Characterization of pathogenic genetic variants in Russian patients with primary ciliary dyskinesia using gene panel sequencing and transcript analysis

Primary ciliary dyskinesia (PCD) is a group of rare genetically heterogeneous disorders caused by defective cilia and flagella motility. The clinical phenotype of PCD patients commonly includes chronic oto-sino-pulmonary disease, infertility, and, in about half of cases, laterality defects due to ra...

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Published in:	Orphanet journal of rare diseases Vol. 19; no. 1; pp. 310 - 23
Main Authors:	Zlotina, Anna, Barashkova, Svetlana, Zhuk, Sergey, Skitchenko, Rostislav, Usoltsev, Dmitrii, Sokolnikova, Polina, Artomov, Mykyta, Alekseenko, Svetlana, Simanova, Tatiana, Goloborodko, Maria, Berleva, Olga, Kostareva, Anna
Format:	Journal Article
Language:	English
Published:	England BioMed Central Ltd 23-08-2024 BMC
Subjects:	Adolescent Adult Analysis Axonemal Dyneins - genetics Child Child, Preschool Cilia - genetics Cilia - pathology Cilia and ciliary motion Ciliary Motility Disorders - genetics Development and progression DNAH5 Female Gene-panel sequencing Genes Genetic aspects Genetic disorders Genetic transcription Health aspects Humans HYDIN Kartagener Syndrome - genetics Male Medical research Medicin och hälsovetenskap Medicine, Experimental Movement disorders Mutation - genetics Physiological aspects Primary ciliary dyskinesia RNA Russia Russian population ZMYND10 Russia China Gene-panel sequencing Splice site variants Founder mutation Primary ciliary dyskinesia Russian population DNAH5 HYDIN ZMYND10 Transcript analysis
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Summary:	Primary ciliary dyskinesia (PCD) is a group of rare genetically heterogeneous disorders caused by defective cilia and flagella motility. The clinical phenotype of PCD patients commonly includes chronic oto-sino-pulmonary disease, infertility, and, in about half of cases, laterality defects due to randomization of left-right body asymmetry. To date, pathogenic variants in more than 50 genes responsible for motile cilia structure and assembly have been reported in such patients. While multiple population-specific mutations have been described in PCD cohorts from different countries, the data on genetic spectrum of PCD in Russian population are still extremely limited. The present study provides a comprehensive clinical and genetic characterization of 21 Russian families with PCD living in various country regions. Anomalies of ciliary beating in patients` respiratory epithelial cells were confirmed by high-speed video microscopy. In the most cases, custom-designed panel sequencing allowed to uncover causative variants in well-known or rarely mentioned PCD-related genes, including DNAH5, DNAH11, CFAP300, LRRC6, ZMYND10, CCDC103, HYDIN, ODAD4, DNAL1, and OFD1. The variations comprised common mutations, as well as novel genetic variants, some of which probably specific for Russian patients. Additional targeted analysis of mRNA transcripts from ciliated cells enabled us to specify functional effects of newly identified genetic variants in DNAH5 (c.2052+3G>T, c.3599-2A>G), HYDIN (c.10949-2A>G, c.1797C>G), and ZMYND10 (c.510+1G>C) on splicing process. In particular, the splice site variant c.2052+3G>T, detected in four unrelated families, resulted in skipping of exon 14 in DNAH5 transcripts and, according to haplotype analysis of affected probands, was proposed as an ancestral founder mutation in Udmurt population. The reported data provide a vital insight into genetic background of primary ciliary dyskinesia in the Russian population. The findings clearly illustrate the utility of gene panel sequencing coupled with transcriptional analysis in identification and clinical interpretation of novel genetic variants.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1750-1172 1750-1172
DOI:	10.1186/s13023-024-03318-3