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

Author(s)

Valente, Flavia O. F. ; Camacho, Cleber 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.

• Document type: Journal article
• Source: AMERICAN JOURNAL OF MEDICAL GENETICS PART A; v. 194, n. 7, p. 5-pg., 2024-02-26.

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. (AU)

• FAPESP's process: 06/60402-1 - Medular carcinoma of the thyroid: revisiting the clinical, molecular biological, biochemical and biological aspects following findings of molecular genetics
• Grantee: Rui Monteiro de Barros Maciel
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 13/01476-9 - Screening of variants of unkown significance (VUS) in the RET proto-oncogene in patients with multiple endocrine neoplasia type 2 and healthy individual controls
• Grantee: Sergio Pereira de Almeida Toledo
• Support Opportunities: Regular Research Grants
• FAPESP's process: 14/06570-6 - Comprehensive whole exome, paired-end RNA and genome sequencing: new insights into genetic bases of thyroid carcinoma in pediatric and adult ages and applications in clinical practice
• Grantee: Janete Maria Cerutti
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 21/02752-6 - Multiple Endocrine Neoplasia type 2 (MEN 2) and Medullary Thyroid Carcinoma (TCM): new issues in developmental biology, genetics, immunology, epidemiology, mechanisms of disease and clinical management
• Grantee: Rui Monteiro de Barros Maciel
• Support Opportunities: Research Projects - Thematic Grants