RESUMEN
Background: Oculocutaneous albinism (OCA) is a Mendelian disorder characterized by hypopigmentation of the skin, hair, and eyes, hypoplastic fovea, and low vision, known to be caused by mutations in the Tyrosinase (TYR) gene. Among the known TYR variants, some reduce but do not completely eliminate tyrosinase activity, allowing residual production of melanin and resulting in a contradictory assignment as either pathogenic or benign, preventing a precise clinical diagnostic.Materials and Methods: In the present work, we performed Whole Exome Sequencing and subsequent Sanger sequencing in a young male clinically diagnosed with OCA.Results: Whole-exome sequencing analysis revealed the identification of two variants in trans in TYR. The first, corresponds to a known pathogenic variant G47D, while the second S192Y, was considered a polymorphism due to its relatively high frequency in the European population.Conclusion: The lack of other pathogenic variants in TYR, the reported reduced enzymatic activity (ca. 40% respect to wt) for S192Y, together with the structural in-silico analysis strongly suggest that both reported variants are jointly disease-causing and that S192Y should be considered as likely pathogenic, especially when it is found in trans with a null variant.
Asunto(s)
Albinismo Oculocutáneo/genética , Monofenol Monooxigenasa/genética , Mutación Missense/genética , Polimorfismo de Nucleótido Simple/genética , Adolescente , Albinismo Oculocutáneo/diagnóstico , Secuencia de Aminoácidos , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Datos de Secuencia Molecular , Linaje , Secuenciación del ExomaRESUMEN
PURPOSE: Each year, 17,000 new breast cancer cases are diagnosed in Argentina, and 5400 women die of breast cancer. The contribution of cancer-related mutations to the incidence of breast cancer in Argentina has not yet been explored. METHODS: We sequenced the entire coding regions of BRCA1, BRCA2, PALB2 and RAD51C in 112 unselected Argentinian breast cancer patients. RESULTS: A pathogenic genetic variant was found in 12 of 112 (10.7%) patients; two in BRCA1 (1.8%), five in BRCA2 (4.5%), four in PALB2 (3.6%) and one in RAD51C (0.9%). Three of four (75%) PALB2 mutation carriers carried the same variant (c.1653T > A). CONCLUSIONS: A founder mutation in PALB2 accounts for up to 4% of breast cancer patients in Argentina. BRCA1, BRCA2, PALB2 and RAD51C should be included in the genetic testing panel of breast cancer patients in Argentina.
Asunto(s)
Neoplasias de la Mama/genética , Proteínas del Grupo de Complementación de la Anemia de Fanconi/genética , Predisposición Genética a la Enfermedad/genética , Adulto , Anciano , Anciano de 80 o más Años , Argentina/epidemiología , Proteína BRCA1/genética , Proteína BRCA2/genética , Biomarcadores de Tumor/genética , Neoplasias de la Mama/sangre , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/patología , Proteínas de Unión al ADN/genética , Proteína del Grupo de Complementación N de la Anemia de Fanconi/genética , Femenino , Estudios de Asociación Genética , Mutación de Línea Germinal , Humanos , Persona de Mediana Edad , LinajeRESUMEN
Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome characterized by macroglossia, macrosomia, and abdominal wall defects. It is a multigenic disorder caused in most patients by alterations in growth regulatory genes. A small number of individuals with BWS (5-10%) have mutations in CDKN1C, a cyclin-dependent kinase inhibitor of G1 cyclin complexes that functions as a negative regulator of cellular growth and proliferation. Here, we report on eight patients with BWS and CDKN1C mutations and review previous reported cases. We analyzed 72 patients (50 BWS, 17 with isolated hemihyperplasia (IH), three with omphalocele, and two with macroglossia) for CDKN1C defects with the aim to search for new mutations and to define genotype-phenotype correlations. Our findings suggest that BWS patients with CDKN1C mutations have a different pattern of clinical malformations than those with other molecular defects. Polydactyly, genital abnormalities, extra nipple, and cleft palate are more frequently observed in BWS with mutations in CDKN1C. The clinical observation of these malformations may help to decide which genetic characterization should be undertaken (i.e., CDKN1C screening), thus optimizing the laboratory evaluation for BWS.