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

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...

Full description

Saved in:
Bibliographic Details
Published inClinical genetics Vol. 103; no. 5; pp. 553 - 559
Main Authors Bryen, Samantha J., Zhang, Katharine, Dziaduch, Gregory, Bommireddipalli, Shobhana, Naseri, Take, Reupena, Muagututi'a Sefuiva, Viali, Satupa'itea, Minster, Ryan L., Waddell, Leigh B., Charlton, Amanda, O'Grady, Gina L., Evesson, Frances J., Cooper, Sandra T.
Format Journal Article
LanguageEnglish
Published Oxford, UK Blackwell Publishing Ltd 01.05.2023
Subjects
Atrophy
Atrophy - genetics
Cerebellum
deep intronic variant
EMC1
Endoplasmic reticulum
Genomes
Humans
Introns - genetics
Membrane proteins
Membrane Proteins - genetics
Mutation
Pathogenicity
Protein biosynthesis
pseudo‐exon
Reverse transcription
RNA Splicing - genetics
RT‐PCR
Splicing
Whole genome sequencing
pseudo-exon
deep intronic variant
EMC1
RT-PCR
Online AccessGet full text
ISSN0009-9163
1399-0004
1399-0004
DOI10.1111/cge.14311

Cover

More Information
Summary: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.
Bibliography:Funding information
Samantha J. Bryen and Katharine Zhang contributed equally to this work. Gina L. O'Grady, Frances J. Evesson, and Sandra T. Cooper contributed equally to this work.
Muscular Dystrophy Association; Muscular Dystrophy New South Wales; National Eye Institute; National Health and Medical Research Council; National Heart, Lung, and Blood Institute, Grant/Award Number: UM1 HG008900; National Human Genome Research Institute, Grant/Award Number: R01 HG009141; National Institutes of Health, Grant/Award Numbers: R01 HL093093, R01 HL133040, TOPMed program (R01 HL117626 02S1), U01 HL120393; contract HHSN268201800001I, contract HHSN268201800002I R01 HL120393
ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 14
content type line 23
R.L.M: Soifua Manuia study analysis of genomic data
T.N. M.S.R, S.V: Soifua Manuia study conceptualization, participant recruitment
L.B.W: Ethics, analysis of genomic data, manuscript editing
Author Contribution Statement
S.B: RNA studies
F.J.E: Project oversight and supervision, CRISPR/Cas9 gene editing, manuscript editing
G.L.O: Clinical data and management of family, analysis of genomic data, manuscript preparation
S.J.B: Genomic analyses, RNA studies, manuscript and figure preparation
G.D: Western blot
These authors contributed equally to this work
A.C: Skeletal muscle histopathology
S.T.C: Project oversight and supervision, analysis, manuscript editing
K.Z: Western blot, RNA studies, CRISPR/Cas9 gene editing, manuscript and figure preparation
ISSN:0009-9163
1399-0004
1399-0004
DOI:10.1111/cge.14311