Postzygotic mosaicism of a novel PTPN11 mutation in monozygotic twins discordant for metachondromatosis

Abstract

Genetic mosaicism caused by postzygotic mutations is of a great interest due to its role in human disease. Monozygotic twins arising from a single zygote are considered as genetically identical, and any differences likely to be caused by postzygotic events. Thus, phenotypically discordant monozygotic twins offer a unique opportunity to study genotype–phenotype correlation. Here, we present a three‐generation family starting from a pair of monozygotic twins discordant for metachondromatosis due to postzygotic p.(Gln175His) variant in the PTPN11 gene. Both phenotypically discordant monozygotic twins harbor p.(Gln175His), however significant differences in mosaic ratio is observed not only between twins, but also within different tissue types within one individual. Phenotypic manifestation of p.(Gln175His) in examined family clearly depends on allele variant fraction (VAF). Individuals harboring constitutional mutation (VAF 50%) present typical metachondromatosis. Milder phenotype is observed in twin harboring high‐level mosaicism in the tissue of ectodermal origin (VAF 45%), but not in a blood (VAF 5%). Finally, her twin sister harboring low‐level mosaicism in blood (VAF 2%) and nonblood (VAF 12%) tissues is phenotypically normal. Our results provide insights into biological role of mosaicism in disease and further support the usefulness of nonblood tissues as an optimal source of DNA for the identification of postzygotic mutations in phenotypically discordant monozygotic twins.

Lateralized overgrowth with vascular malformation caused by a somaticPTPN11pathogenic variant: Another piece added to the puzzle of mosaicRASopathies

“…8 More recently, postzygotic mosaicism of a specific PTPN11 variant, p.(Gln175His), has been linked to metachondromatosis. 15 The p.(Thr507Lys) variant we found in our patient has been previously described as a somatic event in different types of cancers, 16 and as germline event in two severely malformed fetuses 17,18 survival, differentiation, and proliferation in response to extracellular stimuli. 19 Several hints suggest that these two cascades are connected in a complex cross-talk network and intersect regulating their respective downstream functions.…”

“…Somatic PTPN11 variants are associated with cancer, and frequently found inJMML 8 . More recently, postzygotic mosaicism of a specific PTPN11 variant, p.(Gln175His), has been linked to metachondromatosis 15 . The p.(Thr507Lys) variant we found in our patient has been previously described as a somatic event in different types of cancers, 16 and as germline event in two severely malformed fetuses 17,18 but not in live RASopathy patients, indicating the likely lethality of this variant in the germinal state.…”

Mutation in mitochondrial chaperone TRAP1 results in male-specific autism

“…Therefore, even though the TRAP and RUVBL1 variants emerged post-twinning in the ASD-affected brother, they were detected in the phenotypically normal twin blood sample. This may reflect postulated blood chimerism in MZTs due to the transfer of hematopoietic stem cells between the twins in utero, which mask genetic differences between disease-discordant MZTs when mutational screening on blood-derived DNA (18,19), underscoring the importance of using non-hematopoietic tissues (20,21). Any genetic differences between MZTs are considered as postzygotic events.…”