Inferring parental gonadal mosaicism in LMNA-associated muscular dystrophy by ultra-deep next generation sequencing: A sensitive approach providing valuable information for genetic counseling

Abstract

Nuclear laminopathies are a group of human genetic disorders caused by mutations in genes encoding proteins of the nuclear lamina. Among them, mutations in LMNAcause diverse phenotypes. De novo LMNA variants have been reported in sporadic patients. However, familial recurrence caused by parental gonadal mosaicism of LMNA mutations was seldom reported. We describe here two sisters suffering from LMNA-associated muscular dystrophy were ultra-high depth Next-Generation Sequencing (NGS) proved useful for detecting low-level somatic mosaicism in a blood sample of their mother, letting us infer the presence of gonadal mosaicism.Detecting parental gonadal mosaicism is critical for genetic counseling. A phenomenon more frequent than previously though where recurrence risks when one of the parents has confirmed somatic mosaicism may be as high as 28,5%. This knowledge gives the family valuable information for reproductive decision-making and planning prenatal care for additional pregnancies and these advances offer new diagnostic pathways for this group of muscle disorders.