Genetic and clinical features of microcephaly in a prenatal cohort

Fetal microcephaly, defined as a small head circumference in utero or at birth, is a rare but clinically significant condition that may be associated with an increased risk of neurodevelopmental delay and impairment. However, the comprehensive analysis of multiple genetic testing methods for fetal microcephaly remains limited. This study aimed to summarize the clinical characteristics, ultrasound phenotypes, and genetic etiologies of prenatally diagnosed microcephaly.

A single-center retrospective study was performed on fetuses with microcephaly. A total of 197 fetuses with microcephaly undergoing invasive prenatal diagnosis were recruited. Cytogenetic and monogenic abnormalities were investigated using karyotyping, chromosomal microarray analysis (CMA), copy number variant sequencing (CNV-seq) and whole exome sequencing (WES) were further analyzed.

Among the 197 fetuses, 48.7% (96/197) had isolated microcephaly, while 51.3% (101/197) had non-isolated microcephaly. Within the non-isolated group, 24.9% (49/197) presented soft markers and 10.2% (20/197) exhibited structural defects. The incidences of chromosomal abnormalities (12.9%, 13/101) and pathogenic CNVs (6.9%, 7/101) were both higher in nonisolated fetuses than those in isolated fetuses. Significant differences were observed in the rate of chromosomal abnormalities across the borderline, moderate and severe microcephaly subgroups, and pCNVs were detected more commonly in the severe subgroup than in the borderline or moderate subgroup. Trio-WES, performed in 24 cases, revealed single gene variants including the POGZ gene, which was associated with the phenotype of microcephaly. The overall rate of adverse pregnancy outcomes was 33.1% (57/172), excluding ongoing pregnancies and cases lost to follow-up.

Fetal microcephaly represents a genotypically and phenotypically heterogeneous disorder. The comprehensive application of multiple genetic testing approaches provides an effective and essential strategy for the prenatal diagnosis of the diverse etiologies underlying fetal microcephaly.