Monoallelic and Biallelic Variants in EMC1 Identified in Individuals with Global Developmental Delay, Hypotonia, Scoliosis, and Cerebellar Atrophy

• Published in: American journal of human genetics Vol. 98; no. 3; pp. 562 - 570
• Main Authors: Harel, Tamar, Yesil, Gozde, Bayram, Yavuz, Coban-Akdemir, Zeynep, Charng, Wu-Lin, Karaca, Ender, Al Asmari, Ali, Eldomery, Mohammad K., Hunter, Jill V., Jhangiani, Shalini N., Rosenfeld, Jill A., Pehlivan, Davut, El-Hattab, Ayman W., Saleh, Mohammed A., LeDuc, Charles A., Muzny, Donna, Boerwinkle, Eric, Gibbs, Richard A., Chung, Wendy K., Yang, Yaping, Belmont, John W., Lupski, James R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.03.2016; Cell Press; Elsevier
• Subjects: Adolescent; Alleles; Amino Acid Sequence; Atrophy - diagnosis; Atrophy - genetics; cerebellar atrophy; Cerebellum - pathology; Child; Child, Preschool; Developmental Disabilities - diagnosis; Developmental Disabilities - genetics; EMC1; endoplasmic reticulum (ER)-membrane complex; Endoplasmic Reticulum-Associated Degradation; Female; Genetic Association Studies; Genetic Variation; Genotype & phenotype; Heterozygote; Humans; inter-organellar communication; intracellular transport; Magnetic Resonance Imaging; Male; Mitochondria; mitochondrial membrane; Molecular Sequence Data; Muscle Hypotonia - diagnosis; Muscle Hypotonia - genetics; Mutation; neurodegeneration; NMR; Nuclear magnetic resonance; Pedigree; Protein Folding; Proteins - genetics; Proteins - metabolism; Scoliosis - diagnosis; Scoliosis - genetics; Whole-exome sequencing; endoplasmic reticulum (ER)-membrane complex; intracellular transport; Whole-exome sequencing; EMC1; inter-organellar communication; mitochondrial membrane; neurodegeneration; cerebellar atrophy
• ISSN: 0002-9297; 1537-6605; 1537-6605
• DOI: 10.1016/j.ajhg.2016.01.011

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.