小头畸形
错义突变
表型
外显子组测序
生物
遗传学
外显子组
癫痫
基因
神经发育障碍
神经科学
作者
Gianluca D’Onofrio,Claudia Cuccurullo,Silje Kathrine Larsen,Mariasavina Severino,Alessandra D’Amico,Kirsten Brønstad,Mohammed Al‐Owain,Jennifer L. Morrison,Patricia G. Wheeler,Bryn D. Webb,Abdullah Alfalah,Michele Iacomino,Paolo Uva,Antonietta Coppola,Giuseppe Merla,Vincenzo Salpietro,Federico Zara,Pasquale Striano,Andrea Accogli,Thomas Arnesen,Leonilda Bilo
摘要
NAA20 is the catalytic subunit of the NatB complex, which is responsible for N-terminal acetylation of approximately 20% of the human proteome. Recently, pathogenic biallelic variants in NAA20 were associated with a novel neurodevelopmental disorder in five individuals with limited clinical information. We report two sisters harboring compound heterozygous variant (c.100C>T (p.Gln34Ter) and c.11T>C p.(Leu4Pro)) in the NAA20 gene, identified by exome sequencing. In vitro studies showed that the missense variant p.Leu4Pro resulted in a reduction of NAA20 catalytic activity due to weak coupling with the NatB auxiliary subunit. In addition, unpublished data of the previous families were reported, outlining the core phenotype of the NAA20-related disorder mostly characterized by cognitive impairment, microcephaly, ataxia, brain malformations, dysmorphism and variable occurrence of cardiac defect and epilepsy. Remarkably, our two patients featured epilepsy onset in adolescence suggesting this may be a part of syndrome evolution. Functional studies are needed to better understand the complexity of NAA20 variants pathogenesis as well as of other genes linked to N-terminal acetylation.
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