Genetics in medicine : official journal of the American College of Medical Genetics · 2021
Variants in PRKAR1B cause a neurodevelopmental disorder with autism spectrum disorder, apraxia, and insensitivity to pain.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Marbach Felix, Stoyanov Georgi, Erger Florian, Stratakis Constantine A, Settas Nikolaos, London Edra, Rosenfeld Jill A, Torti Erin, Haldeman-Englert Chad, Sklirou Evgenia, Kessler Elena, Ceulemans Sophia, Nelson Stanley F, Martinez-Agosto Julian A, Palmer Christina G S, Signer Rebecca H, Undiagnosed Diseases Network, Andrews Marisa V, Grange Dorothy K, Willaert Rebecca, Person Richard, Telegrafi Aida, Sievers Aaron, Laugsch Magdalena, Theiß Susanne, Cheng YuZhu, Lichtarge Olivier, Katsonis Panagiotis, Stocco Amber, Schaaf Christian P
Аннотация
PURPOSE: We characterize the clinical and molecular phenotypes of six unrelated individuals with intellectual disability and autism spectrum disorder who carry heterozygous missense variants of the PRKAR1B gene, which encodes the R1β subunit of the cyclic AMP-dependent protein kinase A (PKA).
METHODS: Variants of PRKAR1B were identified by single- or trio-exome analysis. We contacted the families and physicians of the six individuals to collect phenotypic information, performed in vitro analyses of the identified PRKAR1B-variants, and investigated PRKAR1B expression during embryonic development.
RESULTS: Recent studies of large patient cohorts with neurodevelopmental disorders found significant enrichment of de novo missense variants in PRKAR1B. In our cohort, de novo origin of the PRKAR1B variants could be confirmed in five of six individuals, and four carried the same heterozygous de novo variant c.1003C>T (p.Arg335Trp; NM_001164760). Global developmental delay, autism spectrum disorder, and apraxia/dyspraxia have been reported in all six, and reduced pain sensitivity was found in three individuals carrying the c.1003C>T variant. PRKAR1B expression in the brain was demonstrated during human embryonal development. Additionally, in vitro analyses revealed altered basal PKA activity in cells transfected with variant-harboring PRKAR1B expression constructs.
CONCLUSION: Our study provides strong evidence for a PRKAR1B-related neurodevelopmental disorder.
METHODS: Variants of PRKAR1B were identified by single- or trio-exome analysis. We contacted the families and physicians of the six individuals to collect phenotypic information, performed in vitro analyses of the identified PRKAR1B-variants, and investigated PRKAR1B expression during embryonic development.
RESULTS: Recent studies of large patient cohorts with neurodevelopmental disorders found significant enrichment of de novo missense variants in PRKAR1B. In our cohort, de novo origin of the PRKAR1B variants could be confirmed in five of six individuals, and four carried the same heterozygous de novo variant c.1003C>T (p.Arg335Trp; NM_001164760). Global developmental delay, autism spectrum disorder, and apraxia/dyspraxia have been reported in all six, and reduced pain sensitivity was found in three individuals carrying the c.1003C>T variant. PRKAR1B expression in the brain was demonstrated during human embryonal development. Additionally, in vitro analyses revealed altered basal PKA activity in cells transfected with variant-harboring PRKAR1B expression constructs.
CONCLUSION: Our study provides strong evidence for a PRKAR1B-related neurodevelopmental disorder.