Publication: Monoallelic and Biallelic Variants in EMC1 Identified in Individuals with Global Developmental Delay, Hypotonia, Scoliosis, and Cerebellar Atrophy
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Date
2016-03-03
Authors
Authors
Harel, Tamar
YEŞİL, GÖZDE
Bayram, Yavuz
Coban-Akdemir, Zeynep
Charng, Wu-Lin
Karaca, Ender
Al Asmari, Ali
Eldomery, Mohammad K.
Hunter, Jill V.
Jhangiani, Shalini N.
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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.
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Keywords
EMC1, Whole-exome sequencing, cerebellar atrophy, endoplasmic reticulum (ER), membrane complex, inter-organellar communication, intracellular transport, mitochondrial membrane, neurodegeneration
Citation
Harel T., YEŞİL G., Bayram Y., Coban-Akdemir Z., Charng W., Karaca E., Al Asmari A., Eldomery M. K. , Hunter J. V. , Jhangiani S. N. , et al., -Monoallelic and Biallelic Variants in EMC1 Identified in Individuals with Global Developmental Delay, Hypotonia, Scoliosis, and Cerebellar Atrophy-, American Journal of Human Genetics, cilt.98, ss.562-570, 2016