First patient with mosaic NOTCH3 gene pathogenic variant. Unrevealed mosaicisms and importance of their detection

Abstract

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited small vessel disease caused predominantly by pathogenic variants in NOTCH3 gene. Neither germline nor somatic mosaicism has been previously published in NOTCH3 gene. CADASIL is inherited in an autosomal dominant manner; only rare cases have been associated with de novo pathogenic variants. Mosaicism is more common than previously thought because mosaic variants often stay unrevealed. An apparently de novo variant might actually be a consequence of a parental mosaicism undetectable with Sanger sequencing, especially in the case of low grade mosaicism. Parental testing by sensitive tools like deep targeted next‐generation sequencing (NGS) analysis could detect cases of unrevealed medium or low level mosaicism in patients tested by Sanger sequencing. Here, we report the first patient with mosaic NOTCH3 gene pathogenic variant to our knowledge; the allelic fraction in the leucocyte DNA was low (13%); the pathogenic variant was inhered by his two daughters. The patient was diagnosed by deep targeted NGS analysis after studying his two affected daughters. This report highlights the importance of parental testing by sensitive tools like deep targeted NGS analysis. Detection of mosaicism is of great importance for diagnosis and adequate family genetic counseling.

Gonosomal Mosaicism for a Novel COL5A1 Pathogenic Variant in Classic Ehlers-Danlos Syndrome

“…More attention on mosaicism thanks to the resources of the novel technologies also allows to increase the rate of “positive results” in the probands, with potentially relevant consequences in their relatives. For example, a targeted NGS analysis identified a first case of the mosaic NOTCH3 pathogenic variant with an allelic fraction in the leucocyte DNA of 13% in the affected proband, while this variant was subsequently demonstrated by his still unaffected two daughters, who were therefore identified as pre-symptomatic carriers [ 16 ].…”