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1.
Cytogenet Genome Res ; 158(1): 25-31, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31055587

RESUMO

Diagnosing a complex genetic syndrome and correctly assigning the concomitant phenotypic traits to a well-defined clinical form is often a medical challenge. In this work, we report the analysis of a family with complex phenotypes, including microcephaly, intellectual disability, dysmorphic features, and polydactyly in the proband, with the aim of adding new aspects for obtaining a clear diagnosis. We performed array-comparative genomic hybridization and quantitative reverse transcriptase PCR (qRT-PCR) analyses. We identified a deletion of chromosome 20p12.1 involving the macrodomain containing 2/mono-ADP ribosylhydrolase 2 gene (MACROD2) in several members of the family. This gene is actually not associated with a specific syndrome but with congenital anomalies of multiple organs. qRT-PCR showed higher levels of a MACROD2 mRNA isoform in the individuals carrying the deletion. Our results, together with other data reported in the literature, support the hypothesis that the deletion in MACROD2 can affect correct embryonic development and that the presence of another associated event, such as epigenetic modifications at the MACROD2 locus, can influence the level of severity of the pathology.


Assuntos
Anormalidades Múltiplas/genética , Enzimas Reparadoras do DNA/genética , Hidrolases/genética , Deficiência Intelectual/genética , Rim/anormalidades , Microcefalia/genética , Pâncreas/anormalidades , Polidactilia/genética , Deleção de Sequência , Adulto , Cromossomos Humanos Par 20/genética , Cromossomos Humanos Par 20/ultraestrutura , Hibridização Genômica Comparativa , Enzimas Reparadoras do DNA/deficiência , Enzimas Reparadoras do DNA/fisiologia , Desenvolvimento Embrionário/genética , Feminino , Humanos , Hidrolases/deficiência , Hidrolases/fisiologia , Masculino , Linhagem , Fenótipo , Transtornos Psicomotores/genética
2.
Am J Med Genet A ; 173(5): 1348-1352, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28322498

RESUMO

Bjornstad syndrome is a rare condition characterized by pili torti and sensorineural hearing loss associated with pathological variations in BCS1L. Mutations in this gene are also associated with the more severe complex III deficiency and GRACILE syndrome. We report the first Italian patients with Bjornstad syndrome, two siblings with pili torti and sensorineural hearing loss, in whom we detected two novel compound heterozygous mutations in BCS1L. A thorough clinical evaluation did not reveal any features consistent with complex III deficiency or GRACILE syndrome.


Assuntos
Complexo III da Cadeia de Transporte de Elétrons/genética , Doenças do Cabelo/genética , Perda Auditiva Neurossensorial/genética , Doenças Mitocondriais/congênito , ATPases Associadas a Diversas Atividades Celulares , Feminino , Doenças do Cabelo/patologia , Doenças do Cabelo/fisiopatologia , Perda Auditiva Neurossensorial/fisiopatologia , Humanos , Masculino , Doenças Mitocondriais/genética , Doenças Mitocondriais/fisiopatologia , Mutação de Sentido Incorreto , Linhagem , Irmãos
4.
Mol Cytogenet ; 8: 18, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25821518

RESUMO

BACKGROUND: Sensorineural hearing impairment is a common pathological manifestation in patients affected by X-linked intellectual disability. A few cases of interstitial deletions at Xq21 with several different phenotypic characteristics have been described, but to date, a complete molecular characterization of the deletions harboring disease-causing genes is still missing. Thus, the aim of this study is to realize a detailed clinical and molecular analysis of a family affected by syndromic X-linked hearing loss with intellectual disability. RESULTS: Clinical analyses revealed a very complex phenotype that included inner ear malformations, vestibular problems, choroideremia and hypotonia with a peculiar pattern of phenotypic variability. Genomic analysis revealed, for the first time, the presence of two close interstitial deletions in the Xq21.1-21.3, harboring 11 protein coding, 9 non-coding genes and 19 pseudogenes. Among these, 3 protein coding genes have already been associated with X-linked hearing loss, intellectual disability and choroideremia. CONCLUSIONS: In this study we highlighted the presence of peculiar genotypic and phenotypic details in a family affected by syndromic X-linked hearing loss with intellectual disability. We identified two, previously unreported, Xq21.1-21.3 interstitial deletions. The two rearrangements, containing several genes, segregate with the clinical features, suggesting their role in the pathogenicity. However, not all the observed phenotypic features can be clearly associated with the known genes thus, further study is necessary to determine regions involved.

5.
Indian J Otolaryngol Head Neck Surg ; 66(3): 297-301, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25032118

RESUMO

The etiology of otosclerosis is unknown. The etiopathogenesis of otosclerosis seems similar to that occurring in Paget's disease of bone, for which mutations or polymorphisms in several genes have been identified. Among these, TNFRSF11B gene encoding the osteoprotegerin is produced at high levels in the normal inner ear and at low level in active otosclerotic stapes footplates. The aim of this work was to verify the presence of a correlation between the rs2073618 (N3K) polymorphism in the TNFRSF11B gene and otosclerosis. Mutational screening in the TNFRSF11B gene was performed by direct sequencing. SNPs analysis was performed by PCR and by specific restriction enzyme assay with HpaI. The significance of the association was analyzed by statistical specific software. No causative mutation has been identified but the data suggested a strong correlation between the rs2073618 (N3K) polymorphism and otosclerosis. This correlation, however, has been excluded in a case-control study. This study excluded the association between the N3K polymorphism and otosclerosis in Campania region population.

6.
Int J Audiol ; 50(12): 866-70, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21916817

RESUMO

OBJECTIVE: To determine the incidence of GJB2 and GJB3 mutations and of two deletions upstream of the GJB6 gene in infants of the Campania region of southern Italy. DESIGN: DNA samples from non-syndromic hearing-impaired infants enrolled in a neonatal screening programme for sensorineural hearing loss were analysed by PCR and by direct sequencing. The audiological features of infants with biallelic GJB2 mutations were also examined to identify genotype-phenotype correlations. STUDY SAMPLE: Molecular analyses were carried out in 129 affected and five unaffected infants. RESULTS: A genetic etiology of hearing loss was identified in 28% of infants, including several at environmental risk of hearing loss. Neither GJB6 nor GJB3 (a gene not previously investigated in the Campania population) mutations were found. CONCLUSIONS: This study confirms the importance of universal neonatal hearing screening. The identification of a genetic cause in infants at environmental risk indicates that such infants should be included when investigating etiology. We confirm that also in our geographical area, c.35delG homozygotes tend to have severe symmetrical hearing loss, whereas hearing impairment is milder in compound heterozygotes.


Assuntos
Conexinas/genética , Perda Auditiva Neurossensorial/genética , Conexina 26 , Conexina 30 , Análise Mutacional de DNA , Estudos de Associação Genética , Perda Auditiva Neurossensorial/epidemiologia , Humanos , Incidência , Lactente , Itália/epidemiologia , Programas de Rastreamento , Deleção de Sequência
7.
Curr Genomics ; 12(7): 475-785, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22547955

RESUMO

The GJB2 gene is located on chromosome 13q12 and it encodes the connexin 26, a transmembrane protein involved in cell-cell attachment of almost all tissues. GJB2 mutations cause autosomal recessive (DFNB1) and sometimes dominant (DFNA3) non-syndromic sensorineural hearing loss. Moreover, it has been demonstrated that connexins are involved in regulation of growth and differentiation of epidermis and, in fact, GJB2 mutations have also been identified in syndromic disorders with hearing loss associated with various skin disease phenotypes. GJB2 mutations associated with skin disease are, in general, transmitted with a dominant inheritance pattern. Nonsyndromic deafness is caused prevalently by a loss-of-function, while literature evidences suggest for syndromic deafness a mechanism based on gain-of-function. The spectrum of skin manifestations associated with some mutations seems to have a very high phenotypic variability. Why some mutations can lead to widely varying cutaneous manifestations is poorly understood and in particular, the reason why the skin disease-deafness phenotypes differ from each other thus remains unclear. This review provides an overview of recent findings concerning pathogenesis of syndromic deafness imputable to GJB2 mutations with an emphasis on relevant clinical genotype-phenotype correlations. After describing connexin 26 fundamental characteristics, the most relevant and recent information about its known mutations involved in the syndromic forms causing hearing loss and skin problems are summarized. The possible effects of the mutations on channel expression and function are discussed.

9.
Int J Audiol ; 49(4): 326-31, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20233142

RESUMO

The aim of this study was to screen 349 patients affected by sensorineural hearing loss (SNHL), mostly from the Campania region (southern Italy), for GJB2 gene mutations and for two deletions of the GJB6 gene (del GJB6 -D13S1830 and del GJB6 -D13S1854). We identified pathogenetic GJB2 mutations in 51 cases (15% of patients). No GJB6 mutation was found. We also examined the audiologic features of the patients for whom we had an etiologic diagnosis, in order to identify correlations between the severity of hearing loss and the type of mutation.


Assuntos
Conexinas/genética , Testes Genéticos , Perda Auditiva Neurossensorial/genética , Programas de Rastreamento/métodos , Mutação , Estimulação Acústica , Adolescente , Adulto , Audiometria , Percepção Auditiva , Criança , Pré-Escolar , Conexina 26 , Conexina 30 , Predisposição Genética para Doença , Perda Auditiva Neurossensorial/epidemiologia , Perda Auditiva Neurossensorial/fisiopatologia , Heterozigoto , Homozigoto , Humanos , Itália/epidemiologia , Pessoa de Meia-Idade , Fenótipo , Fatores de Risco , Índice de Gravidade de Doença , Adulto Jovem
10.
Am J Med Genet A ; 149A(4): 685-8, 2009 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-18688874

RESUMO

The GJB2 gene located on chromosome 13q12 and encoding the connexin 26 (Cx26) protein, a transmembrane protein involved in cell-cell attachment of almost all tissues, including the skin, causes autosomal recessive and sometimes dominant nonsyndromic sensorineural hearing loss. GJB2 mutations have also been identified in syndromic disorders exhibiting hearing loss associated with skin problems. Recently, a new mutation, p.G130V in the GJB2 gene has been reported as causative for Vohwinkel syndrome. In this case the p.G130V mutation was found in two patients (son and father) with palmoplantar keratoderma. The father also showed also skin constrictions of the 2nd and 3rd toes of the right foot. Here, we report on another family with palmoplantar keratoderma associated with a dominant form of hearing loss confirming the genotype-phenotype correlation between the mutation p.G130V and the skin abnormalities observed in syndromic disorders with hearing loss as described by [Snoeckx et al. (2005) Hum Mutat 26:60-65].


Assuntos
Conexinas/genética , Perda Auditiva Neurossensorial/complicações , Perda Auditiva Neurossensorial/genética , Ceratodermia Palmar e Plantar/complicações , Ceratodermia Palmar e Plantar/genética , Mutação Puntual , Audiometria de Tons Puros , Pré-Escolar , Conexina 26 , Feminino , Genes Dominantes , Genótipo , Perda Auditiva Neurossensorial/fisiopatologia , Humanos , Ceratodermia Palmar e Plantar/patologia , Masculino , Linhagem , Fenótipo , Síndrome
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