Genomic profiling of 553 uncharacterized neurodevelopment patients reveals a high proportion of recessive pathogenic variant carriers in an outbred population

Abstract

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. Therefore, 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. Disease-causing variants, including newly discovered variants, were identified in 57.5% of the probands of the KND cohort. Among the patients with the previous reported pathogenic variants, 35.1% inherited these variants in a recessive manner. Genes that cause recessive disorders in our cohort tend to be less constrained by loss-of-function variants and were enriched in lipid metabolism and mitochondrial functions. 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. 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. A large fraction of Mendelian disorders follow a recessive inheritance pattern 1,2. The Online Mendelian Inheritance in Men (OMIM) lists 5,317 disorders and 3,077 of these are categorized as recessive (as of April 2019). For more common complex disorders, the contribution of recessive variants to the disease pathogenesis is less than expected 3-6. For rare diseases, the contribution of recessive variants in inbred populations, such as

Systematic analysis of inheritance pattern determination in genes that cause rare neurodevelopmental diseases

“…Re-evaluation of patients previously determined to be without pathogenic variants often allows for the discovery of new variants due to accumulating understanding of gene-disease relationships and improved bioinformatic pipelines ( Ewans et al, 2018 ; Epilepsy Genetics Initiative, 2019 ; Jalkh et al, 2019 ; Fung et al, 2020 ). Previous re-analysis studies have reported 5%–12% increases in diagnostic yield ( Ewans et al, 2018 ; Epilepsy Genetics Initiative, 2019 ; Jalkh et al, 2019 ; Fung et al, 2020 ); here, we observed a 5.9% increase in diagnostic yield, discovering pathogenic variants in 33 patients among the 553 that were previously analyzed in 2020 (KND553; Figure 1A ) ( Lee et al, 2020 ). The variants implicated in these 33 cases can be broadly divided into two groups, 1) variants for which new entries in OMIM allowed defining them as pathogenic ( n = 8; Table 1 ) and 2) pathogenic calls previously missed during the bioinformatic process ( n = 25; Table 2 ).…”

“…In our previous study using 553 KND patients, we estimated that one in every 17 healthy individuals is a carrier for at least one pathogenic variant for a recessive genes represented in the KND cohort. This estimate remains unchanged using 1,180 patients ( Lee et al, 2020 ), but with a patient set twice as large, we inferred that the power to predict carriers would substantially increase. We first collected a list of pathogenic LoF and missense variants from ClinVar and KND, and aggregated their population frequencies using the gnomAD East Asian and Korean Variant Archive [KOVA 2; 5,305 healthy Korean individual set ( Lee et al, 2017 )].…”

“…WES procedures including exome capturing and sequencing were performed at Theragen Etex Bio Institute (Suwon, Korea). The data were analyzed as described previously ( Lee et al, 2020 ). Briefly, Burrows-wheeler Aligner [v.0.7.15 ( Li and Durbin 2010 )] was used to align sequenced reads and the Picard software [v.2.8.0 ( Broad Institute, 2019 )], samtools [v.1.8 ( Li et al, 2009 )] and Genome Analysis Toolkit [GATK, v.4.1.4 ( Mckenna et al, 2010 )] were used for subsequent data processing steps such as removal of PCR duplicates, base recalibration, and variant quality control.…”

“…Then the variants were classified based on inheritance patterns such as de novo , compound heterozygous, homozygous, and hemizygous by comparing to genotypes in the parents. Copy number variation (CNV) analysis through WES was carried out by comparing the mean coverage depth of each captured interval to the mean coverage depth of parental samples as described previously ( Lee et al, 2020 ).…”

A database of 5,305 healthy Korean individuals reveals genetic and clinical implications for an East Asian population

“…Compared to populations higher burden of consanguinity, homozygous pathogenic variants in ROH are rarely found in an outbred population such as Koreans 40 . Rather, such regions can be used to signify a positive selection that was imposed on the population in the form of a selective sweep 41 .…”