Decoding Fetal Microcephaly: Genetic Insights from a Recent Prenatal Cohort Study

In a prenatal cohort, researchers found marked genotypic and phenotypic heterogeneity among fetuses with clinically identified microcephaly.

In 197 fetuses referred for invasive diagnosis, 96 (48.7%) had isolated microcephaly and 101 (51.3%) had additional anomalies. The team applied karyotype, chromosomal microarray (CMA), copy‑number sequencing (CNV‑seq) and targeted sequencing, then used whole‑exome sequencing (WES) in 24 trios to capture single‑gene variants missed by CMA or karyotype. Chromosomal abnormalities were found in 12.9% and pathogenic CNVs in 6.9% of non‑isolated cases; WES yielded additional monogenic diagnoses within the tested trios.

Combined testing raised diagnostic yield—CMA and karyotype identify abnormalities in roughly one in five non‑isolated cases, and selective WES provides incremental diagnoses.

The cohort contained single‑gene causes, pathogenic CNVs (pCNVs), and nondiagnostic karyotypes across both isolated and syndromic presentations. Central nervous system anomalies clustered more often in non‑isolated cases, and severe microcephaly had higher rates of pCNVs than borderline or moderate groups. In the examined trios, WES detected pathogenic variants (for example, in POGZ), illustrating a spectrum from chromosomal to monogenic etiologies and underscoring the need for individualized prognostic estimation rather than uniform outcome predictions.