Abstract：
Genetic testing for germline RET pathogenic variants, which cause the Multiple Endocrine Neoplasia Type 2 (MEN2) syndrome, has become crucial in managing patients with medullary thyroid carcinoma (MTC). Classically, RET heterozygous missense pathogenic variants are transmitted in a Mendelian autosomal dominant pattern, of which germline/gonadal mosaicism has never been reported. We report the novel occurrence of a MEN2A patient\'s family in which the siblings inherited three different RET 634 genotypes: wild type (p.Cys634), p.Cys634Gly or p.Cys634Arg heterozygous pathogenic variants. We hypothesized that germline/gonadal mosaicism, derived from an inherited + early somatic mutation in the mother or a double de novo mutation during maternal embryogenesis, led to this rare event in the RET gene. Exome analysis of the proband\'s deceased mother\'s paraffin-embedded thyroid tissue confirmed the three nucleotides in the same 634 codon position. For the first time, we describe germline/gonadal mosaicism in RET, generating a second pathogenic amino acid change in the same codon causing MEN2A. Our finding shows that RET parental mosaicism, confirmed by somatic exome sequencing, might explain discrepant genotype cases in siblings with inherited cancers.
摘要：
种系RET致病变异的基因检测，导致多发性内分泌肿瘤2型（MEN2）综合征，在治疗甲状腺髓样癌（MTC）患者中变得至关重要。经典的,RET杂合错义致病变异以孟德尔常染色体显性模式传播，其中种系/性腺镶嵌从未被报道。我们报道了MEN2A患者家庭的新发生，其中兄弟姐妹继承了三种不同的RET634基因型：野生型（p。Cys634),p.Cys634Gly或p.Cys634Arg杂合致病变体。我们假设生殖系/性腺镶嵌，源自母亲的遗传+早期体细胞突变或母亲胚胎发生期间的双重从头突变，导致了RET基因的罕见事件.先证者已故母亲石蜡包埋的甲状腺组织的外显子组分析证实了三个核苷酸位于相同的634个密码子位置。第一次,我们在RET中描述了生殖系/性腺镶嵌，在导致MEN2A的相同密码子中产生第二个致病性氨基酸变化。我们的发现表明RET父母的马赛克，通过体细胞外显子组测序证实，可能解释了遗传性癌症兄弟姐妹中不同基因型的病例。
