Prevalence and genetics of "de novo" MEN2 syndromes

Hereditary medullary thyroid carcinoma (MTC) is an inherited syndrome accounting for 25% of MTC cases. It is caused by germline RET mutations, which can be inherited or occur de novo.

This study aimed to define the prevalence and genetics of de novo MEN2 syndromes, which are not yet fully understood, and to characterize the parental origin of the RET de novo mutation.

We selected 152 of 215 families with hereditary MTC. In de novo cases, we sequenced the wild-type and mutated alleles of the index cases and compared their single nucleotide polymorphism profiles with those of their parents. Digital droplet PCR was performed to determine the presence of mosaicism in both the index case and the parents.

In 24 of 152 (15.78%) families, the index case had a de novo mutation. Single nucleotide polymorphism analysis demonstrated that in all cases, the mutation occurred on the paternal allele. The absence of mosaicism supported the hypothesis that the mutation occurred during spermatogenesis. The mean age of fathers at the time of conception was, in some cases but not all, relatively advanced.

The prevalence of de novo hereditary MEN2 syndromes was approximately 16%, including MEN2B, and around 9% for other phenotypes. All de novo cases were of paternal origin and likely resulted from an acquired alteration in sperm DNA. The possible role of advanced paternal age in promoting de novo mutations could not be ruled out.