Genetic mosaicism – importance of clinical features to improve diagnosis

Abstract Purpose Cri-du-chat syndrome (OMIM 123450) is caused by a deletion of the short arm of chromosome 5 and characterized by a distinct high-pitched cry, developmental delay/intellectual disability, and various dysmorphic features. It occurs in approximately 1 in 50,000 live births. About 80% of affected individuals arise from de novo deletions, mainly of paternal origin. Here, a 13-year-old boy with a 20% mosaic deletion 5p13 in fibroblasts is reported. He exhibited intellectual disability (ID), significant body asymmetry, and skin and hair pigmentation anomalies. At birth, feeding difficulties and muscular hypotonia were noted. cMRI revealed microcephaly without brain malformations. Notably, he lacked the characteristic cat-like cry typical of cri-du-chat syndrome. Methods and results Chromosomal and array analyses on cultured fibroblasts of both body sides revealed a mosaic deletion in around 20% of cells, with findings validated through fluorescence in situ hybridization (FISH). This report emphasizes the importance of recognizing mosaicism in patients with ID, as many remain undiagnosed despite exome/genome sequencing. Conclusion One can assume that individuals with lower proportions of mosaic deletions may display milder and atypical clinical signs, whereas those with higher percentages tend to show more severe and typical manifestations. In diagnostically unresolved patients, attention must be drawn to low-grade mosaicism, especially when asymmetries or pigmentation disorders are present (see Graphical Abstract). Graphical Abstract