Genetic diagnosis of fetal microcephaly at a single tertiary center in China

You Wang; Fang Fu; Tingying Lei; Li Zhen; Qiong Deng; Hang Zhou; Chunling Ma; Ken Cheng; Ruibin Huang; Ru Li; Qiuxia Yu; Lushan Li; Jin Han; Xin Yang; Dongzhi Li; Can Liao

doi:10.3389/fgene.2023.1112153

Genetic diagnosis of fetal microcephaly at a single tertiary center in China

Front Genet. 2023 May 9:14:1112153. doi: 10.3389/fgene.2023.1112153. eCollection 2023.

Authors

You Wang^{1

2}, Fang Fu², Tingying Lei², Li Zhen², Qiong Deng², Hang Zhou², Chunling Ma¹, Ken Cheng^{2

3}, Ruibin Huang², Ru Li², Qiuxia Yu², Lushan Li², Jin Han², Xin Yang², Dongzhi Li², Can Liao^{1

2}

Affiliations

¹ The First School of Clinical Medicine, Southern Medical University, Guangzhou, China.
² Department of Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.
³ School of Medicine, South China University of Technology, Guangzhou, China.

Abstract

Background: Microcephaly is common in patients with neuropsychiatric problems, and it is usually closely related to genetic causes. However, studies on chromosomal abnormalities and single-gene disorders associated with fetal microcephaly are limited. Objective: We investigated the cytogenetic and monogenic risks of fetal microcephaly and evaluated their pregnancy outcomes. Methods: We performed a clinical evaluation, high-resolution chromosomal microarray analysis (CMA), and trio exome sequencing (ES) on 224 fetuses with prenatal microcephaly and closely followed the pregnancy outcome and prognosis. Results: Among 224 cases of prenatal fetal microcephaly, the diagnosis rate was 3.74% (7/187) for CMA and 19.14% (31/162) for trio-ES. Exome sequencing identified 31 pathogenic or likely pathogenic (P/LP) single nucleotide variants (SNVs) in 25 genes associated with fetal structural abnormalities in 37 microcephaly fetuses; 19 (61.29%) of which occurred de novo. Variants of unknown significance (VUS) was found in 33/162 (20.3%) fetuses. The gene variant involved included the single gene MPCH 2 and MPCH 11, which is associated with human microcephaly, and HDAC8, TUBGCP6, NIPBL, FANCI, PDHA1, UBE3A, CASK, TUBB2A, PEX1, PPFIBP1, KNL1, SLC26A4, SKIV2L, COL1A2, EBP, ANKRD11, MYO18B, OSGEP, ZEB2, TRIO, CLCN5, CASK, and LAGE3. The live birth rate of fetal microcephaly in the syndromic microcephaly group was significantly higher than that in the primary microcephaly group [62.9% (117/186) vs 31.56% (12/38), p = 0.000]. Conclusion: We conducted a prenatal study by conducting CMA and ES for the genetic analysis of fetal microcephaly cases. CMA and ES had a high diagnostic rate for the genetic causes of fetal microcephaly cases. In this study, we also identified 14 novel variants, which expanded the disease spectrum of microcephaly-related genes.

Keywords: chromosomal microarray analysis; fetal microcephaly; genetic counseling; prenatal diagnosis; whole exome sequence.

Grants and funding

This study was supported by the sub-project of the National Key Research and Developmental Program (2021YFC2701002), the National Natural Science Foundation of China (81801461, 81873836, 81771594, 81671474, 81501267), the Natural Science Foundation of Guangdong Province (2019A1515012034, 2017A030313460). The Project of Guangzhou Science and Technology, Grant/Award Number 202102020191, and the General Guide Project of Guangzhou Health Commission (20221A011038).