Dataset Information

Exome Sequencing Reveals De Novo Variants in Congenital Scoliosis.

ABSTRACT: Congenital scoliosis (CS) is a lateral curvature of the spine characterized by the presence of vertebral anomalies. Pathogenic genetic variants in the TBX6 gene are one of the causes of CS. However, since many clinically diagnosed cases of CS are without known TBX6 gene variations, this study aims to uncover new genes related to disease susceptibility of CS by exome sequencing (ES). This study employed ES in a cohort of 5 Japanese patients with CS and their healthy parents or a sister for a total of 16 samples among 5 families. Variant interpretation was performed using SIFT, PolyPhen-2, Mutation Taster, and CADD. Four de novo variants were identified by ES and confirmed by Sanger sequencing: 1 frameshift variant ( SHISA3 ) and 3 missense variants ( AGBL5 , HDAC4 , and PDE2A ). ES also uncovered 1 homozygous variant in the MOCOS gene. All of these variants were predicted to be deleterious by SIFT, PolyPhen-2, Mutation Taster, and/or CADD. The number of de novo variants identified in this study was exactly what would be expected by chance. Additional functional studies or gathering matched patients using Gene Matcher are needed.

SUBMITTER: Murakami K

PROVIDER: S-EPMC9578779 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Exome Sequencing Reveals De Novo Variants in Congenital Scoliosis.

Murakami Kohei K Kikugawa Shingo S Seki Shoji S Terai Hidetomi H Suzuki Takako T Nakano Masaki M Takahashi Jun J Nakamura Yukio Y

Journal of pediatric genetics 20210414 4

Congenital scoliosis (CS) is a lateral curvature of the spine characterized by the presence of vertebral anomalies. Pathogenic genetic variants in the <i>TBX6</i> gene are one of the causes of CS. However, since many clinically diagnosed cases of CS are without known <i>TBX6</i> gene variations, this study aims to uncover new genes related to disease susceptibility of CS by exome sequencing (ES). This study employed ES in a cohort of 5 Japanese patients with CS and their healthy parents or a sis ...[more]

PMID: 36267860

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Project description:Understanding the genetic basis of developmental delay (DD) and intellectual disability (ID) remains a considerable clinical challenge. This study evaluated the clinical application of trio whole exome sequencing (WES) in children diagnosed with DD/ID. The study comprised 173 children with unexplained DD/ID. The participants underwent trio-WES and their demographic, clinical, and genetic characteristics were evaluated. Based on their clinical features, the participants were classified into two groups for further analysis: a syndromic DD/ID group and a non-syndromic DD/ID group. The genetic diagnostic yield of the 173 children diagnosed with DD/ID was 49.7% (86/173). This included 58 pathogenic or likely pathogenic single nucleotide variants (SNVs) in 41 genes identified across 54 individuals (31.2%) through trio-WES. Among these, 22 SNVs had not been previously reported. Additionally, 30 copy number variations (CNVs) were detected in 36 individuals (20.8%). The diagnostic yield in the syndromic DD/ID group was higher than that in the non-syndromic DD/ID group (57.8% vs. 47.2%, P < 0.001). Within the syndromic DD/ID subgroup, the diagnostic yield of the DD/ID with epilepsy subgroup (83.9%) was significantly higher than those of the other subgroups (P < 0.001). Based on the analysis of the individuals' clinical phenotypes, the individuals with facial dysmorphism shown a higher diagnostic yield (68.2%, P < 0.001). The diagnostic yield of SNVs was higher in the individuals with DD/ID accompanied by epilepsy, whereas the diagnostic yield of CNVs was higher in the DD/ID without epilepsy group. Similarly, the diagnostic yield of de novo SNVs was higher in the DD/ID with epilepsy group, while the diagnostic yield of de novo CNVs was higher in the DD/ID without epilepsy group (all P < 0.001). Trio-WES is a crucial tool for the genetic diagnosis of DD/ID, demonstrating a diagnostic yield of up to 49.7%. De novo variants in autosomal dominant genes are significant contributors to DD/ID, particularly in non-consanguineous families.

Dataset Information

Exome Sequencing Reveals De Novo Variants in Congenital Scoliosis.

Publications

Exome Sequencing Reveals De Novo Variants in Congenital Scoliosis.

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