Abstract
AbstractStructural anomalies of the central nervous system (CNS) are one of the most common fetal anomalies found during prenatal imaging. However, the genomic architecture of prenatal imaging phenotypes has not yet been systematically studied in a large cohort. Patients diagnosed with fetal CNS anomalies were identified from medical records and images. Fetal samples were subjected to low-pass and deep whole-genome sequencing (WGS) for aneuploid, copy number variation (CNV), single-nucleotide variant (SNV, including insertions/deletions (indels)), and small CNV identification. The clinical significance of variants was interpreted based on a candidate gene list constructed from ultrasound phenotypes. In total, 162 fetuses with 11 common CNS anomalies were enrolled in this study. Primary diagnosis was achieved in 62 cases, with an overall diagnostic rate of 38.3%. Causative variants included 18 aneuploids, 17 CNVs, three small CNVs, and 24 SNVs. Among the 24 SNVs, 15 were novel mutations not reported previously. Furthermore, 29 key genes of diagnostic variants and critical genes of pathogenic CNVs were identified, including five recurrent genes: i.e., TUBA1A, KAT6B, CC2D2A, PDHA1, and NF1. Diagnostic variants were present in 34 (70.8%) out of 48 fetuses with both CNS and non-CNS malformations, and in 28 (24.6%) out of 114 fetuses with CNS anomalies only. Hypoplasia of the cerebellum (including the cerebellar vermis) and holoprosencephaly had the highest primary diagnosis yields (>70%), while only four (11.8%) out of 34 neural tube defects achieved genetic diagnosis. Compared with the control group, rare singleton loss-of-function variants (SLoFVs) were significantly accumulated in the patient cohort.
Funder
Health and Family Planning Commission of Hubei Province
Natural Science Foundation of Hubei Province
Shenzhen Science and Technology Innovation Commission
Guangdong Science and Technology Department
Publisher
Springer Science and Business Media LLC
Subject
Genetics (clinical),Genetics,Molecular Biology
Cited by
11 articles.
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