RESUMO
The translocation of the testis-determining factor, the SRY gene, from the Y to the X chromosome is a rare event that causes abnormalities in gonadal development. In all cases of males and females carrying this translocation, disorder of sex development is reported. In our study, we described a peculiar pedigree with the first evidence of four healthy females from three generations who are carriers of the newly identified t(X;Y)(q28;p11.2)(SRY+) translocation with no evidence of ambiguous genitalia or other SRY-dependent alterations. Our study was a consequence of a Non-Invasive Prenatal Test (NIPT) showing a sexual chromosomal abnormality (XXY) followed by a chorionic villus analysis suggesting a normal karyotype 46,XX and t(X;Y) translocation detected by FISH. Here, we (i) demonstrated the inheritance of the translocation in the maternal lineage via karyotyping and FISH analysis; (ii) characterised the structural rearrangement via chromosomal microarray; and (iii) demonstrated, via Click-iT® EdU Imaging assay, that there was an absolute preferential inactivation of the der(X) chromosome responsible for the lack of SRY expression. Overall, our study provides valuable genetic and molecular information that may lead personal and medical decisions.
Assuntos
Cromossomos Humanos X , Genes sry , Masculino , Gravidez , Humanos , Feminino , Proteína da Região Y Determinante do Sexo/genética , Cromossomos Humanos X/genética , Aberrações Cromossômicas , Cariotipagem , Translocação Genética/genéticaRESUMO
Mutations in the gene HR coding for the hairless protein are associated with atrichia with papular lesions (APL), an autosomal recessive form of alopecia universalis that is characterized by generalized scalp and body atrichia with papular lesions. We here describe a South Italian family of ancient Albanian heritage. The full phenotype with complete atrichia was expressed in 2 siblings, whereas the parents and one sister were unaffected. Direct sequencing of the gene coding for the hairless protein allowed the identification of a new mutation in exon 17. Consistent with the recessive inheritance of the disease, both the siblings were homozygous for the mutation, whereas the parents and the unaffected sister where heterozygous. A relevant discrepancy with a haplotype linkage study is reported, stressing the importance of gene sequencing in genetic diagnosis and counseling because linkage studies can be biased by recombination events.
Assuntos
Fatores de Transcrição/genética , Adulto , Alopecia/genética , Alopecia/patologia , Alopecia/fisiopatologia , Cromossomos Humanos Par 8 , Feminino , Mutação da Fase de Leitura , Ligação Genética , Genótipo , Humanos , Masculino , Mutação , Linhagem , Análise de Sequência de DNA , Fatores de Transcrição/fisiologiaRESUMO
Unverricht-Lundborg disease (ULD) is an inherited form of progressive myoclonus epilepsy caused by mutations in the gene encoding Cystatin B (CSTB), an inhibitor of lysosomal proteases. The most common mutation described in ULD patients is an unstable expansion of a dodecamer sequence located in the CSTB gene promoter. This expansion is causative of the downregulation of CSTB gene expression and, consequently, of its inhibitory activity. Here we report the generation of induced pluripotent stem cell (iPSC) lines from two Italian siblings having a family history of ULD and affected by different clinical and pathological phenotypes of the disease.
Assuntos
Células-Tronco Pluripotentes Induzidas , Síndrome de Unverricht-Lundborg , Cistatina B/genética , Humanos , Itália , IrmãosRESUMO
Here, we described the generation of human induced pluripotent stem cell lines (hiPSCs) from fibroblasts isolated by punch biopsies of two siblings carrying inherited mutation (c.434 T > C) in the SCN1A gene, encoding for the neuronal voltage gated sodium channel NaV1.1. The mutation leads to the substitution of a highly conserved methionine with a threonine (M145T) in the protein sequence, leading to infant febrile seizures (FS). The older brother, affected by complex FS, also developed temporal lobe epilepsy (TLE) during adolescence.
Assuntos
Linhagem Celular , Células-Tronco Pluripotentes Induzidas , Convulsões Febris , Adolescente , Humanos , Lactente , Masculino , Mutação , Mutação de Sentido Incorreto/genética , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Convulsões Febris/genéticaRESUMO
Three relatives carrying a t(4;8)(p15.2;p23.2) translocation had juvenile myoclonic epilepsy, self-limited photosensitive occipital epilepsy and migraine with aura. The t(4;8) translocation interrupted the coding sequence of CSMD1 gene and occurred immediately to the 3'UTR of STIM2 gene. STIM2 was overexpressed in the patient carrying the unbalanced translocation, and all three individuals had a single functional copy of CSMD1. Array CGH study disclosed that these three individuals also carried a deletion at 5q12.3 that involves the RGS7BP gene. The overall results favor the view that CSMD1, STIM2, and RGS7BP genes could contribute to epilepsy and migraine phenotypes in our family.
Assuntos
Epilepsia Reflexa/genética , Proteínas de Membrana/genética , Enxaqueca com Aura/genética , Epilepsia Mioclônica Juvenil/genética , Molécula 2 de Interação Estromal/genética , Proteínas Supressoras de Tumor/genética , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Translocação Genética/genética , Adulto JovemRESUMO
AIMS: HNF1A is a gene coding for the transcription factor HNF1-α, mutated in some forms of MODY and type 2 diabetes mellitus characterized by a strong genetic component. The penetrance of HNF1A variants differs considerably; thus, to assess the genetic risk of diabetes in carrier subjects of a HNF1A mutant allele, a functional characterization of mutant forms is of paramount importance. METHODS: The HNF1A gene was sequenced in two patients with partly discordant diabetic phenotype, carrying the p.Pro409His variant. To evaluate the pathogenicity of the variant, we measured the transactivation power of the corresponding P408H HNF1-α mutant mouse form on HNF1-α target promoters. RESULTS: We found a lower but detectable activity of transactivation of the mutant form compared with the wild-type form and we excluded mechanisms of protein degradation or nuclear mislocalization. CONCLUSIONS: The HNF1A mutation p.Pro409His can be considered a mild variant that confers a moderate risk of type 2 diabetes mellitus in heterozygous carriers.
Assuntos
Diabetes Mellitus Tipo 2/genética , Fator 1-alfa Nuclear de Hepatócito/genética , Células Secretoras de Insulina/metabolismo , Mutação de Sentido Incorreto , Adulto , Animais , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Células HeLa , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Heterozigoto , Humanos , Camundongos , FenótipoRESUMO
We report a case of a woman with a cryptic balanced translocation between chromosomes 5 and 17, suspected during genetic counseling. The woman had a history of previous fetal losses attributed to lissencephaly and intra uterine growth retardation (IUGR) and a daughter with dysmorphic features and mental retardation, previously attributed to a small deletion 5pter, detected years ago by a first generation CGH-array. This peculiar combination of personal and family history suggested the opportunity to carry out a FISH approach, focusing on chromosomes 5 and 17, based on the idea that a malsegregation secondary to a balanced translocation, might have escaped the first CGH array. This approach allowed the identification of a balanced translocation in the mother, FISH in the affected child confirmed the partial 5p deletion predicted by the previous CGH array and identified a new 17p duplication that had not been detected before. The described translocation opens the possibility of alternative imbalances that were probably responsible for previous fetal losses. The imbalances were confirmed by a new high resolution SNP array. We conclude that despite the availability of highly effective and sensitive genomic approaches a careful evaluation of medical history is highly recommended since it can suggest clinical hypothesis that can be confirmed by more classical and molecular cytogenetic based approaches.
RESUMO
May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are autosomal dominant macrothrombocytopenias distinguished by different combinations of clinical and laboratory signs, such as sensorineural hearing loss, cataract, nephritis, and polymorphonuclear Döhle-like bodies. Mutations in the MYH9 gene encoding for the nonmuscle myosin heavy chain IIA (NMMHC-IIA) have been identified in all these syndromes. To understand the role of the MYH9 mutations, we report the molecular defects in 12 new cases, which together with our previous works represent a cohort of 19 families. Since no genotype-phenotype correlation was established, we performed an accurate clinical and biochemical re-evaluation of patients. In addition to macrothrombocytopenia, an abnormal distribution of NMMHC-IIA within leukocytes was observed in all individuals, including those without Döhle-like bodies. Selective, high-tone hearing deficiency and cataract was diagnosed in 83% and 23%, respectively, of patients initially referred as having May-Hegglin anomaly or Sebastian syndrome. Kidney abnormalities, such as hematuria and proteinuria, affected not only patients referred as Fechtner syndrome and Epstein syndrome but also those referred as May-Hegglin anomaly and Sebastian syndrome. These findings allowed us to conclude that May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are not distinct entities but rather a single disorder with a continuous clinical spectrum varying from mild macrothrombocytopenia with leukocyte inclusions to a severe form complicated by hearing loss, cataracts, and renal failure. For this new nosologic entity, we propose the term "MHY9-related disease," which better interprets the recent knowledge in this field and identifies all patients at risk of developing renal, hearing, or visual defects.
Assuntos
Proteínas Motores Moleculares , Cadeias Pesadas de Miosina/genética , Púrpura Trombocitopênica Idiopática/classificação , Púrpura Trombocitopênica Idiopática/genética , Adolescente , Adulto , Idoso , Catarata/complicações , Criança , Análise Mutacional de DNA , Diagnóstico Diferencial , Feminino , Genótipo , Perda Auditiva Neurossensorial/complicações , Hematúria/complicações , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Nefrite/complicações , Neutrófilos/metabolismo , Neutrófilos/ultraestrutura , Miosina não Muscular Tipo IIA/metabolismo , Linhagem , Fenótipo , Mutação Puntual/genética , Proteinúria/complicações , Púrpura Trombocitopênica Idiopática/complicações , Reação em Cadeia da Polimerase Via Transcriptase Reversa , SíndromeRESUMO
Objective. To assess aetiology of a POF in a 33-year-old woman and, if possible, plan a cure. Design. Case report. Setting. medical genetics diagnostic unit in a university hospital. Patient. A 33-year-old woman with premature ovarian failure (POF). Intervention(s). Genetic counseling, karyotyping, FISH study. Result(s). Turner-like diagnosis. Conclusion(s). Most cases of POF remain idiopathic. Turner syndrome can occur in very different phenotypes; cytogenetic and molecular profiling can provide a definitive diagnosis in cases with nonclassical phenotype.