Dados do Resumo

Título

Genetic Mosaicism in Gorlin-Goltz Syndrome: Clinical Case Analysis and Diagnostic Implications

Introdução

Gorlin-Goltz Syndrome (GGS), also known as Basal Cell Nevus Syndrome(BCNS), is a rare, multisystemic hereditary condition with autosomal dominant inheritance, high penetrance, and variable expressivity. It is associated with pathogenic germline variants in the PTCH1 and SUFU genes. GGS is characterized by a predisposition to developing multiple basal cell carcinomas, along with other anomalies such as odontogenic cysts and skeletal abnormalities. Genetic mosaicism is a phenomenon where an individual possesses two or more cell lineages with different genetic compositions. In GGS, the presence of mosaicism may explain the clinical variability observed among patients, including cases where the pathogenic variant is detected only in specific tissues and not in germline DNA. The evaluation of mosaicism is therefore highly relevant, as it can influence both the diagnosis and clinical management of patients, as well as contribute to a deeper understanding of the molecular mechanisms involved in GGS. Studies focusing on the analysis of genetic mosaicism in GGS are essential for identifying underdiagnosed cases and improving surveillance and treatment strategies.

Objetivo

The objective of this study is to assess the occurrence of genetic mosaicism in patients with clinical criteria for Gorlin-Goltz Syndrome

Métodos

To achieve this, we conducted a survey of patients with suspected Gorlin-Goltz Syndrome evaluated by the Oncogenetics Department and the Genomic Diagnostics Laboratory at A.C.Camargo Cancer Center (ACC). The results of genetic tests performed in clinical routine were compiled. The cases evaluated in this study are part of a larger research project (ethics committee number 2505/18). Cases with negative genetic test results or suspected mosaicism were evaluated for the availability of fresh-frozen or FFPE (formalin-fixed, paraffin-embedded) basal cell carcinoma tumor material. The DNA from the obtained tumors was sequenced using a genetic panel containing 409 frequently mutated cancer genes, including PTCH1 and SUFU, on the IonS5 platform (ThermoFisher). For cases with previously identified variants suspected of mosaicism, multiple tumors were evaluated by targeted amplicon sequencing to validate the identified variants. Polymerase chain reaction (PCR) was performed using a primer for the PTCH1 region, followed by amplicon library construction and next-generation sequencing (NGS) on the IonS5 platform. The variants were analyzed using VarSeq (GoldenHelix) and Integrative Genomics Viewer (IGV) software for visual confirmation and annotation of variant allele frequency (VAF).

Resultados

Of 16 patients with clinical suspicion of Gorlin-Goltz Syndrome followed at ACC, 7 underwent germline genetic testing, 3 were positive for the detection of a pathogenic germline variant in PTCH1

Conclusões

This study demonstrates the importance of evaluating genetic mosaicism in patients with Gorlin-Goltz Syndrome, especially in cases where conventional genetic tests yield negative or inconclusive results. The identification of mosaicism in specific tissues underscores the need for more comprehensive diagnostic approaches that consider the evaluation of other tissues. These findings have significant implications for genetic counseling, clinical management, and monitoring strategies for these patients

Financiador do resumo

FAPESP

Palavras Chave

Basal cell nevus syndrome; Genetic mosaicism; PTCH1