Clinical use of whole exome sequencing in children with developmental delay/intellectual disability

Yoon Hee Jo; Soo Han Choi; Hye Won Yoo; Min Jung Kwak; Kyung Hee Park; Juhyun Kong; Yun-Jin Lee; Sang Ook Nam; Bo Lyun Lee; Woo Yeong Chung; Seung Hwan Oh; Young Mi Kim

doi:10.1016/j.pedneo.2023.05.015

Clinical use of whole exome sequencing in children with developmental delay/intellectual disability

Pediatr Neonatol. 2024 Jan 23:S1875-9572(24)00004-4. doi: 10.1016/j.pedneo.2023.05.015. Online ahead of print.

Authors

Affiliations

¹ Department of Pediatrics, Pusan National University Hospital, Biomedical Research Institute, School of Medicine, Pusan National University, Busan, Republic of Korea.
² Department of Pediatrics, Pusan National University Children's Hospital, Biomedical Research Institute, School of Medicine, Pusan National University, Yangsan, Republic of Korea.
³ Department of Pediatrics, Busan Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea.
⁴ Department of Laboratory Medicine, Pusan National University Yangsan Hospital, Biomedical Research Institute, School of Medicine, Pusan National University, Yangsan, Republic of Korea.
⁵ Department of Pediatrics, Pusan National University Hospital, Biomedical Research Institute, School of Medicine, Pusan National University, Busan, Republic of Korea. Electronic address: youngmi.kim@pusan.ac.kr.

PMID: 38281861
DOI: 10.1016/j.pedneo.2023.05.015

Abstract

Background: Identifying the underlying etiology of developmental delay/intellectual disability (DD/ID) is challenging but important. The genetic diagnosis of unexplained DD/ID helps in the treatment and prognosis of the disability in patients. In this study, we reported our experience of using whole exome sequencing (WES) of children with unexplained DD/ID.

Methods: We conducted a retrospective analysis of WES results of children under 19 years of age with unexplained DD/ID between January 2020 and December 2021. The demographic data of all patients and variants identified through WES were evaluated. Furthermore, we evaluated the clinical characteristics that influenced the identification of genetic causes.

Results: Forty-one patients with DD/ID were included, of whom 21 (51.2 %) were male. The average age at symptom onset was 1.6 ± 1.3 years, and the duration from symptom onset to diagnosis was 3.1 ± 3.7 years. Hypotonia was the most common symptom (17 patients, 41.5 %), and epilepsy was confirmed in 10 patients (24.4 %). Twenty-two pathogenic/likely pathogenic variants were identified in 20 patients, and three variants of uncertain significance were identified in three patients. Family-based trio Sanger sequencing for candidate variants of 12 families was conducted; 10 variants were de novo, one variant paternally inherited, and two variants compound heterozygous. The diagnostic yield of WES for DD/ID was 48.8 % and was significantly high in patients with an early onset of DD/ID and facial dysmorphism. In contrast, patients with autism spectrum disorder (ASD) were more likely to have negative WES results compared with others without ASD.

Conclusion: The diagnostic yield of WES was 48.8 %. We conclude that patients' characteristics, such as dysmorphic features and the age of symptom onset, can predict the likelihood that WES will identify a causal variant of a phenotype.

Keywords: Developmental delay; Intellectual disability; Next generation sequencing; Whole exome sequencing.