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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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>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 one cell type.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Exome sequencing identified de novo variants in EMC1 in three individuals affected by global developmental delay, hypotonia, seizures, visual impairment and cerebellar atrophy. All variants were located at Pro582 or Pro584. Drosophila studies indicated that imbalance of EMC1\u2014either overexpression or knockdown\u2014results in pupal lethality and suggest that the tested homologous variants are LoF alleles. In addition, glia-specific gene dosage, overexpression or knockdown, of EMC1 led to lethality, whereas neuron-specific alterations were tolerated.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Discussion<\/jats:title>\n                  <jats:p>We establish de novo monoallelic EMC1 variants as causative of a neurological disease trait by providing functional evidence in a Drosophila model. The identified variants failed to rescue the lethality of a null allele. Variations in dosage of the wild-type EMC1, specifically in glia, lead to pupal lethality, which we hypothesize results from the altered stoichiometry of the multi-subunit protein complex EMC.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/hmg\/ddac053","type":"journal-article","created":{"date-parts":[[2022,3,1]],"date-time":"2022-03-01T04:11:27Z","timestamp":1646107887000},"page":"3231-3244","source":"Crossref","is-referenced-by-count":16,"title":["De novo variants in <i>EMC1<\/i> lead to neurodevelopmental delay and cerebellar degeneration and affect glial function in <i>Drosophila<\/i>"],"prefix":"10.1093","volume":"31","author":[{"given":"Hyung-Lok","family":"Chung","sequence":"first","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine , Houston, TX 77030 , USA"},{"name":"Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital , Houston, TX 77030 , USA"},{"name":"Howard Hughes Medical Institute, Baylor College of Medicine , Houston, TX 77030 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick","family":"Rump","sequence":"additional","affiliation":[{"name":"University of Groningen, University Medical Centre Groningen , Department of Genetics, Groningen 9700 RB , The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Di","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine , Houston, TX 77030 , USA"},{"name":"Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital , Houston, TX 77030 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Megan R","family":"Glassford","sequence":"additional","affiliation":[{"name":"Division of Pediatric Genetics , Metabolism & Genomic Medicine, , Ann Arbor, MI 48109 , USA"},{"name":"University of Michigan Medical School , Metabolism & Genomic Medicine, , Ann Arbor, MI 48109 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jung-Wan","family":"Mok","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine , Houston, TX 77030 , USA"},{"name":"Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital , Houston, TX 77030 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jawid","family":"Fatih","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine , Houston, TX 77030 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adily","family":"Basal","sequence":"additional","affiliation":[{"name":"Department of Genetics, Hadassah Medical Organization , Jerusalem 9112001 , Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul C","family":"Marcogliese","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine , Houston, TX 77030 , USA"},{"name":"Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital , Houston, TX 77030 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oguz","family":"Kanca","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine , Houston, TX 77030 , USA"},{"name":"Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital , Houston, TX 77030 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michele","family":"Rapp","sequence":"additional","affiliation":[{"name":"University of Colorado Anschutz Medical Campus , Aurora, CO 60045 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johanna M","family":"Fock","sequence":"additional","affiliation":[{"name":"University of Groningen, University Medical Centre Groningen , Department of Neurology, Groningen 9700 RB , The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erik-Jan","family":"Kamsteeg","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Radboud University Medical Centre , Nijmegen 6500 HB , The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James R","family":"Lupski","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine , Houston, TX 77030 , USA"},{"name":"Human Genome Sequencing Center, Baylor College of Medicine , Houston, TX 77030 , USA"},{"name":"Department of Pediatrics, Texas Children's Hospital , Houston, TX 77030 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Austin","family":"Larson","sequence":"additional","affiliation":[{"name":"University of Colorado School of Medicine and Children's Hospital Colorado , Aurora, CO 60045 , United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark 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