RESUMEN
Structural variation is a source of genetic variation that, in some cases, may trigger pathogenicity. Here, we describe two cases, a mother and son, with the same partial inverted duplication of the long arm of chromosome 8 [invdup(8)(q24.21q24.21)] of 17.18 Mb, showing different clinical manifestations: microcephaly, dorsal hypertrichosis, seizures and neuropsychomotor development delay in the child, and a cleft lip/palate, down-slanted palpebral fissures and learning disabilities in the mother. The deleterious outcome, in general, is reflected by the gain or loss of genetic material. However, discrepancies among the clinical manifestations raise some concerns about the genomic configuration within the chromosome and other genetic modifiers. With that in mind, we also performed a literature review of research published in the last 20 years about the duplication of the same, or close, chromosome region, seeking the elucidation of at least some relevant clinical features.
Asunto(s)
Cromosomas Humanos Par 8 , Humanos , Femenino , Masculino , Cromosomas Humanos Par 8/genética , Adulto , Inversión Cromosómica/genética , Microcefalia/genética , Microcefalia/patología , Duplicación Cromosómica/genética , Niño , PreescolarRESUMEN
PURPOSE: Li-Fraumeni Syndrome (LFS) is a rare cancer predisposing condition caused by germline pathogenic TP53 variants, in which core tumors comprise sarcomas, breast, brain and adrenocortical neoplasms. Clinical manifestations are highly variable in carriers of the Brazilian germline founder variant TP53 p.R337H, possibly due to the influence of modifier genes such as miRNA genes involved in the regulation of the p53 pathway. Herein, we investigated the potential phenotypic effects of two miRNA-related functional SNPs, pri-miR-34b/c rs4938723 and 3'UTR KRAS rs61764370, in a cohort of 273 LFS patients from Southern and Southeastern Brazil. METHODS: The genotyping of selected SNPs was performed by TaqMan® allelic discrimination and subsequently custom TaqMan® genotyping results were confirmed by Sanger sequencing in all SNP-positive LFS patients. RESULTS: Although the KRAS SNP showed no effect as a phenotype modulator, the rs4938723 CC genotype was significantly associated with development of LFS non-core tumors (first tumor diagnosis) in p.R337H carriers (p = 0.039). Non-core tumors were also more frequently diagnosed in carriers of germline TP53 DNA binding domain variants harboring the rs4938723 C variant allele. Previous studies described pri-miR-34b/c rs4938723 C as a risk allele for sporadic occurrence of thyroid and prostate cancers (non-core tumors of the LFS spectrum). CONCLUSION: With this study, we presented additional evidence about the importance of analyzing miRNA genes that could indirectly regulate p53 expression, and, therefore, may modulate the LFS phenotype, such as those of the miR-34 family.