Clinical Utility of Multitissue Genomic Arrays in Diagnosing Pigmentary Mosaicism Associated with Neurodevelopmental...

Genomic mosaicism is underdiagnosed owing to its variable tissue distribution and the limitations of single-tissue testing. Cytogenomic techniques applied across multiple tissues can uncover clinically actionable variants and clarify genotype-phenotype relationships. DNA from 21 patients (14 females and 7 males) with pigmentary mosaicism and global developmental delay was analyzed. Each patient underwent G-band karyotyping and array (Infinium CytoSNP-850K) on peripheral blood, skin fibroblasts, and buccal mucosa samples. Pathogenic or likely pathogenic variants were found in 13 of 21 patients (62%). Of these 13 patients, 10 (77%) exhibited mosaicism, with variant allele fractions as low as 15%. On the basis of tissue distribution, 3 cases were classified as germline events and 10 as somatic mosaicism. Patients with positive findings were subdivided into: i) mosaic numerical chromosomal alterations (n = 6), ii) pathogenic copy number variations (n = 5), and iii) structural rearrangements (n = 2). Notably, several mosaic variants-particularly aneuploidies-were detected exclusively in fibroblast DNA, underlining the added diagnostic yield of multitissue sampling. In this cohort, a multitissue cytogenomic approach achieved a 62% overall diagnostic rate and identified mosaicism in 77% of positive cases. These results support the routine incorporation of genomic arrays with multisample analysis into diagnostic workflows for rare developmental disorders, enhancing detection sensitivity and enabling precise genotype-phenotype correlations.