Deep sequencing refines prior genomic analysis in families with apparent gonadal mosaicism

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Background Gonadal and gonosomal mosaicism describe a phenomenon in which a seemingly healthy individual carries a disease-causing variant in their gonadal tissue or gonadal and somatic tissue, respectively, with risk of transmitting the variant to their offspring. De novo variants play a significant role in the development of genetic diseases and can be an indicator of mosaicism in either parent. Here, we present a study to elucidate the origin of mosaicism in apparently unaffected parents in two unrelated families with familial PIK3CD pathogenic variants. Methods We performed exome , Sanger, chromosomal microarray analysis , and panel deep sequencing for both families. DNA extracted from blood (proband and half-sibling) and saliva (mother) in family one (fam1), and blood samples (proband and sibling) and cultured fibroblast (parents) in family two (fam2) were utilized for analysis. Results We identified two families with more than one affected sibling and apparently unaffected parents. In fam1 we report three half-siblings, who share the same mother, with an apparent de novo (c.1002C>G, p. Asn334Lys) pathogenic variant in PIK3CD. In the proband and half-sibling, we detected the PIK3CD variant in 40/90 reads (44.4% variant allele fraction (VAF)) and 121/228 reads (53% VAF), respectively. The third half-sibling was tested at an outside laboratory. The mother was negative on exome (43X coverage); however deep sequencing analysis of her sample showed the PIK3CD variant in 29/11,811 reads (0.25% VAF), supporting gonosomal mosaicism. In fam2 we report two siblings, born to non-consanguineous parents, with the same apparently de novo (c. 3061G>A, p.Glu1021Lys) pathogenic variant in PIK3CD. In the proband and sibling, we detected the PIK3CD variant in 27/43 reads (62.7% VAF) and 19/31 reads (61.2% VAF), respectively. Prior testing in a clinical laboratory did not detect this variant in the parents. Parental samples are undergoing deep sequencing. Conclusions We report two families with apparent gonosomal and/or gonadal mosaicism for a PIK3CD pathogenic variant. Knowing parental carrier status is crucial for genetic counseling , accurate risk assessment and understanding the implications of bone marrow transplant donation. Molecular analysis on DNA samples from multiple tissues may be considered to further elucidate mosaicism in apparently unaffected parents.

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