Chromosomal Microarray Analysis in Spina Bifida: Genetic Heterogeneity and Its Clinical Implications.

Background: The etiology of spina bifida is multifactorial; the phenotype is the end result of both genetic and environmental influences. While whole exome sequencing has identified several pathogenic variants in Indian cohorts, the role of chromosomal imbalances and long contiguous stretches of homozygosity (LCSHs) remains largely unexplored in this population. Chromosomal microarray analysis (CMA) is an important tool that provides insights into such genetic aberrations, making it significant for evaluating patients with spina bifida.

Objective: To identify LCSHs and chromosomal imbalances in three spina bifida patients through CMA analysis as a pilot investigation.

Materials and methods: Genomic DNA was isolated from three spina bifida patients (P1: 10-year-old female, P2: 1-year-old male, and P3: 2.8-year-old male) and subjected to CMA using the Affymetrix 750K high-density array platform. The submicroscopic chromosomal imbalances and LCSHs were cross-referenced with public databases (Database of Genomic Variants, ClinVar, and OMIM) to evaluate their clinical significance. Functional annotations of the affected genes were performed to understand their role in neural tube development.

Results: CMA revealed significant LCSH on chromosomes 2, 3, and 7 involving the genes SOX11, WNT7A, FZD9, SEMA3A, and VHL, all of which are involved in neural tube closure. Mosaic Klinefelter syndrome (25.9% mosaicism) was identified in the second patient while the third patient had a normal genetic profile. The detection of significant genetic variations in two of three cases underscores the potential utility of CMA in spina bifida patients.

Conclusions: This study has generated valuable insights into the complex genetic landscape underlying the multifactorial etiopathogenesis of spina bifida. The findings not only underscore the importance of an integrated approach but also support the cause of a platform for large-scale investigations in the Indian population.