%0 Journal Article %J Am J Hum Genet %D 2016 %T Monoallelic and Biallelic Variants in EMC1 Identified in Individuals with Global Developmental Delay, Hypotonia, Scoliosis, and Cerebellar Atrophy. %A Harel, Tamar %A Yesil, Gozde %A Bayram, Yavuz %A Coban-Akdemir, Zeynep %A Charng, Wu-Lin %A Karaca, Ender %A Al Asmari, Ali %A Eldomery, Mohammad K %A Hunter, Jill V %A Jhangiani, Shalini N %A Rosenfeld, Jill A %A Pehlivan, Davut %A El-Hattab, Ayman W %A Saleh, Mohammed A %A LeDuc, Charles A %A Muzny, Donna %A Boerwinkle, Eric %A Gibbs, Richard A %A Chung, Wendy K %A Yang, Yaping %A Belmont, John W %A Lupski, James R %K Adolescent %K Alleles %K Amino Acid Sequence %K Atrophy %K Cerebellum %K Child %K Child, Preschool %K Developmental Disabilities %K Endoplasmic Reticulum-Associated Degradation %K Female %K Genetic Association Studies %K Genetic Variation %K Heterozygote %K Humans %K Magnetic Resonance Imaging %K Male %K Membrane Proteins %K Molecular Sequence Data %K Muscle Hypotonia %K Mutation %K Pedigree %K Protein Folding %K Proteins %K Scoliosis %X

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.

%B Am J Hum Genet %V 98 %P 562-570 %8 2016 Mar 03 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/26942288?dopt=Abstract %R 10.1016/j.ajhg.2016.01.011