EMC10 Gene Variants May Cause Dual Molecular Effects on the Neuropsychiatric Disease Pattern

ABSTRACT The EMC10 gene on chromosome 19 encodes one of the highly conserved endoplasmic reticulum membrane complexes (EMC). Specific mutations in EMC10 cause a disorder known as neurodevelopmental disorder with dysmorphic facies and variable seizures (NEDDFAS) (OMIM #619264), characterized by global developmental delay and dysmorphic facial features, which become apparent in early childhood. This study aims to present the clinical data associated with a novel variant of a patient diagnosed with NEDDFAS (OMIM #619264), a condition rarely reported in the literature. By examining the phenotypic implications and molecular mechanisms of pathogenic variants in the EMC10 gene, this study seeks to contribute to a better understanding of the genetic and clinical spectrum of the disease. Our case was followed up in the Child and Adolescent Psychiatry clinic with the diagnosis of intellectual disability. Initial genetic testing included karyotype analysis, FMR1 CGG repeat analysis, and chromosomal microarray analysis. Subsequently, whole‐exome sequencing (WES) was performed, and Sanger sequencing was used to confirm the identified variant and conduct familial segregation analysis. We identified a novel homozygous frameshift variant in the EMC10 gene, NM_206538.4:c.431del, resulting in NP_996261.1:p.Asp144AlafsTer3 using WES. This variant was classified as pathogenic (P) according to ACMG criteria, which was clinically relevant to the patient's condition. Segregation analysis revealed that both the mother and the father were heterozygous carriers of this variant. To date, the phenotype associated with this variant has been reported in 31 individuals from 16 different families. To our knowledge, our case is the first reported patient in the Turkish population carrying an EMC10 gene variant. Among reported cases, variations in symptom distribution and severity have been observed. We propose that EMC10 gene variants may exhibit dual molecular effects. There are two types of neurodevelopmental clinical presentations: (1) a classic disease pattern with mild‐to‐moderate intellectual disability (ID) and no neurological findings and (2) a progressive disease pattern with severe ID, hypotonia, and abnormalities in gait.