCDF) in 2018 (Stephen et al., PMID: 30526868). IDDCDF is a syndromic neurodevelopmental disorder characterized by globally impaired development with intellectual disability and speech delay, congenital cardiac malformations, and dysmorphic facial features. Individuals with this condition present with various types of structural congenital heart disease, including atrial septal defect, ventricular septal defect, and tetralogy of fallot. Ten unique variants (6 frameshift, 1 nonsense, 3 splice-site) that have been reported in 12 probands with IDDCDF in 7 publications are included in this curation (PMIDs: 30526868, 32825426, 30919572, 31607746, 32552793, 37644014, 34374989). Most probands were born from consanguineous parents and variants were identified in a homozygous state in 10 of the 12 probands. More evidence is available in the literature but the maximum score for genetic evidence (12 pts) has been reached.The mechanism of pathogenicity is reported to be loss of function. This gene-disease relationship is also supported by a mouse modelwhere the homozygous null variants fully replicated the human phenotype (PMID: 30526868). In summary, there is definitive evidence to support the relationship between TMEM94 and autosomal recessive tntellectual developmental disorder with cardiac defects and dysmorphic facies. 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 Syndromic GCEP on the meeting date June 5th, 2024 (SOP Version 10).