Utility of whole-exome sequencing for patients with multiple congenital anomalies with or without intellectual disability/developmental delay in East Asia population

Rai-Hseng Hsu; Chen-Hao Lee; Yin-Hsiu Chien; Shuan-Pei Lin; Miao-Zi Hung; Nai-Chi Chen; Yi-Lin Lin; Wuh-Liang Hwu; Ni-Chung Lee

doi:10.1002/mgg3.2160

Utility of whole-exome sequencing for patients with multiple congenital anomalies with or without intellectual disability/developmental delay in East Asia population

Mol Genet Genomic Med. 2023 Jun;11(6):e2160. doi: 10.1002/mgg3.2160. Epub 2023 Feb 27.

Authors

Rai-Hseng Hsu^{1

2}, Chen-Hao Lee^{3

4

5}, Yin-Hsiu Chien^{1

2}, Shuan-Pei Lin^{6

7

8}, Miao-Zi Hung¹, Nai-Chi Chen¹, Yi-Lin Lin¹, Wuh-Liang Hwu^{1

2}, Ni-Chung Lee^{1

2}

Affiliations

¹ Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan.
² Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.
³ Department of Pediatrics, E-Da Hospital, Kaohsiung, Taiwan.
⁴ School of Medicine, I-Shou University, Kaohsiung, Taiwan.
⁵ Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
⁶ Rare Disease Center, MacKay Memorial Hospital, Taipei, Taiwan.
⁷ Department of Genetics and Metabolism, MacKay Children's Hospital, Taipei, Taiwan.
⁸ Department of Medicine, MacKay Medical College, New Taipei City, Taiwan.

Abstract

Background: Congenital anomalies (CAs) with or without intellectual disability (ID)/developmental delay (DD) comprise a heterogeneous spectrum of diseases that affect approximately 3% of live births worldwide. Recently, whole-exome sequencing (WES) demonstrated the highly heterogeneous genetic causes of CAs. The purpose of this study was to evaluate a referral system to increase the yield of WES for CAs.

Methods: From August 2018 to July 2019, patients with CAs, with or without ID/DD, after excluding gross chromosomal aberrations, were referred to geneticists in two medical centers. Variant prioritization was conducted with an AI-assisted tool for whole exomes or a CA-related gene panel.

Results: Forty patients (27 males and 13 females) with CAs were enrolled in the study with a mean age of 4.71 years (range, 0.01-18.2). Pathogenic variants in 14 genes were discovered in 16 patients (three patients with CHD7 and 13 patients with one gene each of ATP6V1B2, TAF6, COL4A3BP, ANKH, BMP2, SMARCA4, CUL4B, PGAP3, SOX11, FBN2, PTPN11, SOS1, or PROKR2), with a positive diagnostic rate of 40%. Among the 16 positive cases, 13 (81%) also had ID/DD. The inheritance was autosomal dominant in 13 (81%), autosomal recessive in two (13%), and X-linked in one (6%). Only five patients received a correct clinical diagnosis before WES. The analyses of patients with a negative genetic diagnosis revealed a phenotype and gene mutation load similar to those of the positive-finding patients but with a lower percentage of ID/DD.

Conclusions: The careful selection of patients by experienced geneticists and the exclusion of chromosomal aberrations raises the positive rate of the molecular diagnosis for CAs to 40%. However, more than half of the patients with CAs still do not have a genetic diagnosis by current technologies.

Keywords: chromosomal aberration; developmental delay; intellectual disability; multiple congenital anomalies; whole-exome sequencing.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Abnormalities, Multiple* / genetics
Asia, Eastern
Child
Chromosome Aberrations
Cullin Proteins / genetics
DNA Helicases / genetics
Developmental Disabilities / diagnosis
Developmental Disabilities / genetics
Exome Sequencing
Female
Humans
Intellectual Disability* / diagnosis
Intellectual Disability* / genetics
Male
Nuclear Proteins / genetics
TATA-Binding Protein Associated Factors* / genetics
Transcription Factors / genetics

Substances

SMARCA4 protein, human
DNA Helicases
Nuclear Proteins
Transcription Factors
TAF6 protein, human
TATA-Binding Protein Associated Factors
CUL4B protein, human
Cullin Proteins