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

Youngha Lee ,Jana Kneissl,Won Seop Kim ,Sung Eun Hong ,Sang Moon Lee ,Soo Yeon Kim ,Murim Choi,Jon Soo Kim,Hyoungseok Jeon,Soo‐Jin Park ,Moses Lee,Eun Young Jeon ,Jung Min Ko,Jin Sook Lee ,Yongjin Yoo,Jean Lee ,Byung Chan Lim,Jaeso Cho,Hyuna Kim ,Anna Cho,Woo Joong Kim ,Tae Kyung Yoo ,Jieun Seo,Eunha Kim,Jeongeun Lee ,Jong Hee Chae

doi:10.1038/s41598-020-58101-8

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.

Highlights

A substantial portion of Mendelian disease patients suffers from genetic variants that are inherited in a recessive manner
The majority of the patients visited multiple tertiary hospitals for diagnosis (88.8% visited more than one hospital, mean of 2.3 hospitals), required a mean of 2.3 specialists (31.6% required more than two) and a mean of 5.6 years elapsed before whole-exome sequencing (WES) analysis at Seoul National University Children’s Hospital (SNUCH) (Table 1, Supplementary Fig. S2)
Integrative assessments of genetic variants, their clinical impacts, and patient symptoms allowed us to diagnose 40.3% (223/553) of the cohort with high confidence. This group of patients included carriers of copy number variation (CNV) (23/553 = 4.2%; 16 heterozygous deletions and 7 duplications; Supplementary Table S1), in which 20 CNVs originated de novo (3.6% of the entire cohort), which is slightly lower but comparable to a previous observation[20,21,22,23]

Summary

Introduction

A substantial portion of Mendelian disease patients suffers from genetic variants that are inherited 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. Diagnosis of neurological disorders that affect children is frequently hampered by rare and overlapping clinical features, which makes it difficult for clinicians to readily recognize and properly treat the disease entity This makes pediatric neurologic patients an impending target for genome-wide genetic studies[10,11,12]. As many rare neurologic disorders in children follow Mendelian inheritance, disease-causing variant discovery by trio-based whole-exome sequencing (WES) has proved to be the most robust methodology, yielding instant diagnosis rates of 25–41%10–12,14,16. We describe the establishment of a system that efficiently integrates advanced genetic techniques with clinical diagnostic processes to maximize benefits for pediatric patients and their families

Methods

Results

Conclusion