AUTHOR=Park Soojin , Jang Se Song , Lee Seungbok , Kim Minsoo , Sim Hyungtai , Jeon Hyeongseok , Hong Sung Eun , Lee Jean , Lee Jeongeun , Jeon Eun Young , Lee Jeongha , Lee Cho-Rong , Kim Soo Yeon , Kim Man Jin , Yoon Jihoon G. , Lim Byung Chan , Kim Woo Joong , Kim Ki Joong , Ko Jung Min , Cho Anna , Lee Jin Sook , Choi Murim , Chae Jong-Hee TITLE=Systematic analysis of inheritance pattern determination in genes that cause rare neurodevelopmental diseases JOURNAL=Frontiers in Genetics VOLUME=13 YEAR=2022 URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2022.990015 DOI=10.3389/fgene.2022.990015 ISSN=1664-8021 ABSTRACT=

Despite recent advancements in our understanding of genetic etiology and its molecular and physiological consequences, it is not yet clear what genetic features determine the inheritance pattern of a disease. To address this issue, we conducted whole exome sequencing analysis to characterize genetic variants in 1,180 Korean patients with neurological symptoms. The diagnostic yield for definitive pathogenic variant findings was 50.8%, after including 33 cases (5.9%) additionally diagnosed by reanalysis. Of diagnosed patients, 33.4% carried inherited variants. At the genetic level, autosomal recessive-inherited genes were characterized by enrichments in metabolic process, muscle organization and metal ion homeostasis pathways. Transcriptome and interactome profiling analyses revealed less brain-centered expression and fewer protein-protein interactions for recessive genes. The majority of autosomal recessive genes were more tolerant of variation, and functional prediction scores of recessively-inherited variants tended to be lower than those of dominantly-inherited variants. Additionally, we were able to predict the rates of carriers for recessive variants. Our results showed that genes responsible for neurodevelopmental disorders harbor different molecular mechanisms and expression patterns according to their inheritance patterns. Also, calculated frequency rates for recessive variants could be utilized to pre-screen rare neurodevelopmental disorder carriers.