Monoallelic and Biallelic Variants in EMC1 Identified in Individuals with Global Developmental Delay, Hypotonia, Scoliosis, and Cerebellar Atrophy
Date
2016-03-03Author
Boerwinkle, EricSaleh, Mohammed A.
Leduc, Charles A.
Muzny, Donna
Gibbs, Richard A.
YEŞİL, GÖZDE
Eldomery, Mohammad K.
Lupski, James R.
Belmont, John W.
Yang, Yaping
Chung, Wendy K.
Harel, Tamar
Bayram, Yavuz
Coban-Akdemir, Zeynep
Charng, Wu-Lin
Karaca, Ender
Al Asmari, Ali
Hunter, Jill V.
Jhangiani, Shalini N.
Rosenfeld, Jill A.
Pehlivan, Davut
El-Hattab, Ayman W.
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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.
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