A recurrent, homozygous EMC10 frameshift variant is associated with a syndrome of developmental delay with variable seizures and dysmorphic features
Year: 2021
Type: article
Study design: Observational Study
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.
Source: Genetics in Medicine
Authors: 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. Rento, Jiin 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
Institutions: Boston Children's Hospital, Tel Aviv University, Schneider Children's Medical Center, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, King Abdullah International Medical Research Center, National Guard Health Affairs, Harvard University, Howard Hughes Medical Institute, Centogene (Germany), Shaikh Khalifa Medical City, SingHealth, SingHealth Duke-NUS Academic Medical Centre, Duke-NUS Medical School, Harvard Stem Cell Institute, United Arab Emirates University, Tawam Hospital, Rabin Medical Center, New York University, University of California, San Francisco, Genetikum, University Hospital Ulm
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,900
Funders: Howard Hughes Medical Institute, Burroughs Wellcome Fund, Paul G. Allen Family Foundation, American Society of Nephrology, Yale University, PKD Australia, National Institutes of Health, Intellectual and Developmental Disabilities Research Center, Harvard Stem Cell Institute, Harvard Digestive Diseases Center, Harvard University, National Human Genome Research Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G1253130474, G1820584063, Research Training in Pediatric Nephrology, G2663813066, Yale Center for Mendelian Genomics, G309250844, G332990701, CH/BIDMC/Harvard Medical School Neurology Resident Research Education Program, Role for ion conducting proteins in cortical malformation diseases, G4209679750, Human Epilepsy Genetics - Neuronal Migration Disorders, Molecular mechanism for retrograde transport of tetanus neurotoxin, Boston Intellectual and Developmental Disabilities Research Center, G5857948765, Intellectual and Developmental Disablities Research Center, Novel genetics, pathobiology and therapy of nephronophthisis-related ciliopathies, NHGRI Genome Sequencing Program Coordinating Center, Delineation of pathogenic mechanisms of NOS1AP and TRIM8 mutations in monogenic SRNS/FSGS., Integrated Epithelial and Muscosal Biology, Biology and Engineering of Botulinum Neurotoxins.
OpenAlex ID: W3126236318