Studies of genetic mosaicism in rare diseases

Sammanfattning: Mosaicism in human genetics refers to an individual harboring two or more genetic compositions, all derived from the same fertilized egg. Common signs of genetic mosaicism are asymmetric growth, skin aberrations or vascular malformations. Each clinical picture is in itself rare, but together mosaic disorders form a growing group of identifiable characteristic abnormalities. Interestingly, several pharmacological treatment possibilities for these conditions have evolved in the last couple of years. In study I, we found mosaic hotspot PIK3CA variants in two patients with ectopic muscles and muscular overgrowth, by performing whole genome sequencing and digital PCR. This adds information about timing of PIK3CA mutagenesis during embryogenesis in correlation to phenotype and confirms the diagnostic entity PIK3CA-related muscular overgrowth with ectopic muscles. In study II, we describe a genetic mechanism in DICER1-related overgrowth. We show that a constitutional DICER1 variant encoding the RNase IIIa domain causes a severe subtype of DICER1 syndrome with intellectual disability, macrocephaly, extensive bilateral lung cysts, early onset of Wilms tumor, and well-differentiated fetal lung adenocarcinoma. This phenotype is similar to, but distinct from, the phenotype reported in two patients with GLOW syndrome caused by mosaic hotspot variants encoding the RNase IIIb domain. In study III, we add knowledge of genotype-phenotype correlations in male focal dermal hypoplasia patients by describing a previously unknown disease-causing variant in a male patient, and by highlighting that focal dermal hypoplasia can be suspected in patients with characteristic limb malformations, such as ectrodactyly, or ocular manifestations, even in the absence of typical skin findings. In study IV, we used droplet digital PCR to analyze blood- and sperm-derived DNA from 87 parents to children with intellectual disability syndromes caused by de novo variants. We found germline mosaicism in two fathers and showed that analysis of blood alone may underestimate germline mosaicism. Taken together, these studies have improved our understanding of methodological approaches in mosaicism diagnostics. In addition, these studies contribute to our understanding of the phenotypic and/or genetic spectrum of PIK3CA-related overgrowth, DICER1-related overgrowth, focal dermal hypoplasia and germline mosaicism in rare diseases.