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

Diane D. Shao, Rachel Straussberg, Hind Ahmed, Amjad Khan, Songhai Tian, R. Sean Hill, Richard S. Smith, Amar J. Majmundar, Najim Ameziane, Jennifer E. Neil, Edward Yang, Amal Al Tenaiji, Saumya S. Jamuar, Thorsten M. Schlaeger, Muna Al-Saffar, Iris Hovel, Aisha Al-Shamsi, Lina Basel-Salmon, Achiya Z. Amir, Lariza M. RentoJiin Ying Lim, Indra Ganesan, Shirlee Shril, Gilad Evrony, A. James Barkovich, Peter Bauer, Friedhelm Hildebrandt, Min Dong, Guntram Borck, Christian Beetz, Lihadh Al-Gazali, Wafaa Eyaid, Christopher A. Walsh*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1158-1162
Number of pages5
JournalGenetics in Medicine
Volume23
Issue number6
DOIs
StatePublished - Jun 2021
Externally publishedYes

ASJC Scopus subject areas

  • Genetics(clinical)

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