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.

Figure 1

Classification of the KND cohort and results of clinical WES analysis. (a) Subjects by disease inheritance patterns. Class 1: autosomal dominant families; Class 2: families with affected siblings; Class 3: affected individuals with no family history. (b) Major clinical features of the KND cohort. (c) Diagnostic yield of 553 patients with undiagnosed symptoms using WES. (d) Pathogenic variants divided by inheritance patterns. (e) GO and disease enrichment analysis of 164 known genes. (f) Brain anatomical and developmental categorization used for our analysis. Components of each brain region is shown in Supplementary Fig. S9. (g) Strength of the co-expression network composed of our known/novel genes compared to random networks as measured by 10⁵ permutations.

Figure 2

Genetic properties of pathogenic recessive variants. (a) Burden of recessive variants in KND patients (Pt) and their parents as controls (Ct). Recessive variants are divided into compound heterozygous (CH), rare homozygous (RHo) and rare hemizygous (RHe) groups. Numbers found from all variants from all genes (“All”), LoF variants from all genes (“LoF”), all variants from OMIM-listed genes (“OMIM”) and all variants from intellectual disability gene set (“ID”, from DisGeNET) are plotted. Numbers of samples used for each category are as following: patients for CH = 145; controls for CH = 290; patients for RHo = 247; controls for RHo = 341; patients for RHe = 134; controls for RHe = 168. Data are mean ± standard deviation. (b) Venn diagrams displaying high correlations of recessive or dominant inheritance patterns with their known inheritance patterns. The asterisks denote two exceptional cases, ACOX1 and C19orf12 (see text). (c) Allele frequency distribution of dominant and recessive variants. (d) PhyloP and amino acid conservation differences between dominant and recessive missense variants. Amino acid conservation is determined by the number of vertebrate species that contain an amino acid that is different from its human orthologous residue. The solid lines denote medians and the dotted lines denote means. (e) ACMG code distribution of variants that are in recessive or dominant inheritance pattern. (f) Distributions of o/e LoF values for dominant and recessive genes found from KND patients (left) and dominant and recessive genes from OMIM (right) plotted against all genes and known haploinsufficiency genes (n = 291). (g) Functional differences between dominant and recessive genes by GO analysis. Ontologies in dark blue suggest non-neuronal signals specific to the recessive gene group. (h) Relative position of LoF variants in genes. Positions of pathogenic LoF variants in genes from KND patients are plotted against those LoF variant positions from all genes in gnomAD.

Figure 3

Screen for rare severe neurodevelopmental disorder carriers. (a) A schematic diagram describing processes used to estimate neurodevelopmental disorder carrier frequency in the Korean population. The dotted lines in the map denote the Korea Train Express network, the high-speed railway system of Korea. (b–d) Distribution differences of various parameters between pathogenic recessive variants from KND patients and gnomAD variants from the same genes that were found in KND patients. (b) Allele frequency. The rare frequency portion of the left panel is seperately plotted in the right panel. (c) PhyloP and amino acid conservation. The solid lines denote medians and the dotted lines denote means. (d) CADD, GERP and SIFT score. (e) Recessive variants found from KND patients, o/e LoF values, and accumulated frequencies of LoF and ClinVar variants from gnomAD East Asians (EAS) for genes that harbor known pathogenic recessive variants in KND patients. Finally, portion that were attributable to ClinVar or LoF variants for pre-screening parents for each recessive gene are shown.