From Face to Function: SEC24C Deficiency Mimics GPI-Anchor Biosynthesis Disorder

Averdunk, L. (2023). From Face to Function: SEC24C Deficiency Mimics GPI-Anchor Biosynthesis Disorder (Version 1) [DataSet]. GestaltMatcher Database.

Background SEC24C encodes a cargo-selective COP II subunit required for ER export of glycosyl-phosphatidylinositol-anchored proteins (GPI-APs). To date, a single case from a consanguineous pedigree with biallelic loss-of-function variants has defined a provisional clinical entity characterised by congenital cataracts, epileptic encephalopathy, dyserythropoietic anaemia and defective protein trafficking. We describe a child with biallelic single-amino-acid changes in SEC24C who shares high clinical and facial similarity of the only previously reported family, thereby strengthening the evidence for a human SEC24C disorder and illustrating how AI-based facial analysis can direct gene discovery. Methods Comprehensive neurological, ophthalmological, haematological and neuro-imaging examinations were followed by AI-driven facial phenotyping with GestaltMatcher, which prompted targeted analysis of genes involved in GPI-anchored protein (GPI-AP) transport. Trio exome sequencing revealed two rare variants in SEC24C: a maternally inherited in-frame deletion (p.Ser156del) within the cargo-binding loop and a missense substitution (p.Arg1040Gln) in the C-terminal domain, paternally inherited. No other variants were found in the trio WES data that could explain the clinical features of the index. Pathophysiological characterization via peripheral-blood flow cytometry of CD55, CD59, CD73 and FLAER as well as plasma N-glycan profiling are in progress. Results The child displays global developmental delay, pronounced hypotonia with absent reflexes, unilateral sensorineural hearing impairment, optic atrophy with nystagmus and strabismus, plagiocephaly, diffuse hypomyelination and a thin corpus callosum on MRI, gingival hypertrophy with a tented upper lip, and mild anaemia. At three years no cataract is detectable, suggesting either age-dependent expression or an attenuated effect of the missense allele relative to the previously reported loss-of-function genotype. Conclusion AI-driven facial-gestalt analysis steered us toward SEC24C as the prime suspect in this second, unrelated patient, allowing rapid identification of two biallelic single-amino-acid variants. The concordant clinical and craniofacial overlap with the original SEC24C family—and with classic GPI-anchor disorders—strengthens the gene’s candidacy for a human ER-to-Golgi protein-trafficking syndrome that phenocopies GPI-anchor deficiencies. Upcoming clinical analysis, flow-cytometric GPI-AP profiling and plasma N-glycan analysis will define the pathogenicity of these alleles and further refine the emerging SEC24C phenotype-genotype relationship.