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

Am J Hum Genet. 2016 Mar 3;98(3):562-570. doi: 10.1016/j.ajhg.2016.01.011.

Tamar Harel ¹, Gozde Yesil ², Yavuz Bayram ³, Zeynep Coban-Akdemir ³, Wu-Lin Charng ³, Ender Karaca ³, Ali Al Asmari ⁴, Mohammad K Eldomery ³, Jill V Hunter ⁵, Shalini N Jhangiani ⁶, Jill A Rosenfeld ⁷, Davut Pehlivan ³, Ayman W El-Hattab ⁸, Mohammed A Saleh ⁴, Charles A LeDuc ⁹, Donna Muzny ⁶, Eric Boerwinkle ¹⁰, Baylor-Hopkins Center for Mendelian Genomics, Richard A Gibbs ¹¹, Wendy K Chung ¹², Yaping Yang ⁷, John W Belmont ³, James R Lupski ¹³

Affiliations

1 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: [email protected].
2 Department of Medical Genetics, Bezmialem University, Istanbul 34093, Turkey.
3 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
4 Section of Medical Genetics, Children's Specialist Hospital, King Fahad Medical City, Riyadh 11525, Saudi Arabia.
5 Department of Pediatric Radiology, Texas Children's Hospital, Houston, TX 77030, USA.
6 Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
7 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Miraca Genetics Laboratories, Baylor College of Medicine, Houston, TX 77030, USA.
8 Division of Clinical Genetics and Metabolic Disorders, Department of Pediatrics, Tawam Hospital, Al-Ain 15258, United Arab Emirates.
9 Department of Pediatrics, Columbia University Medical Center, New York, NY 10032, USA.
10 Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Human Genetics Center, University of Texas Health Science Center, Houston, TX 77030, USA.
11 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
12 Departments of Pediatrics and Medicine, Columbia University Medical Center, New York, NY 10032, USA.
13 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston TX 77030, USA.

PMID: 26942288 DOI: 10.1016/j.ajhg.2016.01.011

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.

Keywords

EMC1; Whole-exome sequencing; cerebellar atrophy; endoplasmic reticulum (ER)-membrane complex; inter-organellar communication; intracellular transport; mitochondrial membrane; neurodegeneration.

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