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,Human Mutation

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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
Human Mutation ( IF 3.3 ) Pub Date : 2022-11-09 , DOI: 10.1002/humu.24493
Jordan Eboreime ₁ , Soo-Kyung Choi ₁ , Song-Ro Yoon ₁ , Anastasiia Sadybekov ₂ , Vsevolod Katritch ₂ , Peter Calabrese ₃ , Norman Arnheim ₁

Affiliation

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).

中文翻译：

PTPN11 (HGNC:9644) 变体的种系选择对努南综合征的高出生率和导致胎儿异常的散发性癌症变体的传播做出了重大贡献

一些自发的种系功能获得性突变促进精原干细胞克隆扩增和不成比例的变异精子产生，导致某些人类遗传条件下意外的高传播率。为了测量从头突变的频率和空间分布，我们将三个睾丸分成 192 块，并对每块进行纠错深度测序。我们专注于包含 30 个不同PTPN11努南综合征 (NS) 突变位点的PTPN11 (HGNC:9644) 外显子 3 。我们发现这些变体中有 14 个在睾丸中形成了簇；一个睾丸有 11 个不同的变异簇。这些不同簇的突变频率与其病例复发率无关，也与PTPN11的病例复发率无关变体与其酪氨酸磷酸酶水平相关，从而混淆了PTPN11在种系克隆扩增中的作用。与体细胞突变诱导的散发性癌症（但不是 NS）相关的PTPN11外显子 3 从头变体中的六个也形成了睾丸簇。此外，在接受产前超声筛查 NS 样特征的胎儿中观察到这六种变体中的三种。数学模型表明，种系选择可以解释突变簇和 NS 的高发病率 (1/1000–1/2500)。

更新日期：2022-11-09

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