biostudies-literatureBryen SJNational Eye InstituteNHLBI NIH HHSNational Heart, Lung, and Blood InstituteNHGRI NIH HHSNational Health and Medical Research CouncilNational Institutes of HealthNational Human Genome Research InstituteMuscular Dystrophy Association553-559https://www.ebi.ac.uk/biostudies/studies/S-EPMC10101692biostudies-literatureUnknown103(5)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.Clinical geneticsCompound heterozygous splicing variants expand the genotypic spectrum of EMC1-related disorders.PMC10101692U01 HL120393HHSN268201800001CR01 HL093093R01 HL120393R01 HL117626R01 HG009141R01 HL133040contract HHSN268201800002I R01 HL120393U01 HL120393; contract HHSN268201800001ITOPMed program (R01 HL117626 02S1)UM1 HG008900Reupena MSZhang KCooper STNaseri TViali SDziaduch GEvesson FJBryen SJBommireddipalli SMinster RLO'Grady GLWaddell LBCharlton AfalseCompound 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 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.2023-01-01T00:00:00Z2023 May2026-05-28T21:57:03.096Z2026-04-08T03:19:13.369ZS-EPMC101016923679955710.1111/cge.14311