Phenotypic and Genotypic characterization of Indian microcephaly.

BACKGROUND

Congenital microcephaly (CM) is a genetically and clinically heterogeneous neurodevelopmental disorder characterized by reduced occipitofrontal head circumference present prenatally or at birth. It may occur as an isolated/non-syndromic microcephaly, or as part of a syndromic disorder with developmental delay, structural brain abnormalities, and multisystem anomalies.

METHODS

We evaluated 23 pediatric patients with postnatally diagnosed congenital microcephaly referred to a tertiary care genetics clinic in North India (2020-2024). Detailed clinical phenotyping, neuroimaging, and systemic evaluation were performed. Whole exome sequencing (WES) was used as the first-tier test in patients with suspected single gene disorders, while chromosomal microarray analysis (CMA) was performed in selected patients with suspected copy number variants (CNVs) or CNVs flagged on exome data. Variants were prioritized using in silico tools, phenotype-based filtering and classified according to ACMG guidelines.

RESULTS

Age at presentation ranged from 1 month to 12 years. Facial features were the most commonly observed findings (69.6%), followed by skeletal abnormalities (52%). Global developmental delay and ophthalmological abnormalities were present in 47.8% of patients, while neuroimaging findings were informative in 35% of cases. SNVs were identified in 19 patients, including pathogenic or likely pathogenic variants in ASPM, AIMP2, NCAPD2, ZEB2, MAP2K1, MAP2K2, NAA15, NIPBL, and RPL5 while CNVs were detected in four patients. A definitive molecular diagnosis was established in 15 (65.2%) cases with either pathogenic or likely pathogenic SNVs and CNVs. The most frequently implicated gene was ASPM (3 unrelated patients) followed by ZEB2 in two unrelated patients. Five SNVs were novel. Variants of uncertain significance were found in 34.8% patients.

CONCLUSION

In this study, congenital microcephaly demonstrated marked phenotypic and genetic heterogeneity. Combined WES and CMA provided a high diagnostic yield in this North Indian cohort. Recurrent variants in ASPM and ZEB2 support the presence of population-specific recurrent alleles. Novel findings broaden the mutational spectrum of congenital microcephaly in the Indian population.