Homozygosity for the pathogenic RET hotspot variant p.Cys634Trp: A consanguineous family with MEN2A.

ABSTRACT

Multiple endocrine neoplasia type 2 (MEN2) is a dominantly inherited condition with defined correlations between the genetic variant and clinical presentations. The location of pathogenic variants in the RET gene is a significant determinant of disease presentation and is associated with variable gene activation. Heterozygous pathogenic variants in codon 634 result in earlier onset of medullary thyroid carcinoma and higher incidence of phaeochromocytoma. Here we describe a consanguineous family with MEN2A that includes two children homozygous for the established pathogenic variant p. Cys634Trp. Both parents and a sibling were confirmed to being heterozygotes. Previous reports of biallelic or multiple RET variants have been limited to weakly activating variants. We present the first report of individuals homozygous for the highly activating RET p. Cys634Trp pathogenic variant and discuss disease severity and onset in this rare occurrence.