Journal Article

Identifying pathogenic variants in rare pediatric neurological diseases using exome sequencing

Yamoto, Kaori, Hiraide, Takuya, Kato, Mitsuhiro, Hayashi, Taiju, Saitsu, Hirotomo, Yamada, Keitaro, Watanabe, Kazuki, Isogai, Masaharu, Nakashima, Mitsuko, Kubota, Kazuo, Miyamoto, Sachiko, Aoki, Shintaro, Fukumura, Shinobu, Harasaki, Takuma, Shimizu, Kenji, Komatsu, Kazuyuki, Furukawa, Shogo, Hori, Ikumi

2024

Overview

Variant annotations are crucial for efficient identification of pathogenic variants. In this study, we retrospectively analyzed the utility of four annotation tools (allele frequency, ClinVar, SpliceAI, and Phenomatcher) in identifying 271 pathogenic single nucleotide and small insertion/deletion variants (SNVs/small indels). Although variant filtering based on allele frequency is essential for narrowing down on candidate variants, we found that 13 de novo pathogenic variants in autosomal dominant or X-linked dominant genes are registered in gnomADv4.0 or 54KJPN, with an allele frequency of less than 0.001%, suggesting that very rare variants in large cohort data can be pathogenic de novo variants. Notably, 38.4% candidate SNVs/small indels are registered in the ClinVar database as pathogenic or likely pathogenic, which highlights the significance of this database. SpliceAI can detect candidate variants affecting RNA splicing, leading to the identification of four variants located 11 to 50 bp away from the exon–intron boundary. Prioritization of candidate genes by proband phenotype using the PhenoMatcher module revealed that approximately 95% of the candidate genes had a maximum PhenoMatch score ≥ 0.6, suggesting the utility of phenotype-based variant prioritization. Our results suggest that a combination of multiple annotation tools and appropriate evaluation can improve the diagnosis of rare diseases.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/208 / 692/617 / 692/699 / Alleles / Annotation / Annotations / Child / Databases, Genetic / De novo variant / Exome - genetics / Exome sequencing / Exome Sequencing - methods / Female / Gene deletion / Gene Frequency / Genetic disorders / Genetic Predisposition to Disease / Genetics / Genomes / Genotype & phenotype / Hospitals / Humanities and Social Sciences / Humans / INDEL Mutation / Male / Medicine / Molecular Sequence Annotation / multidisciplinary / Nervous System Diseases - diagnosis / Nervous System Diseases - genetics / Neurological diseases / Neurological rare diseases / Ontology / Pediatrics / Phenotype / Phenotypes / Polymorphism, Single Nucleotide / Rare diseases / Rare Diseases - diagnosis / Rare Diseases - genetics / Retrospective Studies / Science / Science (multidisciplinary) / Software / Splicing abnormality / Whole genome sequencing