{"doi":"10.1016/j.gim.2023.101057","title":"Biallelic loss-of-function variants in CACHD1 cause a novel neurodevelopmental syndrome with facial dysmorphism and multisystem congenital abnormalities","abstract":"PURPOSE: We established the genetic etiology of a syndromic neurodevelopmental condition characterized by variable cognitive impairment, recognizable facial dysmorphism, and a constellation of extra-neurological manifestations. METHODS: We performed phenotypic characterization of 6 participants from 4 unrelated families presenting with a neurodevelopmental syndrome and used exome sequencing to investigate the underlying genetic cause. To probe relevance to the neurodevelopmental phenotype and craniofacial dysmorphism, we established two- and three-dimensional human stem cell-derived neural models and generated a stable cachd1 zebrafish mutant on a transgenic cartilage reporter line. RESULTS: Affected individuals showed mild cognitive impairment, dysmorphism featuring oculo-auriculo abnormalities, and developmental defects involving genitourinary and digestive tracts. Exome sequencing revealed biallelic putative loss-of-function variants in CACHD1 segregating with disease in all pedigrees. RNA sequencing in CACHD1-depleted neural progenitors revealed abnormal expression of genes with key roles in Wnt signaling, neurodevelopment, and organ morphogenesis. CACHD1 depletion in neural progenitors resulted in reduced percentages of post-mitotic neurons and enlargement of 3D neurospheres. Homozygous cachd1 mutant larvae showed mandibular patterning defects mimicking human facial dysmorphism. CONCLUSION: Our findings support the role of loss-of-function variants in CACHD1 as the cause of a rare neurodevelopmental syndrome with facial dysmorphism and multisystem abnormalities.","journal":"Genetics in Medicine","year":2023,"id":348946,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":11,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9505,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":362321,"name":"Kamal Khan","orcid":"0000-0002-8366-4237","position":1,"is_corresponding":false},{"id":863488,"name":"Claire Bénéteau","orcid":"0000-0002-1682-523X","position":2,"is_corresponding":false},{"id":553432,"name":"Rachel Fox","orcid":"0000-0001-6265-2256","position":3,"is_corresponding":false},{"id":640168,"name":"Sandra von Hardenberg","orcid":"0000-0002-3680-7450","position":4,"is_corresponding":false},{"id":1091701,"name":"Ayaz Khan","orcid":"0000-0002-4743-7387","position":5,"is_corresponding":false},{"id":945034,"name":"Madeleine Joubert","orcid":"0000-0002-6270-4885","position":6,"is_corresponding":false},{"id":348151,"name":"Lorraine Fievet","orcid":"0000-0002-0332-3417","position":7,"is_corresponding":false},{"id":1092171,"name":"Marie Denis Musquer","orcid":null,"position":8,"is_corresponding":false},{"id":1091702,"name":"Claudine Le Vaillant","orcid":"0000-0001-5547-3575","position":9,"is_corresponding":false},{"id":537953,"name":"Julie Korda Holsclaw","orcid":"0000-0002-5654-9938","position":10,"is_corresponding":false},{"id":919490,"name":"Derek Lim","orcid":"0000-0002-6915-1363","position":11,"is_corresponding":false},{"id":1091703,"name":"Ann-Cathrine Berking","orcid":"0000-0003-2658-4211","position":12,"is_corresponding":false},{"id":465610,"name":"Andrea Accogli","orcid":"0000-0001-8724-6721","position":13,"is_corresponding":false},{"id":865578,"name":"Thea Giacomini","orcid":"0000-0002-7802-8789","position":14,"is_corresponding":false},{"id":865583,"name":"Lino Nobili","orcid":"0000-0001-9317-5405","position":15,"is_corresponding":false},{"id":52257,"name":"Pasquale Striano","orcid":null,"position":16,"is_corresponding":false},{"id":473779,"name":"Federico Zara","orcid":"0000-0001-9744-5222","position":17,"is_corresponding":false},{"id":338857,"name":"Annalaura Torella","orcid":"0000-0003-2479-6018","position":18,"is_corresponding":false},{"id":338856,"name":"Vincenzo Nigro","orcid":"0000-0002-3378-5006","position":19,"is_corresponding":false},{"id":242569,"name":"Benjamin Cogné","orcid":"0000-0002-5503-6292","position":20,"is_corresponding":false},{"id":395303,"name":"Max R. 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