Abstract
Background A substantial portion of Mendelian disease patients suffers from genetic variants that are inherited in a recessive manner. A precise understanding of pathogenic recessive variants in a population would assist in pre-screening births of such patients. However, a systematic understanding of the contribution of recessive variants to Mendelian diseases is still lacking.
Methods Genetic diagnosis and variant discovery of 553 undiagnosed Korean patients with complex neurodevelopmental problems (KND for Korean NeuroDevelopmental cohort) were performed using whole exome sequencing of patients and their parents. Pathogenic variants were selected and evaluated based on a comparison to patient symptoms and genetic properties of the variants were analyzed.
Results Disease-causing variants, including newly discovered variants, were identified in in 57.5% of the probands of the KND cohort. Of the 553 patients, 47.4% harbored variants that were previously reported as being pathogenic, and 35.1% of the previous reported pathogenic variants were inherited in a recessive manner. Genes that cause recessive disorders tend to be less constrained by loss-of-function variants and enriched in metabolic and mitochondrial pathways. This observation was applied to an estimation that approximately 1 in 17 healthy Korean individuals carry at least one of these pathogenic variants that develop severe neurodevelopmental problems in a recessive manner. Furthermore, the feasibility of these genes for carrier screening was evaluated.
Conclusions We suggest that the odds are high for healthy individuals carrying a potentially pathogenic variant, and its genetic properties. Our results will serve as a foundation for recessive variant screening to reduce occurrences of rare Mendelian disease patients. Additionally, our results highlight the utility and necessity of whole exome sequencing-based diagnostics for improving patient care in a country with a centralized medical system.
Abbreviations
- CADD
- Combined Annotation Dependent Depletion
- CH
- Compound heterozygous
- CNV
- Copy number variation
- DDD
- Deciphering Developmental Disorders
- GERP
- Genomic Evolutionary Rate Profiling
- gnomAD
- Genome Aggregation Database
- GO
- Gene Ontology
- KND
- Korean neurodevelopmental disorder
- LoF
- Loss-of-function
- OMIM
- Online Mendelian Inheritance in Man
- phyloP
- phylogenetic P-values
- RHe
- Rare hemizygous
- RHo
- Rare homozygous
- SIFT
- Sorting Intolerant From Tolerant
- WES
- Whole exome sequencing
- WGS
- Whole genome sequencing