Compound heterozygous splicing variants expand the genotypic spectrum of EMC1-related disorders.

Autor: Bryen SJ; Kids Neuroscience Centre, The Children's Hospital at Westmead, New South Wales, Australia.; School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, New South Wales, Australia., Zhang K; Kids Neuroscience Centre, The Children's Hospital at Westmead, New South Wales, Australia.; Functional Neuromics, Children's Medical Research Institute, Westmead, New South Wales, Australia., Dziaduch G; Kids Neuroscience Centre, The Children's Hospital at Westmead, New South Wales, Australia.; Functional Neuromics, Children's Medical Research Institute, Westmead, New South Wales, Australia., Bommireddipalli S; Kids Neuroscience Centre, The Children's Hospital at Westmead, New South Wales, Australia.; School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, New South Wales, Australia., Naseri T; Ministry of Health, Apia, Samoa.; International Health Institute, School of Public Health, Brown University, Providence, Rhode Island, USA., Reupena MS; Lutia i Puava 'ae Mapu i Fagalele, Apia, Samoa., Viali S; School of Medicine, National University of Samoa, Apia, Samoa., Minster RL; Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Waddell LB; Kids Neuroscience Centre, The Children's Hospital at Westmead, New South Wales, Australia.; School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, New South Wales, Australia., Charlton A; Auckland City Hospital, University of Auckland, Auckland, New Zealand., O'Grady GL; Kids Neuroscience Centre, The Children's Hospital at Westmead, New South Wales, Australia.; School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, New South Wales, Australia.; Paediatric Neuroservices, Starship Child Health, Auckland, New Zealand., Evesson FJ; Kids Neuroscience Centre, The Children's Hospital at Westmead, New South Wales, Australia.; Functional Neuromics, Children's Medical Research Institute, Westmead, New South Wales, Australia., Cooper ST; Kids Neuroscience Centre, The Children's Hospital at Westmead, New South Wales, Australia.; School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, New South Wales, Australia.; Functional Neuromics, Children's Medical Research Institute, Westmead, New South Wales, Australia.
Jazyk: angličtina
Zdroj: Clinical genetics [Clin Genet] 2023 May; Vol. 103 (5), pp. 553-559. Date of Electronic Publication: 2023 Feb 27.
DOI: 10.1111/cge.14311
Abstrakt: EMC1 encodes subunit 1 of the endoplasmic reticulum (ER) membrane protein complex (EMC), a transmembrane domain insertase involved in membrane protein biosynthesis. Variants in EMC1 are described as a cause of global developmental delay, hypotonia, cortical visual impairment, and commonly, cerebral atrophy on MRI scan. We report an individual with severe global developmental delay and progressive cerebellar atrophy in whom exome sequencing identified a heterozygous essential splice-site variant in intron-3 of EMC1 (NM_015047.3:c.287-1G>A). Whole genome sequencing (WGS) identified a deep intronic variant in intron-20 of EMC1 (NM_015047.3:c.2588-771C>G) that was poorly predicted by in silico programs to disrupt pre-mRNA splicing. Reverse Transcription-PCR (RT-PCR) revealed stochastic activation of a pseudo-exon associated with the c.2588-771C>G variant and mis-splicing arising from the c.287-1G>A variant. This case highlights the utility of WGS and RNA studies to identify and assess likely pathogenicity of deep intronic variants and expands the genotypic and phenotypic spectrum of EMC1-related disorders.
(© 2023 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)
Databáze: MEDLINE
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