Title | Monoallelic and Biallelic Variants in EMC1 Identified in Individuals with Global Developmental Delay, Hypotonia, Scoliosis, and Cerebellar Atrophy. |
Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | Harel 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 |
Secondary Authors | Lupski JR |
Corporate Authors | Baylor-Hopkins Center for Mendelian Genomics |
Journal | Am J Hum Genet |
Volume | 98 |
Issue | 3 |
Pagination | 562-570 |
Date Published | 2016 Mar 03 |
ISSN | 1537-6605 |
Keywords | Adolescent, 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, Molecular Sequence Data, Muscle Hypotonia, Mutation, Pedigree, Protein Folding, Proteins, Scoliosis |
Abstract | 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. |
DOI | 10.1016/j.ajhg.2016.01.011 |
Alternate Journal | Am J Hum Genet |
PubMed ID | 26942288 |
PubMed Central ID | PMC4800043 |
Grant List | U54 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 |