title: Monoallelic and Biallelic Variants in EMC1 Identified in Individuals with Global Developmental Delay, Hypotonia, Scoliosis, and Cerebellar Atrophy.
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.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: tamar.harel@bcm.edu.
authors.forename: Tamar
authors.initials: T
authors.lastname: Harel
authors.affiliation: Department of Medical Genetics, Bezmialem University, Istanbul 34093, Turkey.
authors.forename: Gozde
authors.initials: G
authors.lastname: Yesil
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Yavuz
authors.initials: Y
authors.lastname: Bayram
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Coban-Akdemir
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Wu-Lin
authors.initials: WL
authors.lastname: Charng
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Ender
authors.initials: E
authors.lastname: Karaca
authors.affiliation: Section of Medical Genetics, Children's Specialist Hospital, King Fahad Medical City, Riyadh 11525, Saudi Arabia.
authors.forename: Ali
authors.initials: A
authors.lastname: Al Asmari
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Mohammad K
authors.initials: MK
authors.lastname: Eldomery
authors.affiliation: Department of Pediatric Radiology, Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: Jill V
authors.initials: JV
authors.lastname: Hunter
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Shalini N
authors.initials: SN
authors.lastname: Jhangiani
authors.affiliation: 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.
authors.forename: Jill A
authors.initials: JA
authors.lastname: Rosenfeld
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Davut
authors.initials: D
authors.lastname: Pehlivan
authors.affiliation: Division of Clinical Genetics and Metabolic Disorders, Department of Pediatrics, Tawam Hospital, Al-Ain 15258, United Arab Emirates.
authors.forename: Ayman W
authors.initials: AW
authors.lastname: El-Hattab
authors.affiliation: Section of Medical Genetics, Children's Specialist Hospital, King Fahad Medical City, Riyadh 11525, Saudi Arabia.
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Saleh
authors.affiliation: Department of Pediatrics, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Charles A
authors.initials: CA
authors.lastname: LeDuc
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Donna
authors.initials: D
authors.lastname: Muzny
authors.affiliation: 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.
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.affiliation: 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.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.affiliation: Departments of Pediatrics and Medicine, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Chung
authors.affiliation: 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.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Belmont
authors.affiliation: 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.
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
mesh_terms: D000293:Adolescent; D000483:Alleles; D000595:Amino Acid Sequence; D001284:Atrophy / Q000175:diagnosis / Q000235:genetics*; D002531:Cerebellum / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D002658:Developmental Disabilities / Q000175:diagnosis / Q000235:genetics*; D060746:Endoplasmic Reticulum-Associated Degradation; D005260:Female; D056726:Genetic Association Studies; D014644:Genetic Variation; D006579:Heterozygote; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D009123:Muscle Hypotonia / Q000175:diagnosis / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D017510:Protein Folding; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D012600:Scoliosis / Q000175:diagnosis / Q000235:genetics*
chemical_list: C543592:EMC10 protein, human; D008565:Membrane Proteins; D011506:Proteins
keywords: EMC1; Whole-exome sequencing; cerebellar atrophy; endoplasmic reticulum (ER)-membrane complex; inter-organellar communication; intracellular transport; mitochondrial membrane; neurodegeneration