A pediatric case of productive cough caused by novel variants in DNAH9

We report the first Japanese case of primary ciliary dyskinesia caused by DNAH9 variations. The patient, a 5-year-old girl, had repeated episodes of productive cough after contracting the common cold at the age of 1 year and 6 months. She did not have a situs abnormality or congenital heart defect. We identified two novel DNAH9 variants, NM_001372.3: c. [1298C>G];[5547_5550delTGAC], (p.[Ser433Cys];[Asp1850fs])

Attitudes toward and current status of disclosure of secondary findings from next-generation sequencing: a nation-wide survey of clinical genetics professionals in Japan

The management of secondary findings (SFs), which are beyond the intended purpose of the analysis, from clinical comprehensive genomic analysis using next generation sequencing (NGS) presents challenges. Policy statements regarding their clinical management have been announced in Japan and other countries. In Japan, however, the current status of and attitudes of clinical genetics professionals toward reporting them are unclear. We conducted a questionnaire survey of clinical genetics professionals at two time points (2013 and 2019) to determine the enforcement of the SF management policy in cases of comprehensive genetic analysis of intractable diseases and clinical cancer genome profiling testing. According to the survey findings, 40% and 70% of the respondents stated in the 2013 and 2019 surveys, respectively, that they had an SF policy in the field of intractable diseases, indicating that SF policy awareness in Japan has changed significantly in recent years. Furthermore, a total of 80% of respondents stated that their facility had established a policy for clinical cancer genome profiling testing in the 2019 survey. In both surveys, the policies included the selection criteria for genes to be disclosed and the procedure to return SFs, followed by recommendations and proposals regarding SFs in Japan and other countries. To create a better list of the genes to be disclosed, further examination is needed considering the characteristics of each analysis

NFKB1 and MANBA Confer Disease Susceptibility to Primary Biliary Cholangitis via Independent Putative Primary Functional VariantsSummary

Background & Aims: Primary biliary cholangitis (PBC) is a chronic and cholestatic liver disease that eventually leads to cirrhosis and hepatic failure. We recently identified several susceptibility genes included NFKB1 and MANBA for PBC in the Japanese population by genome-wide association study. However, the primary functional variants in the NFKB1/MANBA region and the molecular mechanism for conferring disease susceptibility to PBC have not yet been clarified. Methods: We performed high-density association mapping based on a single-nucleotide polymorphism (SNP) imputation analysis, using data from a whole-genome sequence reference panel of 1070 Japanese individuals and the previous genome-wide association study (1389 PBC patients, 1508 healthy controls). Among SNPs (P < 5.0 × 10-7) in the NFKB1/MANBA region, putative primary functional variants and the molecular mechanism for conferring disease susceptibility to PBC were identified by in silico/in vitro functional analysis. Results: Among the SNPs in the NFKB1/MANBA region, rs17032850 and rs227361, which changed the binding of transcription factors lymphoid enhancer-binding factor 1 (LEF-1) and retinoid X receptor α (RXRα), respectively, were identified as putative primary functional variants that regulate gene expression. In addition, expression-quantitative trait locus data and gene editing using a clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 system supported the potential role of rs17032850 and rs227361 in regulating NFKB1 and MANBA expression, respectively. Conclusions: We identified independent putative primary functional variants in NFKB1/MANBA and showed the distinct molecular mechanism by which each putative primary functional variant conferred susceptibility to PBC. Our approach was useful to dissect the pathogenesis not only of PBC, but also other digestive diseases in which NFKB1/MANBA has been reported as a susceptibility locus. Keywords: PBC, GWAS, Disease Susceptibility Gene, e-QTL, CRISPR/Cas

遺伝子パネルと全エクソーム解析による原発性線毛運動不全症の原因遺伝子の解析

application/pdf原発性線毛運動不全症は線毛に関連する遺伝子の病的バリアントにより、慢性鼻副鼻腔炎、中耳炎、気管支拡張症、内臓逆位などをきたす遺伝性疾患である。約５０の原因遺伝子が知られているが、本邦での原因遺伝子の頻度は不明であった。原因遺伝子は人種によって異なることが知られており、本邦における原因遺伝子を効率よく明らかにする目的で、３２の既知遺伝子からなるパネルにて検索し、それで不明の場合、全エクソーム解析にて解析した。その結果、DRC1の両アレルの欠損が最も多く、次にDNAH5が多いことが明らかになった。DRC1は他の人種では頻度が低く、本邦あるいは東アジアに特徴的な原因遺伝子であると推定される。Primary ciliary dyskinesia is a hereditary disease that causes chronic nasal sinusitis, otitis media, bronchiectasis, and situs inversus due to pathogenic variants of cilia-related genes. About 50 causative genes are known, but the frequency of causative genes in Japan had been unknown. It is known that the causative gene differs depending on the race, and in order to clarify the causative gene in Japan efficiently, gene analysis by a panel consisting of 32known genes, followed by whole exosome analysis in case the panel failed to reveal the causative genes, was performed. As a result, it was clarified that the deletion of both alleles of DRC1 was the most frequent gene variant, followed by DNAH5. DRC1 is rare in other races and is presumed to be the causative gene characteristic of Japan or East Asia.2019年度～2021年度科学研究費補助金(基盤研究(C))研究成果報告書19K0988