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

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

JOURNAL=Frontiers in Genetics

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2023.1112153

DOI=10.3389/fgene.2023.1112153

ISSN=1664-8021

ABSTRACT=<p><bold>Background:</bold> 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.</p><p><bold>Objective:</bold> We investigated the cytogenetic and monogenic risks of fetal microcephaly and evaluated their pregnancy outcomes.</p><p><bold>Methods:</bold> 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.</p><p><bold>Results:</bold> 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 <italic>de novo</italic>. Variants of unknown significance (VUS) was found in 33/162 (20.3%) fetuses. The gene variant involved included the single gene <italic>MPCH 2</italic> and <italic>MPCH 11</italic>, which is associated with human microcephaly, and <italic>HDAC8, TUBGCP6, NIPBL, FANCI, PDHA1, UBE3A, CASK, TUBB2A, PEX1, PPFIBP1, KNL1, SLC26A4, SKIV2L, COL1A2, EBP, ANKRD11, MYO18B, OSGEP, ZEB2, TRIO, CLCN5, CASK,</italic> and <italic>LAGE3</italic>. 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), <italic>p</italic> = 0.000].</p><p><bold>Conclusion:</bold> 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.</p>