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1.
Mol Genet Genomic Med ; 8(1): e1056, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31851782

RESUMO

BACKGROUND: Chromosomal microarray analysis (CMA) is nowadays widely used in the diagnostic path of patients with clinical phenotypes. However, there is no ascertained evidence to date on how to assemble single/combined clinical categories of developmental phenotypic findings to improve the array-based detection rate. METHODS: The Italian Society of Human Genetics coordinated a retrospective study which included CMA results of 5,110 Italian patients referred to 17 genetics laboratories for variable combined clinical phenotypes. RESULTS: Non-polymorphic copy number variants (CNVs) were identified in 1512 patients (30%) and 615 (32%) present in 552 patients (11%) were classified as pathogenic. CNVs were analysed according to type, size, inheritance pattern, distribution among chromosomes, and association to known syndromes. In addition, the evaluation of the detection rate of clinical subgroups of patients allowed to associate dysmorphisms and/or congenital malformations combined with any other single clinical sign to an increased detection rate, whereas non-syndromic neurodevelopmental signs and non-syndromic congenital malformations to a decreased detection rate. CONCLUSIONS: Our retrospective study resulted in confirming the high detection rate of CMA and indicated new clinical markers useful to optimize their inclusion in the diagnostic and rehabilitative path of patients with developmental phenotypes.


Assuntos
Aberrações Cromossômicas , Deficiências do Desenvolvimento/genética , Testes Genéticos/normas , Análise de Sequência com Séries de Oligonucleotídeos/normas , Guias de Prática Clínica como Assunto , Variações do Número de Cópias de DNA , Deficiências do Desenvolvimento/classificação , Deficiências do Desenvolvimento/diagnóstico , Testes Genéticos/métodos , Genética Médica/organização & administração , Humanos , Itália , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Fenótipo , Sensibilidade e Especificidade , Sociedades Médicas/normas
3.
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.
Clin J Pain ; 31(1): 52-7, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24469609

RESUMO

OBJECTIVES: Cluster headache (CH) is characterized by severe, recurrent, unilateral attacks of extreme intensity and brief duration. Variants in a myriad of genes were studied in sporadic CH patients, often with conflicting results. METHODS: We studied gene mutations in some candidate genes, hypocretin receptor 2, Clock, and alcohol dehydrogenase 4 (ADH4), in 54 unrelated sporadic CH patients and in 200 controls in 8 kindreds/families that included more affected and nonaffected cases. Furthermore, we performed the whole-genome scanning by comparative genomic hybridization, searching for rearrangements associated with DNA gain or loss in a subset of sporadic and familial CH and control participants. RESULTS: The analysis of candidate genes revealed that only allele and genotype frequency of the 2 ADH4 mutations resulted significantly between sporadic CH and controls; the same mutations were homozygous in CH patients from 2 families. The comparative genomic hybridization analysis revealed 2 novel rearrangements that involved the intron regions of thyrotropin-releasing hormone-degrading enzyme and neurexin 3 (NRXN3) genes, respectively. The first arrangement was present either in CH or in controls, whereas the second one was specifically found in some sporadic and familial CH cases. CONCLUSIONS: Our data (although obtained on a small number of cases) confirm the genetic heterogeneity of CH, suggesting that mutations in the ADH4 gene and a novel rearrangement involving NRXN3 gene might be related to CH in a subset of cases.


Assuntos
Álcool Desidrogenase/genética , Cefaleia Histamínica/genética , Predisposição Genética para Doença/genética , Mutação/genética , Proteínas do Tecido Nervoso/genética , Adolescente , Adulto , Feminino , Frequência do Gene , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Receptores de Orexina/genética , Adulto Jovem
6.
Gene ; 536(1): 213-6, 2014 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-24315824

RESUMO

The 22q11.2 microduplication is a genomic disorder, characterized from a variable phenotype ranging from different defects to normality. The most common microduplication of 22q11.2 is 3 Mb in size, but there are also cases reported with atypical duplications between 0.8 Mb and 6Mb. Here, we describe a case of a child with macrocephaly, overgrowth with advanced bone age, attention deficits, evidence of mild mental retardation and dysmorphic features. An array-CGH analysis detected a 252 Kb duplication at the 22q11.2 region inherited from mother and 142 Kb duplication at 8q22.1 region inherited from father. Both parents show mild dysmorphic features. The duplicated genes in chromosomes 22q and 8q are TOP3B and PGCP, respectively. We describe for the first time a patient carrying the smaller atypical 22q11.2 duplication who also presents with mild mental retardation and generalized overgrowth. This patient has an additional duplication in 8q22.1 which may act as a genomic modifier of its clinical phenotype.


Assuntos
Anormalidades Múltiplas/genética , Duplicação Cromossômica/genética , Síndrome de DiGeorge/genética , Transtornos do Crescimento/genética , Deficiência Intelectual/genética , Trissomia/genética , Adolescente , Adulto , Cromossomos Humanos Par 22/genética , Cromossomos Humanos Par 8/genética , Feminino , Humanos , Masculino
7.
Gene ; 535(2): 376-9, 2014 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-24295889

RESUMO

We evaluated a patient, born after a normal 38-week pregnancy, with psychomotor retardation, poor coordination of ocular movements, recurrent vomiting and severe lactic acidosis. The patient was admitted to hospital at 2 months of age because of a mitochondrial-like syndrome and died at the age of 4.5 months. Array-comparative genomic hybridization (a-CGH) analysis revealed a homozygous deletion in 5q11.2 involving NADH dehydrogenase (ubiquinone) Fe-S protein 4, 18 kDa (NADH-coenzyme Q reductase; NDUFS4). Both parents were heterozygous for the mutation. The array revealed a deletion of ~32kb that includes exon 2 of NDUFS4 subsequently confirmed by real time-PCR and multiplex PCR. NDUFS4 was previously correlated to Leigh syndrome since mutations in this gene block the assembly of complex I. This result demonstrates the relevance of a-CGH screening in patients affected by metabolic disorders of unknown etiology.


Assuntos
Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , NADH Desidrogenase/genética , Deleção de Sequência , Deleção Cromossômica , Cromossomos Humanos Par 5 , Hibridização Genômica Comparativa , Complexo I de Transporte de Elétrons , Éxons , Evolução Fatal , Feminino , Ordem dos Genes , Homozigoto , Humanos , Lactente , Síndrome
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