ESPE2024 Poster Category 2 Late Breaking (107 abstracts)
Copy number variations from whole exome sequencing in children with skeletal dysplasia
Takuo Kubota 1 , Kenich Yamamoto 2 , Chieko Yamada 1 , Hirofumi Nakayama 1,3 , Yukako Nakano 1 , Makoto Fujiwara 1 , Yasuhisa Ohata 1 , Taichi Kitaoka 4 , Keiichi Ozono 5 & Yasuji Kitabatake 1
1Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan. 2Laboratory of Children’s Health and Genetics, Division of Health Science, Osaka University Graduate School of Medicine, Suita, Japan. 3Department of Oral and Maxillofacial Surgery, Osaka University Graduate School of Dentistry, Suita, Japan. 4Department of Pediatrics, ISEIKAI International General Hospital, Osaka, Japan. 5Center for Promoting Treatment of Intractable Diseases, ISEIKAI International General Hospital, Osaka, Japan
Germline copy number variations (CNVs) can lead to rare diseases. Despite the widespread use of whole exome sequencing (WES), array comparative genomic hybridization (aCGH) and multiplex ligation-dependent probe amplification (MLPA) remain the first-line methods for detecting CNVs in clinical genetics due to technical biases in WES. Recently, a new pipeline (GATK-gCNV) has been developed to account for these biases, allowing for the detection of high-resolution CNVs from WES data. However, clinical applications of this pipeline are still limited. In our study, we applied GATK-gCNV to children with skeletal dysplasia who did not have detected pathogenic single nucleotide variants. We first established a cohort model using data from 93 healthy or genetically diagnosed patients. Using cohort-estimated parameters, we identified CNVs from the WES data of 59 patients. Functional annotation was performed using AnnotSV, and CNVs were filtered based on ACMG guideline. After manual curation, pathogenic CNVs were detected in 4 children. Case 1 involved a 15-year-old boy suspected of having Aarskog-Scott syndrome. While no pathogenic variants were detected in FGD1, a 5 Mb heterozygous deletion on chromosome 14 was observed, indicating Frias syndrome. This deletion was confirmed by aCGH. Case 2 involved a 8-year-old boy diagnosed with fibroblast growth factor 23-related hypophosphatemic rickets. A hemizygous 3 kb deletion in exons 21-22 of the PHEX gene was detected, and the deletion of these exons was confirmed using MLPA, revealing X-linked hypophosphatemic rickets. Case 3 involved a 9-year-old boy diagnosed with multiple exostosis, in whom a heterozygous 6 kb deletion in exons 2-3 of the EXT2 gene was identified. Case 4 involved a 5-year-old boy diagnosed with osteogenesis imperfecta, in whom a heterozygous 57 kb deletion on chromosome 17q21.33, including the COL1A1 gene, was identified. This deletion was confirmed by whole genome sequencing (WGS) more clearly. Collectively, The loss of function in those deletions is likely pathogenic, given their impact on genes and exons. Our findings demonstrate that GATK-gCNV in WES enables the detection of pathogenic CNVs ranging from a few kilobases to megabases, which can be further validated by aCGH, MLPA or WGS.
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