biostudies-literatureChung HLNational Institute of Neurological Disorders and StrokeBaylor-Hopkins Center for Mendelian GenomicsNHGRI NIH HHSNINDS NIH HHSNational Institutes of HealthNational Heart Lung and Blood InstituteNational Human Genome Research InstituteNIH HHSWarren Alpert FoundationCIHR3231-3244https://www.ebi.ac.uk/biostudies/studies/S-EPMC9523557biostudies-literatureUnknown31(19)<h4>Background</h4>The endoplasmic reticulum (ER)-membrane protein complex (EMC) is a multi-protein transmembrane complex composed of 10 subunits that functions as a membrane-protein chaperone. Variants in EMC1 lead to neurodevelopmental delay and cerebellar degeneration. Multiple families with biallelic variants have been published, yet to date, only a single report of a monoallelic variant has been described, and functional evidence is sparse.<h4>Methods</h4>Exome sequencing was used to investigate the genetic cause underlying severe developmental delay in three unrelated children. EMC1 variants were modeled in Drosophila, using loss-of-function (LoF) and overexpression studies. Glial-specific and neuronal-specific assays were used to determine whether the dysfunction was specific to oneHuman molecular geneticsDe novo variants in EMC1 lead to neurodevelopmental delay and cerebellar degeneration and affect glial function in Drosophila.PMC9523557U01 HG007703UM1 HG006542R24 OD031447R35 NS105078R24 OD022005R35NS105078P50HD103555MFE-164712Chung HLBasal AMarcogliese PCRapp MRump PHarel TLu DFatih JKanca OFock JMLarson AMok JWHaninbal MCLupski JRBellen HGlassford MRKamsteeg EJfalseDe novo variants in EMC1 lead to neurodevelopmental delay and cerebellar degeneration and affect glial function in Drosophila.<h4>Background</h4>The endoplasmic reticulum (ER)-membrane protein complex (EMC) is a multi-protein transmembrane complex composed of 10 subunits that functions as a membrane-protein chaperone. Variants in EMC1 lead to neurodevelopmental delay and cerebellar degeneration. Multiple families with biallelic variants have been published, yet to date, only a single report of a monoallelic variant has been described, and functional evidence is sparse.<h4>Methods</h4>Exome sequencing was used to investigate the genetic cause underlying severe developmental delay in three unrelated children. EMC1 variants were modeled in Drosophila, using loss-of-function (LoF) and overexpression studies. Glial-specific and neuronal-specific assays were used to determine whether the dysfunction was specific to one2022-01-01T00:00:00Z2022 Sep2026-05-27T21:06:26.128Z2025-04-25T17:08:16.593ZS-EPMC95235573523490110.1093/hmg/ddac053