RET 634 germline/gonadal mosaicism generating a second pathogenic amino acid change in multiple endocrine neoplasia type 2A

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 autosom...

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Published in:American journal of medical genetics. Part A 2024-07, Vol.194 (7), p.e63576-n/a
Main Authors: Valente, Flávia O. F., Camacho, Cléber P., Lindsey, Susan C., Yang, Ji H., Kunii, Ilda S., Santos, Roberto B., Kizys, Marina M. L., Cerutti, Janete M., Dias‐da‐Silva, Magnus R., Maciel, Rui M. B.
Format: Article
Language:English
Subjects:
Amino acids
Embryogenesis
exome
Genetic screening
Genotypes
medullary thyroid cancer
Mosaicism
Multiple endocrine neoplasia
Mutation
Neuroendocrine tumors
Nucleotides
RET
Ret protein
Siblings
Thyroid cancer
Thyroid carcinoma
Thyroid gland
Whole genome sequencing
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Summary: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.
ISSN:1552-4825
1552-4833
1552-4833
DOI:10.1002/ajmg.a.63576