Germline selection of PTPN11 (HGNC:9644) variants make a major contribution to both Noonan syndrome's high birth rate and the transmission of sporadic cancer variants resulting in fetal abnormality. Issue 12 (24th November 2022)

• Record Type: Journal Article
• Authors: Eboreime, Jordan; Choi, Soo‐Kyung; Yoon, Song‐Ro; Sadybekov, Anastasiia; Katritch, Vsevolod; Calabrese, Peter; Arnheim, Norman
• Is Part Of: Human mutation. Volume 43:Issue 12(2022)
• Page Start: 2205
• Page End: 2221
• Publication Date: 2022-11-24
• Subjects: fetal abnormality -- germline selection -- Noonan syndrome -- RASopathies -- sporadic cancer -- SSC clonal expansion; Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.24493
• Languages: English
• ISSNs: 1059-7794

Abstract

Abstract: Some spontaneous germline gain‐of‐function mutations promote spermatogonial stem cell clonal expansion and disproportionate variant sperm production leading to unexpectedly high transmission rates for some human genetic conditions. To measure the frequency and spatial distribution of de novo mutations we divided three testes into 192 pieces each and used error‐corrected deep‐sequencing on each piece. We focused on PTPN11 (HGNC:9644) Exon 3 that contains 30 different PTPN11 Noonan syndrome (NS) mutation sites. We found 14 of these variants formed clusters among the testes; one testis had 11 different variant clusters. The mutation frequencies of these different clusters were not correlated with their case‐recurrence rates nor were case recurrence rates of PTPN11 variants correlated with their tyrosine phosphatase levels thereby confusing PTPN11 's role in germline clonal expansion. Six of the PTPN11 exon 3 de novo variants associated with somatic mutation‐induced sporadic cancers (but not NS) also formed testis clusters. Further, three of these six variants were observed among fetuses that underwent prenatal ultrasound screening for NS‐like features. Mathematical modeling showed that germline selection can explain both the mutation clusters and the high incidence of NS (1/1000–1/2500). Abstract : Mutation frequency heat map of spontaneous PTPN11 variants show spatial clustering in the testis due to germline selection explaining the high birth incidence of Noonan syndrome. Some somatic PTPN11 cancer mutations are similarly clustered in testis.