A recurrent, homozygous EMC10 frameshift variant is associated with a syndrome of developmental delay with variable seizures and dysmorphic features

Abstract

Purpose The endoplasmic reticulum membrane complex (EMC) is a highly conserved, multifunctional 10-protein complex related to membrane protein biology. In seven families, we identified 13 individuals with highly overlapping phenotypes who harbor a single identical homozygous frameshift variant in EMC10. Methods Using exome, genome, and Sanger sequencing, a recurrent frameshift EMC10 variant was identified in affected individuals in an international cohort of consanguineous families. Multiple families were independently identified and connected via Matchmaker Exchange and internal databases. We assessed the effect of the frameshift variant on EMC10 RNA and protein expression and evaluated EMC10 expression in normal human brain tissue using immunohistochemistry. Results A homozygous variant EMC10 c.287delG (Refseq NM_206538.3, p.Gly96Alafs*9) segregated with affected individuals in each family, who exhibited a phenotypic spectrum of intellectual disability (ID) and global developmental delay (GDD), variable seizures and variable dysmorphic features (elongated face, curly hair, cubitus valgus, and arachnodactyly). The variant arose on two founder haplotypes and results in significantly reduced EMC10 RNA expression and an unstable truncated EMC10 protein. Conclusion We propose that a homozygous loss-of-function variant in EMC10 causes a novel syndromic neurodevelopmental phenotype. Remarkably, the recurrent variant is likely the result of a hypermutable site and arose on distinct founder haplotypes.

EMC10 reduction in human neurons and adult mouse brain rescues cellular and behavioral deficits linked to 22q11.2 deletion

“…The effect of further reductions of EMC10 levels remains unknown. Homozygous EMC10 mutations were recently reported in consanguineous families of Middle Eastern origin with developmental delay, seizures and dysmorphic features 51 suggesting that EMC10 levels both above or below an optimal range may be deleterious. Nevertheless, increased consanguinity and lack of data on the prevalence of deleterious EMC10 mutations among healthy individuals in these populations complicate interpretation of these findings.…”

Expanding EMC Foldopathies: Topogenesis Deficits Alter the Neural Crest

“…Because of the critical importance of the EMC in inserting transmembrane proteins, we wondered whether other variants in genes encoding EMC subunits might also contribute to early human disease. In our review of the literature, we focused on variants that where likely to disrupt protein function (protein truncations, frameshifts, or splicing disruptions) which included EMC9 and EMC10 (Table 1), prompting us to focus on these EMC components (Jin et al 2017; Shao et al 2021; Umair et al 2020). Patient phenotypes included congenital heart disease (CHD), neurodevelopmental delay (NDD), craniofacial dysmorphology (CFD), umbilical/inguinal hernias, renal anomalies, and limb abnormalities.…”

The Molecular Biodiversity of Protein Targeting and Protein Transport Related to the Endoplasmic Reticulum

“…Mutations in the subunits of the EMC are also related or causative for different diseases including neurological disorders or cancer. For instance, a defect of the EMC1 protein is related to visual disorders, craniofacial abnormalities, and epilepsy [ 416 , 417 ].A recessive loss of function related to the mutation of the EMC10 gene has been reported in patients with intellectual disabilities and developmental delay [ 418 ]. Interestingly, the overexpression of either EMC6 or EMC10 has been reported to provide anti-tumor activity in glioblastoma cells.…”