Monoallelic and Biallelic Variants in EMC1 Identified in Individuals with Global Developmental Delay, Hypotonia, Scoliosis, and Cerebellar Atrophy.

TitleMonoallelic and Biallelic Variants in EMC1 Identified in Individuals with Global Developmental Delay, Hypotonia, Scoliosis, and Cerebellar Atrophy.
Publication TypeJournal Article
Year of Publication2016
AuthorsHarel, T, Yesil, G, Bayram, Y, Coban-Akdemir, Z, Charng, W-L, Karaca, E, Asmari, AAl, Eldomery, MK, Hunter, JV, Jhangiani, SN, Rosenfeld, JA, Pehlivan, D, El-Hattab, AW, Saleh, MA, LeDuc, CA, Muzny, D, Boerwinkle, E, Gibbs, RA, Chung, WK, Yang, Y, Belmont, JW, Lupski, JR
Corporate AuthorsBaylor-Hopkins Center for Mendelian Genomics
JournalAm J Hum Genet
Date Published2016 Mar 03
KeywordsAdolescent, Alleles, Amino Acid Sequence, Atrophy, Cerebellum, Child, Child, Preschool, Developmental Disabilities, Endoplasmic Reticulum-Associated Degradation, Female, Genetic Association Studies, Genetic Variation, Heterozygote, Humans, Magnetic Resonance Imaging, Male, Membrane Proteins, Molecular Sequence Data, Muscle Hypotonia, Mutation, Pedigree, Protein Folding, Proteins, Scoliosis

The paradigm of a single gene associated with one specific phenotype and mode of inheritance has been repeatedly challenged. Genotype-phenotype correlations can often be traced to different mutation types, localization of the variants in distinct protein domains, or the trigger of or escape from nonsense-mediated decay. Using whole-exome sequencing, we identified homozygous variants in EMC1 that segregated with a phenotype of developmental delay, hypotonia, scoliosis, and cerebellar atrophy in three families. In addition, a de novo heterozygous EMC1 variant was seen in an individual with a similar clinical and MRI imaging phenotype. EMC1 encodes a member of the endoplasmic reticulum (ER)-membrane protein complex (EMC), an evolutionarily conserved complex that has been proposed to have multiple roles in ER-associated degradation, ER-mitochondria tethering, and proper assembly of multi-pass transmembrane proteins. Perturbations of protein folding and organelle crosstalk have been implicated in neurodegenerative processes including cerebellar atrophy. We propose EMC1 as a gene in which either biallelic or monoallelic variants might lead to a syndrome including intellectual disability and preferential degeneration of the cerebellum.

Alternate JournalAm J Hum Genet
PubMed ID26942288
PubMed Central IDPMC4800043
Grant ListU54 HG006542 / HG / NHGRI NIH HHS / United States
T32 GM007526 / GM / NIGMS NIH HHS / United States
U54HG006542 / HG / NHGRI NIH HHS / United States
T32 GM07526 / GM / NIGMS NIH HHS / United States
P30 DK026687 / DK / NIDDK NIH HHS / United States
R01 NS058529 / NS / NINDS NIH HHS / United States

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