Clinical utility of multitissue genomic arrays in diagnosing pigmentary mosaicism associated with neurodevelopmental delay.

Abstract

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, 7 males) with pigmentary mosaicism and global developmental delay was analyzed. Each patient underwent G-band karyotyping and array (Infinium CytoSNP-850K, Illumina) on peripheral blood, skin fibroblasts, and buccal mucosa samples. Pathogenic or likely pathogenic variants were found in 13/21 (62%) patients. Of these 13, 10 (77%) exhibited mosaicism, with variant allele fractions as low as 15%. Based on tissue distribution, 3 cases were classified as germline events and 10 as somatic mosaicism. Patients with positive findings were subdivided into: 1) mosaic numerical chromosomal alterations (n=6), 2) pathogenic CNVs (n=5), and 3) structural rearrangements (n=2). Notably, several mosaic variants- particularly aneuploidies -were detected exclusively in fibroblast DNA, underscoring 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.