Uncovering potential causal genes for undiagnosed congenital anomalies using an in-house pipeline for trio-based whole-genome sequencing

被引:0
作者
Kim, Jeong-Min [1 ]
Cho, Hye-Won [1 ]
Shin, Dong Mun [1 ]
Kim, Oc-Hee [1 ]
Kim, Jihyun [1 ]
Lee, Hyeji [2 ,3 ,4 ]
Lee, Gang-Hee [2 ,3 ,4 ]
An, Joon-Yong [2 ,3 ,4 ,5 ]
Yang, Misun [6 ,7 ]
Jo, Heui Seung [8 ]
Jang, Ja-Hyun [9 ]
Chang, Yun Sil [6 ,7 ,10 ]
Park, Hyun-Young [11 ]
Park, Mi-Hyun [1 ]
机构
[1] Korea Dis Control & Prevent Agcy, Korea Natl Inst Hlth, Dept Precis Med, Div Genome Sci, Cheongju 28159, Chungbuk, South Korea
[2] Korea Univ, Dept Integrated Biomed & Life Sci, Seoul 02841, South Korea
[3] Korea Univ, Grad Sch, Dept Healthcare Sci, Transdisciplinary Major Learning Hlth Syst, Seoul 02841, South Korea
[4] Korea Univ, R&E Ctr Learning Hlth Syst BK21FOUR, Seoul 02841, South Korea
[5] Korea Univ, Coll Hlth Sci, Sch Biosyst & Biomed Sci, Seoul 02841, South Korea
[6] Sungkyunkwan Univ, Samsung Med Ctr, Dept Pediat, Sch Med, Seoul 06351, South Korea
[7] Samsung Med Ctr, Cell & Gene Therapy, Seoul 06351, South Korea
[8] Kangwon Natl Univ, Kangwon Natl Univ Sch Hosp, Dept Pediat, Sch Med, Chunchon 24289, South Korea
[9] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Lab Med & Genet, Seoul 06351, South Korea
[10] Sungkyunkwan Univ, Samsung Adv Inst Hlth Sci & Technol, Dept Hlth Sci & Technol, Seoul 06351, South Korea
[11] Korea Dis Control & Prevent Agcy, Korea Natl Inst Hlth, Cheongju 28159, South Korea
关键词
Congenital Anomalies; Whole Genome Sequencing; Genetic Variant; Rare Disease; DATA-COLLECTION; RARS CAUSE; MUTATIONS; HYPOMYELINATION; GUIDELINES; MICROARRAY;
D O I
10.1186/s40246-024-00709-2
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
BackgroundCongenital anomalies (CAs) encompass a wide spectrum of structural and functional abnormalities during fetal development, commonly presenting at birth. Identifying the cause of CA is essential for accurate diagnosis and treatment. Using a target-gene approach, genetic variants could be found in certain CA patients. However, some patients were genetically undiagnosed; therefore, it is imperative to identify the causative variants from whole genome sequence (WGS) data of these patients.ResultsAn in-house pipeline utilizing DRAGEN-GATK-Hail was established for trio-based WGS data analysis (n = 18 undiagnosed CA patients and their parents) and thirty-five candidate variants, including SNV/Indel, CNV, and SV were identified. Among them, 10 variants of seven coding genes were selected as possible causal variants by variant pathogenicity, genotype-phenotype analysis, and a multidisciplinary team. Finally, functional validation of six genes including RYR3, NRXN1, FREM2, CSMD1, RARS1, and NOTCH1, revealed various phenotypes in zebrafish models that aligned with those observed in each patient. In addition to the above findings, eleven diagnostic variants initially discovered in a targeted-gene analysis from a previous study were also identified as diagnostic variants and the in-house pipeline demonstrated a significant advantage in accurately and efficiently identifying de novo variants (DNVs), compound heterozygous (CH), and homozygous variants.ConclusionsTaken together, the in-house pipeline established in this study provides a highly valuable diagnostic tool for the identification of potential candidate variants in patients with CA. Further research into the molecular mechanisms related to the development of CAs could shed light on the functional aspects of these genetic variations and contribute to the development of therapeutic drugs.
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页数:14
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