[PDF][PDF] Monoallelic and biallelic variants in EMC1 identified in individuals with global developmental delay, hypotonia, scoliosis, and cerebellar atrophy

T Harel, G Yesil, Y Bayram, Z Coban-Akdemir… - The American Journal of …, 2016 - cell.com
T Harel, G Yesil, Y Bayram, Z Coban-Akdemir, WL Charng, E Karaca, A Al Asmari…
The American Journal of Human Genetics, 2016cell.com
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 …
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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