{"doi":"10.1101/2020.09.10.20190314","title":"Variants in <i>PRKAR1B</i> cause a neurodevelopmental disorder with autism spectrum disorder,apraxia, and insensitivity to pain","abstract":"Abstract Purpose We characterize the phenotypes of six unrelated individuals with intellectual disability and autism spectrum disorder, who carry heterozygous missense-variants of the PRKAR1B gene. Methods Variants of PRKAR1B were identified by single-exome or trio-exome analysis. We contacted the families and physicians of the six individuals in order to collect clinical and phenotypic information. Results PRKAR1B encodes the R1β subunit of the cyclic AMP-dependent protein kinase A (PKA), and is predominantly expressed in the central nervous system. Recent studies of patient cohorts with neurodevelopmental disorders found significant enrichment of de novo missense variants in PRKAR1B , and in vivo studies of the murine ortholog demonstrated altered hippocampal function and reduced neurogenic inflammation and long-term nociceptive pain in R1β-deficient mice. In our study, de novo origin of the PRKAR1B -variants could be confirmed in five out of six individuals, and four carried the same heterozygous de novo variant c.1003C&gt;T (p. Arg335Trp; NM_001164760). Global developmental delay, autism spectrum disorder, and apraxia/dyspraxia has been reported in all six, and reduced pain sensitivity was found in three individuals carrying the c.1003C&gt;T variant. Conclusion Our study provides strong evidence for a novel, PRKAR1B -related neurodevelopmental disorder.","journal":"medRxiv","year":2020,"id":127358,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9502,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":576663,"name":"Georgi Stoyanov","orcid":null,"position":1,"is_corresponding":false},{"id":307791,"name":"Florian Erger","orcid":"0000-0002-2768-1702","position":2,"is_corresponding":false},{"id":15091,"name":"Jill A. 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Palmer","orcid":"0009-0005-6253-8425","position":11,"is_corresponding":false},{"id":23575,"name":"Rebecca Signer","orcid":"0000-0001-8564-4267","position":12,"is_corresponding":false},{"id":276384,"name":"Undiagnosed Diseases Network","orcid":null,"position":13,"is_corresponding":false},{"id":576067,"name":"Marisa V. Andrews","orcid":"0000-0002-5448-1204","position":14,"is_corresponding":false},{"id":286592,"name":"Dorothy K. 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