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1.
Am J Med Genet A ; 185(4): 1204-1210, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33442900

RESUMO

Feingold Syndrome type 1 (FS1) is an autosomal dominant disorder due to a loss of function mutations in the MYCN gene. FS1 is generally clinically characterized by mild learning disability, microcephaly, short palpebral fissures, short stature, brachymesophalangy, hypoplastic thumbs, as well as syndactyly of toes, variably associated with organ abnormalities, the most common being gastrointestinal atresia. In current literature, more than 120 FS1 patients have been described, but diagnostic criteria are not well agreed upon, likewise the genotype-phenotype correlations are not well understood. Here, we describe 11 FS1 patients, belonging to six distinct families, where we have identified three novel MYCN mutations along with three pathogenetic variants, the latter which have already been reported. Several patients presented a mild phenotype of the condition and they have been diagnosed as being affected only after segregation analyses of the MYCN mutation identified in the propositus. We also describe here the first ever FS1 patient with severe intellectual disability having a maternally inherited MYCN variant together with an additional GNAO1 mutation inherited paternally. Mutations in the GNAO1 gene are associated with a specific form of intellectual disability and epilepsy, thus the finding of two different rare diseases in the same patient could explain his severe phenotype. Therein, a thorough investigation is merited into the possibility that additional variants in patients with a MYCN mutation and severe phenotype do exist. Finally, in order to guarantee a more reliable diagnosis of FS1, we suggest using both major and minor clinical-molecular diagnostic criteria.


Assuntos
Pálpebras/anormalidades , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/genética , Predisposição Genética para Doença , Deficiência Intelectual/genética , Deformidades Congênitas dos Membros/genética , Microcefalia/genética , Proteína Proto-Oncogênica N-Myc/genética , Fístula Traqueoesofágica/genética , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Adolescente , Criança , Pré-Escolar , Pálpebras/patologia , Feminino , Estudos de Associação Genética , Testes Genéticos , Genótipo , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/complicações , Deficiência Intelectual/patologia , Deformidades Congênitas dos Membros/complicações , Deformidades Congênitas dos Membros/patologia , Masculino , Microcefalia/complicações , Microcefalia/patologia , Fenótipo , Sindactilia/complicações , Sindactilia/genética , Sindactilia/patologia , Fístula Traqueoesofágica/complicações , Fístula Traqueoesofágica/patologia
2.
Genes (Basel) ; 15(9)2024 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-39336746

RESUMO

Background: Wiedemann-Steiner syndrome (WSS), a rare autosomal-dominant disorder caused by haploinsufficiency of the KMT2A gene product, is part of a group of disorders called chromatinopathies. Chromatinopathies are neurodevelopmental disorders caused by mutations affecting the proteins responsible for chromatin remodeling and transcriptional regulation. The resulting gene expression dysregulation mediates the onset of a series of clinical features such as developmental delay, intellectual disability, facial dysmorphism, and behavioral disorders. Aim of the Study: The aim of this study was to investigate a 10-year-old girl who presented with clinical features suggestive of WSS. Methods: Clinical and genetic investigations were performed. Whole exome sequencing (WES) was used for genetic testing, performed using Illumina technology. The bidirectional capillary Sanger resequencing technique was used in accordance with standard methodology to validate a mutation discovered by WES in all family members who were available. Utilizing computational protein modeling for structural and functional studies as well as in silico pathogenicity prediction models, the effect of the mutation was examined. Results: WES identified a de novo heterozygous missense variant in the KMT2A gene KMT2A(NM_001197104.2): c.3451C>G, p.(Arg1151Gly), absent in the gnomAD database. The variant was classified as Likely Pathogenetic (LP) according to the ACMG criteria and was predicted to affect the CXXC-type zinc finger domain functionality of the protein. Modeling of the resulting protein structure suggested that this variant changes the protein flexibility due to a variation in the Gibbs free energy and in the vibrational entropy energy difference between the wild-type and mutated domain, resulting in an alteration of the DNA binding affinity. Conclusions: A novel and de novo mutation discovered by the NGS approach, enhancing the mutation spectrum in the KMT2A gene, was characterized and associated with WSS. This novel KMT2A gene variant is suggested to modify the CXXC-type zinc finger domain functionality by affecting protein flexibility and DNA binding.


Assuntos
Sequenciamento do Exoma , Histona-Lisina N-Metiltransferase , Proteína de Leucina Linfoide-Mieloide , Humanos , Feminino , Sequenciamento do Exoma/métodos , Proteína de Leucina Linfoide-Mieloide/genética , Criança , Histona-Lisina N-Metiltransferase/genética , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Deficiência Intelectual/diagnóstico , Mutação de Sentido Incorreto , Anormalidades Múltiplas/genética
3.
Genes (Basel) ; 14(7)2023 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-37510285

RESUMO

BACKGROUND: Essential tremor (ET) is one of the more common movement disorders. Current diagnosis is solely based on clinical findings. ET appears to be inherited in an autosomal dominant pattern. Several loci on specific chromosomes have been studied by linkage analysis, but the causes of essential tremor are still unknown in many patients. Genetic studies described the association of several genes with familial ET. However, they were found only in distinct families, suggesting that some can be private pathogenic variants. AIM OF THE STUDY: to characterize the phenotype of an Italian family with ET and identify the genetic variant associated. METHODS: Clinical and genetic examinations were performed. Genetic testing was done with whole-exome sequencing (WES) using the Illumina platform. Bidirectional capillary Sanger sequencing was used to investigate the presence of variant in all affected members of the family. In silico prediction of pathogenicity was used to study the effect of gene variants on protein structure. RESULTS: The proband was a 15-year-old boy. The patient was the first of two children of a non-consanguineous couple. Family history was remarkable for tremor in the mother line. His mother suffered from bilateral upper extremity kinetic tremors (since she was 20 years old), anxiety, and depression. Other relatives referred bilateral upper extremity tremors. In the index case, WES analysis performed supposing a dominant mode of inheritance, identified a novel heterozygous missense variant in potassium calcium-activated channel subfamily N member 2 (KCNN2) (NM_021614.3: c.1145G>A, p.Gly382Asp). In the pedigree investigation, all carriers of the gene variant had ET and showed variable expressivity, the elder symptomatic relative showing cognitive impairment and hallucinations in the last decade, in addition to tremor since a young age. The amino acid residue #382 is located in a transmembrane region and in silico analysis suggested a causative role for the variant. Modelling of the mutant protein structure showed that the variant causes a clash in the protein structure. Therefore, the variant could cause a conformational change that alters the ability of the protein in the modulation of ion channels Conclusions: The KCNN2 gene variant identified could be associated with ET. The variant could modify a voltage-independent potassium channel activated by intracellular calcium.


Assuntos
Tremor Essencial , Feminino , Humanos , Tremor Essencial/genética , Tremor Essencial/patologia , Tremor/genética , Cálcio , Mutação de Sentido Incorreto , Testes Genéticos , Canais de Potássio Ativados por Cálcio de Condutância Baixa/genética
4.
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
5.
Am J Med Genet A ; 146A(2): 238-44, 2008 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-18080328

RESUMO

Complex chromosomal rearrangements with more than two breakpoints are rare. We report on a 5-year-old girl, evaluated because of psychomotor delay, ectrodactyly of right hand and feet, craniofacial dysmorphic features, cleft palate, deafness, and tetralogy of Fallot. A standard karyotype suggested a small intrachromosomal duplication of chromosome 7q. The chromosomal rearrangement was characterized by mBAND, which disclosed a reciprocal interstitial translocation t(7;8)(q21q22;q23q24). FISH analysis and array-CGH analysis showed a paracentric inversion of 7q and a microdeletion of 7q21.13. The parents had normal chromosomes. The deletion found in the present patient confirms that candidate region of ectrodactyly-deafness (OMIM 220600) maps to 7q21 and suggests new candidate genes for that disorder. This patient also had facial features reminiscent of tricho-rhino-phalangeal syndrome and one chromosome breakpoint involved band 8q24, a locus for this disorder. In addition, FOG1 gene maps to 8q23 and has been implicated in a subset of subjects with tretralogy of Fallot. We suggest that the aberration of 8q may have contributed to her facial and cardiac findings.


Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 7 , Surdez/genética , Deformidades Congênitas do Pé/genética , Deformidades Congênitas da Mão/genética , Pré-Escolar , Mapeamento Cromossômico , Cromossomos Humanos Par 8 , Surdez/diagnóstico , Feminino , Deformidades Congênitas do Pé/diagnóstico , Predisposição Genética para Doença , Deformidades Congênitas da Mão/diagnóstico , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Proteínas Nucleares/genética , Fatores de Transcrição/genética
6.
Hum Mutat ; 28(1): 98, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17154281

RESUMO

Autosomal recessive parkinsonism is a genetic condition closely resembling Parkinson disease, the only distinguishing features being an earlier age at onset and a slower disease progression. Three causative genes have been identified so far. While exon rearrangements are frequently encountered in the Parkin gene, most PINK1 mutations are represented by single nucleotide changes. We report a sporadic parkinsonian patient carrying a deletion of the entire PINK1 gene and a splice site mutation (g.15445_15467del23) which produces several aberrant mRNAs. This report expands the genotypic spectrum of PINK1 mutations, with relevant implications for molecular analysis of this gene.


Assuntos
Deleção de Genes , Heterogeneidade Genética , Proteínas Quinases/genética , Sítios de Splice de RNA/genética , Sequência de Aminoácidos , Sequência de Bases , Análise Mutacional de DNA , Feminino , Genótipo , Humanos , Hibridização in Situ Fluorescente , Pessoa de Meia-Idade , Dados de Sequência Molecular , Mutação , Transtornos Parkinsonianos/genética , Linhagem , Splicing de RNA/fisiologia
7.
Eur J Hum Genet ; 12(7): 579-83, 2004 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15083169

RESUMO

Brody disease is a rare muscle disorder characterized by exercise-induced impairment in muscle relaxation, due to a markedly reduced influx of calcium ions in the sarcoplasmic reticulum. A subset of autosomal recessive families harbour mutations in the ATP2A1 gene, encoding the fast-twitch skeletal muscle sarcoplasmic reticulum Ca(2+) ATPase (SERCA1). Rare autosomal dominant families have been described, in which ATP2A1 was excluded as the causative gene, further supporting genetic heterogeneity. We report four individuals from a three-generation Italian family with a clinical phenotype of Brody disease, in which linkage analysis excluded ATP2A1 as the responsible gene. The disease cosegregates in an autosomal dominant fashion with an apparently balanced constitutional chromosome translocation (2;7)(p11.2;p12.1), suggesting a causal relationship between the rearrangement and the phenotype. FISH analysis using YAC and PAC clones as probes refined the breakpoint regions to genomic segments of about 164 and 120 kb, respectively, providing a possible clue to pinpoint the location of a novel gene responsible for this rare muscle disorder.


Assuntos
Cromossomos Humanos Par 2/genética , Cromossomos Humanos Par 7/genética , Ligação Genética , Transtornos Miotônicos/genética , Translocação Genética/genética , Adulto , ATPases Transportadoras de Cálcio/genética , Mapeamento Cromossômico , Coloração Cromossômica , Cromossomos Artificiais de Levedura/genética , Feminino , Heterogeneidade Genética , Humanos , Itália , Escore Lod , Masculino , Pessoa de Meia-Idade , Linhagem , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático
8.
Cancer Genet Cytogenet ; 150(2): 168-72, 2004 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-15066327

RESUMO

Neurofibromatosis type 1 (NF1) is a common autosomal dominant condition associated with germline mutations of the NF1 gene located at chromosome band 17q11.2. Molecular analysis of a number of NF1-specific tumors has shown the inactivation of both NF1 alleles during tumorigenesis, supporting the tumor suppressor hypothesis for the NF1 gene. Using interphase dual-color fluorescence in situ hybridization (FISH) technique on paraffin-embedded tissues, we studied 11 plexiform, 4 cutaneous, and 6 subcutaneous neurofibromas. Cytogenetic analysis was conducted using two probes, one specific for the NF1 region (RP11-229K15) and one for the centromeric region of chromosome 17 as control. No large somatic deletions were found. Only in one of the plexiform neurofibromas loss of a whole chromosome 17 was observed. If we assume that dual-color FISH analysis is sensitive enough to detect the majority of large somatic deletions present, then other mutational mechanisms affecting the NF1 gene are probably involved in neurofibroma formation, and other tumor suppressor genes may play an important role in NF1 tumorigenesis.


Assuntos
Cromossomos Humanos Par 17/genética , Neurofibromatose 1/genética , Adolescente , Adulto , Criança , Pré-Escolar , Mapeamento Cromossômico , Feminino , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Deleção de Sequência
9.
Gene ; 513(1): 111-7, 2013 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-23124038

RESUMO

Herein, we describe a case of an infertile man detected in postnatal diagnosis with FISH characterization and array-CGH used for genome-wide screening which allowed the identification of a complex rearrangement involving sex chromosomes, apparently without severe phenotypic consequences. The deletion detected in our patient has been compared with previously reported cases leading us to propose a hypothetical diagnostic algorithm that would be useful in similar clinical situations, with imperative multi disciplinary approach integrated with genetic counseling. Our patient, uniquely of reproductive age, is one of six reported cases of duplication of Xp22.3 (~8.4Mb) segment and contemporary deletion of Yq (~42.9Mb) with final karyotype as follows: 46,X,der(Y),t(X;Y)(Ypter→Yq11.221::Xp22.33→Xpter).ish der(Y) (Yptel+,Ycen+,RP11-529I21+,RP11-506M9-Yqtel−,Xptel+). arrXp22.33p22.31(702­8,395,963, 8,408,289x1), Yq11.221q12 (14,569,317x1, 14,587,321­57,440,839x0).


Assuntos
Duplicação Cromossômica , Cromossomos Humanos X/genética , Cromossomos Humanos Y/genética , Infertilidade Masculina/genética , Deleção de Sequência , Aberrações dos Cromossomos Sexuais , Adulto , Sequência de Bases , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Masculino , Translocação Genética/genética
11.
Am J Med Genet A ; 143(4): 343-8, 2007 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-17256793

RESUMO

We report on three siblings with mild mental retardation and minor dysmorphic features carrying an interstitial duplication of the long arm of chromosome 18 inherited from a healthy mosaic carrier mother. The duplicated region spanned between 18q21.31 and 18q22.2 for about 12 Mb. The distal duplications of 18q are rare and only a small number of subjects, manifesting quite different clinical outcomes, have been described. However, in most of these cases, molecular characterization was not available. We have reviewed nine patients, including three familial cases, displaying overlapping duplicated regions, and compared them with the present individuals in an attempt to delineate karyotype-phenotype correlation.


Assuntos
Anormalidades Múltiplas/genética , Aneuploidia , Cromossomos Humanos Par 18 , Deficiência Intelectual/genética , Adulto , Análise Citogenética , Sobrancelhas/anormalidades , Feminino , Dedos/anormalidades , Humanos , Masculino , Fenótipo , Irmãos , Estrabismo/genética , Sindactilia/genética
12.
Prenat Diagn ; 25(4): 283-5, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15849782

RESUMO

OBJECTIVES: Mosaic autosomal duplications are rare and often result in mental retardation and congenital anomalies. Phenotype is not predictable depending on the chromosomal imbalance involved and the percentage and tissues distribution of unbalanced cells. We report on a young woman carrying a mosaic duplication of chromosome 4p, evaluated because of three abortions due to IUGR and fetal malformation. METHODS: Mosaic dup(4p) was detected by standard and molecular cytogenetics. RESULTS: Unbalanced cells accounted for about 20 to 30% of nuclei in four examined tissues and did not cause any obvious phenotypic effect. CONCLUSION: It is likely that mosaic duplications are underascertained because they are not associated with obvious clinical effects in some individuals. Prenatal diagnosis is the method of choice to predict the karyotype in the offspring of subjects carrying mosaic chromosome imbalances.


Assuntos
Aneuploidia , Amostra da Vilosidade Coriônica/métodos , Cromossomos Humanos Par 4/genética , Mosaicismo , Complicações na Gravidez , História Reprodutiva , Aborto Espontâneo/genética , Adulto , Feminino , Retardo do Crescimento Fetal/genética , Humanos , Hibridização in Situ Fluorescente , Linfócitos/citologia , Linfócitos/fisiologia , Metáfase , Gravidez
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