RESUMO
The histone H3 variant H3.3, encoded by two genes H3-3A and H3-3B, can replace canonical isoforms H3.1 and H3.2. H3.3 is important in chromatin compaction, early embryonic development, and lineage commitment. The role of H3.3 in somatic cancers has been studied extensively, but its association with a congenital disorder has emerged just recently. Here we report eleven de novo missense variants and one de novo stop-loss variant in H3-3A (n = 6) and H3-3B (n = 6) from Baylor Genetics exome cohort (n = 11) and Matchmaker Exchange (n = 1), of which detailed phenotyping was conducted for 10 individuals (H3-3A = 4 and H3-3B = 6) that showed major phenotypes including global developmental delay, short stature, failure to thrive, dysmorphic facial features, structural brain abnormalities, hypotonia, and visual impairment. Three variant constructs (p.R129H, p.M121I, and p.I52N) showed significant decrease in protein expression, while one variant (p.R41C) accumulated at greater levels than wild-type control. One H3.3 variant construct (p.R129H) was found to have stronger interaction with the chaperone death domain-associated protein 6.
Assuntos
Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Neoplasias/diagnóstico , Neoplasias/genética , Adulto , Deleção Cromossômica , Transtornos Cromossômicos/terapia , Cromossomos Humanos Par 22/genética , Eletroencefalografia , Feminino , Estudos de Associação Genética/métodos , Testes Genéticos , Humanos , Cariótipo , Cariotipagem/métodos , Imageamento por Ressonância Magnética/métodos , FenótipoRESUMO
OBJECTIVE: To report a novel association between a cancer predisposition syndrome (hereditary leiomyomatosis and renal cell carcinoma [HLRCC]) and male infertility. DESIGN: Case report. SETTING: University medical center adult genetics clinic. PATIENT(S): A 31-year-old male of Chinese ancestry referred for evaluation of immotile sperm. INTERVENTION(S): Physical examination, family history assessment, genetic testing, and cancer screening. MAIN OUTCOME MEASURE(S): Genetic testing results. RESULT(S): Physical exam: cutaneous leiomyomata on the upper back and left arm. Family history: the patient has a sister with uterine leiomyomata. Genetic testing revealed a mutation in the fumarate hydratase gene, which codes for an enzyme (fumarase) that has previously been implicated in sperm number and motility. More recently, heterozygous mutations in this gene have been associated with HLRCC. However, male infertility is not a recognized manifestation of this condition. CONCLUSION(S): A comprehensive medical (including family) history and physical examination are important when evaluating male infertility. Genetics consultation enabled our patient and his family to begin appropriate cancer screening and provided reproductive options, including prenatal/preimplantation diagnosis. Further studies of the relationship between fumarase, HLRCC, and male infertility are needed to provide accurate counseling to families and to better understand genotype-phenotype correlations.
