Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.002
Filtrar
1.
Gene ; 715: 143970, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31330235

RESUMO

BACKGROUND: Bicuspid aortic valve (BAV) formation is genetically determined, with reduced penetrance and variable expressivity. NOTCH1 is a proven candidate gene and its mutations have been found in familial and sporadic cases of BAV. METHODS: 66 BAV patients from the GISSI VAR study were genotyped for the NOTCH1 gene. RESULTS: We identified 63 variants, in heterozygous and homozygous states. Fifty-two are common polymorphisms present in almost all patients. Eleven variants are new and never yet reported: two are non-synonymous substitutions, Gly540Asp in exon 10 and Glu851Gln in exon 16; one is in the 3'UTR region and seven in introns, one corresponds to a T allele insertion in intron 27. We selected four statistically noteworthy and seven new variants identified in six BAV patients and correlated them with clinical and demographic variables and with imaging and histological parameters. Preliminary data show that four were BAV patients with isolated stenosis in patients over 60 aged. These variants may correlate with a later need for surgery for the presence of stenosis and not aortic valve regurgitation or ascending aortic aneurysm. CONCLUSIONS: Completing the genotyping of 62 BAV patients we found 11 new variants in the NOTCH1 gene never yet reported. These findings confirm that the identification of new, clinically remarkable biomarkers for BAV requires a deeper genetic understanding of the NOTCH1 gene variants, which could be targeted by future diagnostic and therapeutic strategies.


Assuntos
Estenose da Valva Aórtica/genética , Valva Aórtica/anormalidades , Doenças das Valvas Cardíacas , Mutação de Sentido Incorreto , Penetrância , Receptor Notch1/genética , Adulto , Alelos , Substituição de Aminoácidos , Éxons , Feminino , Heterozigoto , Homozigoto , Humanos , Íntrons , Itália , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Análise de Sequência de DNA
2.
N Engl J Med ; 380(15): 1421-1432, 2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30970187

RESUMO

BACKGROUND: Hirschsprung's disease, or congenital aganglionosis, is a developmental disorder of the enteric nervous system and is the most common cause of intestinal obstruction in neonates and infants. The disease has more than 80% heritability, including significant associations with rare and common sequence variants in genes related to the enteric nervous system, as well as with monogenic and chromosomal syndromes. METHODS: We genotyped and exome-sequenced samples from 190 patients with Hirschsprung's disease to quantify the genetic burden in patients with this condition. DNA sequence variants, large copy-number variants, and karyotype variants in probands were considered to be pathogenic when they were significantly associated with Hirschsprung's disease or another neurodevelopmental disorder. Novel genes were confirmed by functional studies in the mouse and human embryonic gut and in zebrafish embryos. RESULTS: The presence of five or more variants in four noncoding elements defined a widespread risk of Hirschsprung's disease (48.4% of patients and 17.1% of controls; odds ratio, 4.54; 95% confidence interval [CI], 3.19 to 6.46). Rare coding variants in 24 genes that play roles in enteric neural-crest cell fate, 7 of which were novel, were also common (34.7% of patients and 5.0% of controls) and conferred a much greater risk than noncoding variants (odds ratio, 10.02; 95% CI, 6.45 to 15.58). Large copy-number variants, which were present in fewer patients (11.4%, as compared with 0.2% of controls), conferred the highest risk (odds ratio, 63.07; 95% CI, 36.75 to 108.25). At least one identifiable genetic risk factor was found in 72.1% of the patients, and at least 48.4% of patients had a structural or regulatory deficiency in the gene encoding receptor tyrosine kinase (RET). For individual patients, the estimated risk of Hirschsprung's disease ranged from 5.33 cases per 100,000 live births (approximately 1 per 18,800) to 8.38 per 1000 live births (approximately 1 per 120). CONCLUSIONS: Among the patients in our study, Hirschsprung's disease arose from common noncoding variants, rare coding variants, and copy-number variants affecting genes involved in enteric neural-crest cell fate that exacerbate the widespread genetic susceptibility associated with RET. For individual patients, the genotype-specific odds ratios varied by a factor of approximately 67, which provides a basis for risk stratification and genetic counseling. (Funded by the National Institutes of Health.).


Assuntos
Variação Genética , Genótipo , Doença de Hirschsprung/genética , Exoma , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Mutação , Razão de Chances , Penetrância , Análise de Sequência de DNA , Sequenciamento Completo do Exoma
3.
Gene ; 705: 16-21, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-30981840

RESUMO

TTR-related amyloidosis (ATTR) is manifested in two allelic forms: familial amyloid polyneuropathy (TTR-FAP) and cardiomyopathy (TTR-FAC), both caused by mutations in the TTR gene. The most prevalent mutation in Bulgaria is p.Glu89Gln. Markedly different age at onset and disease penetrance is noticed in Bulgarian p.Glu89Gln cases even in a single family or between genetically identical twins. The present study aimed to evaluate the transcription profile of the TTR gene in order to better understand the difference in disease onset and penetrance. Six p.Glu89Gln positive families were selected from our registry, based on intrafamilial differences in disease onset and penetrance. Plasma and urine specimens were collected from 13 patients and subjected to transcription analysis. Both mutant and wild type transcripts were visualized in a mixed transcription profile, which is the traditional model of autosomal gene expression. The results from a relative quantification of the mutant versus wild type transcript showed presence of the mutant transcript between 0.14 and 1.14 times against the wild type. In addition, monoallelic expression signature was also detected. Based on our results we propose a model of natural selection, which includes age-related allele exclusion or suppression: predominant expression of a wild type (at an early age) and mutant (at the process of ageing) alleles. The intrafamilial differences in disease onset and penetrance need to be considered in genetic counselling and in follow-up of mutation carriers.


Assuntos
Substituição de Aminoácidos , Neuropatias Amiloides Familiares/genética , Cardiomiopatias/genética , Penetrância , Pré-Albumina/genética , Adulto , Idade de Início , Alelos , Bulgária , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Seleção Genética
4.
BMC Med Genet ; 20(1): 40, 2019 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-30866851

RESUMO

BACKGROUND: Hyperekplexia also known as Startle disease is a rare neuromotor hereditary disorder characterized by exaggerated startle responses to unexpected auditory, tactile, and visual stimuli and generalized muscle stiffness, which both gradually subside during the first months of life. Although the diagnosis of Hyperekplexia is based on clinical findings, pathogenic variants in five genes have been reported to cause Hyperekplexia, of which GLRA1 accounts for about 80% of cases. Dominant and recessive mutations have been identified in GLRA1 gene as pathogenic variants in many individuals with the familial form of Hyperekplexia and occasionally in simplex cases. CASE PRESENTATION: In the present study, we describe clinical and genetic features of two Italian siblings, one with the major and one with the minor form of the disease. DNA samples from the probands and their parents were performed by NGS approach and validated by Sanger sequencing. The analysis of the GLRA1 gene revealed, in both probands, compound heterozygous mutations: c.895C > T or p.R299X inherited from the mother and c.587C > A or p.D98E inherited from the father. CONCLUSIONS: Until now, these two identified mutations in GLRA1 have not been reported before as compound mutations. What clearly emerges within our study is the clinical heterogeneity in the same family. In fact, even though in the same pedigree, the affected mother showed only mild startle responses to unexpected noise stimuli, which might be explained by variable expressivity, while the father, showed no clear signs of symptomatology, which might be explained by non-penetrance. Finally, the two brothers have different form of the disease, even if the compound heterozygous mutations in GLRA1 are the same, showing that the same mutation in GLRA1 could have different phenotypic expressions and suggesting an underling mechanism of variable expressivity.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala/métodos , Hiperecplexia/diagnóstico , Mutação Puntual , Receptores da Glicina/genética , Feminino , Heterozigoto , Humanos , Hiperecplexia/genética , Itália , Masculino , Herança Materna , Herança Paterna , Linhagem , Penetrância , Fenótipo , Análise de Sequência de DNA/métodos
6.
J Mol Neurosci ; 68(2): 214-220, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30911941

RESUMO

Dopa-responsive dystonia (DRD), a movement disorder, is characterized by young onset dystonia and dramatic response to levodopa treatment. However, the wide range of phenotypic spectrum of the disease often leads to misdiagnosis. DRD is usually caused by mutation in GCH1 gene coding for GTP cyclohydrolase 1 (GTPCH1) enzyme, which is involved in biosynthesis of tetrahydrobiopterin (BH4) and dopamine. In this study, the entire GCH1 gene was screened in 14 Indian DRD patients and their family members. A family was identified where the proband was found to be a compound heterozygote for GCH1 (p.R184H and p.V204I) variants; the former variant being inherited from the father and the latter from the mother. All other family members harboring one of these GCH1 variants were asymptomatic except for one (heterozygous for p.R184H) who was diagnosed with DRD. In silico analyses predicted these two variants to be pathogenic and disruptive to GCH1enzymatic activity. This proband was misdiagnosed as cerebral palsy and remained untreated for 25 years. He developed retrograde movements and gait problems in lower limbs, deformity in upper limbs, and difficulty in swallowing, and became mute. However, most of his symptoms were alleviated upon levodopa administration. Our study confirms the variability of DRD phenotype and the reduced penetrance of GCH1 mutations. It also emphasizes the need of molecular diagnostic test and L-dopa trial especially for those with atypical DRD phenotype.


Assuntos
Distúrbios Distônicos/genética , GTP Cicloidrolase/genética , Mutação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Diagnóstico Diferencial , Distúrbios Distônicos/patologia , Feminino , GTP Cicloidrolase/química , GTP Cicloidrolase/metabolismo , Heterozigoto , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Linhagem , Penetrância
7.
Atheroscler Suppl ; 36: 28-30, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30876530

RESUMO

Familial hypercholesterolemia is an Mendelian dominant disorder characterized by defects of the low density lipoprotein receptor (LDLR) that result in a defective removal of LDL from plasma, which promotes deposition of cholesterol in the skin (xanthelasma), tendons (xanthomas), and arteries (atherosclerosis). Diagnosis severe clinical phenotype FH with Dutch Lipid Clinic Network Criteria, encompassing history of premature ASCVD, tendon xanthomas, and a family history of hypercholesterolemia and premature ASCVD in relatives is rare in the Portuguese FH patients. There is a variability of the phenotype in FH individuals with clinical diagnosis or genetic mutation (carriers and patients) probably due to environmental factors in the last century, a Mediterranean diet, or a diet without fat food, trans fat food, no smoking, no sedentary life that can interfere with our metabolism, or are consequences of polygenic, epigenetic, acquired defects, modifiers genes and beta-globin asymptomatic carriers. We have several concepts/mechanisms in genetics that are transversal to hereditary diseases and common in FH, such as somatic mosaicism, germinal mosaicism, variable expression and variable penetrance of mutations. A negative blood genetic test result does not exclude FH, because the pathogenic LDLR mutation can be expressed only in the liver (a mutation in somatic tissue) or occasionally there is a vertical transmission from partner to future child by a mutation on germinal line - germinal mosaicism. Unlike north European countries, the most FH carriers and patients had less severe phenotypes, for example with have children and young adult carriers with LDL-R mutation had normal TC and LDL-C, old women had a milder phenotype without ASCVD events, tendon xanthomas are seen in <1% patients, and most homozygous FH patients are under combined therapy.


Assuntos
LDL-Colesterol/sangue , Interação Gene-Ambiente , Hiperlipoproteinemia Tipo II/genética , Penetrância , Receptores de LDL/genética , Adulto , Idoso de 80 Anos ou mais , Dieta com Restrição de Gorduras , Dieta Mediterrânea , Exercício , Feminino , Marcadores Genéticos , Predisposição Genética para Doença , Hereditariedade , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/epidemiologia , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Portugal/epidemiologia , Fatores de Risco , Resultado do Tratamento
8.
Ophthalmic Surg Lasers Imaging Retina ; 50(2): 120-124, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30768221

RESUMO

Familial exudative vitreoretinopathy (FEVR) is a rare hereditary ocular disorder characterized by incomplete or abnormal development of peripheral retinal vasculature. The genes responsible for this disorder are associated with the wingless-related integration site (Wnt) signaling pathway, a critical pathway for the development of normal retinal vasculature. A pathogenic variant in any one of these genes may disrupt retinal vasculogenesis. Furthermore, the type and number of pathogenic variants may influence the severity of disease and clinical course. Here, the authors identify a novel pathogenic variant in the NDP gene, not previously described in the literature. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:120-124.].


Assuntos
Oftalmopatias Hereditárias/genética , Proteínas do Olho/genética , Doenças Genéticas Ligadas ao Cromossomo X , Mutação , Proteínas do Tecido Nervoso/genética , Doenças Retinianas/genética , Pré-Escolar , Predisposição Genética para Doença , Humanos , Masculino , Linhagem , Penetrância
9.
Stem Cell Res ; 34: 101357, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30611018

RESUMO

We report the generation of the human iPSC line LEIi008-A from a patient with retinitis pigmentosa-11 caused by a dominant nonsense mutation in the PRPF31 gene (NM_015629.3:c.1205C > A p.(Ser402Ter)). A second line, LEIi009-A, was generated from a related non-penetrant carrier of the same mutation with no retinal disease. Reprogramming of patient dermal fibroblasts using episomal plasmids containing OCT4, SOX2, KLF4, L-MYC, LIN28, shRNA for p53 and mir302/367 microRNA generated cell lines displaying pluripotent stem cell marker expression, a normal karyotype and the capability to differentiate into the three germ layer lineages. Resource table.


Assuntos
Técnicas de Cultura de Células/métodos , Proteínas do Olho/genética , Genes Dominantes , Células-Tronco Pluripotentes Induzidas/patologia , Mutação/genética , Penetrância , Adolescente , Adulto , Sequência de Bases , Linhagem Celular , Criança , Pré-Escolar , Feminino , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
10.
Breast Cancer Res Treat ; 174(3): 553-560, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30610487

RESUMO

BACKGROUND: The identification of new hereditary breast cancer genes is an area of highly active research. In 2015, two independent studies provided initial evidence for a novel breast cancer susceptibility gene, RECQL, a DNA helicase which plays an important role in the DNA damage response. Several subsequent studies in independent patient cohorts have provided further data on RECQL variant frequency in additional populations, some of which have brought in to question the increased breast cancer risk associated with RECQL mutations. RESULTS: The initial reports present findings from whole exome sequencing of high-risk familial breast cancer cases in the French-Canadian, Polish and Han Chinese populations and estimate the carrier frequency of pathogenic RECQL mutations in high-risk breast cancer patients who have previously tested negative for BRCA1 and BRCA2 mutations to be approximately 1-2%. Proposed founder mutations were identified in French-Canadian and Polish populations. Functional studies support loss of function of the helicase activity of RECQL for some of the reported pathogenic mutations. An additional study in a cohort of Southern Chinese high-risk breast cancer patients estimated the frequency of pathogenic RECQL mutations to be 0.54%. A possible Chinese founder mutation was identified, but only a small number of controls were sequenced. Subsequent case-control studies screening for the Polish founder mutation in patients from Germany and Belarus did not find any evidence for increased breast cancer risk for this variant. An Australian case-control study also failed to identify an increased risk of breast cancer associated with RECQL loss of function variants. CONCLUSIONS: RECQL plays an important role in DNA repair, and is a plausible candidate breast cancer susceptibility gene. Initial studies showed evidence of an association between variants in this gene and an increased breast cancer risk in three separate populations, and identified founder mutations with significantly increased odds ratios. However, several subsequent studies have failed to support the association. With the limited and conflicting evidence available, there remains debate as to whether there is an increased breast cancer risk in individuals carrying RECQL loss of function variants. Further studies are required to better quantify the risks associated with RECQL variants and the current evidence base is not sufficient to justify routine inclusion of RECQL on breast cancer gene panels in clinical use. Management of patients in whom RECQL variants have been identified should be based on clinician assessment, in the context of the family history. Further studies are required to better quantify the risks to RECQL mutation carriers and may also guide management and potential therapeutic targeting for patients.


Assuntos
Neoplasias da Mama/genética , Mutação em Linhagem Germinativa , RecQ Helicases/genética , Neoplasias da Mama/etnologia , Canadá/etnologia , Estudos de Casos e Controles , China/etnologia , Feminino , Predisposição Genética para Doença , Humanos , Linhagem , Penetrância , Polônia , Sequenciamento Completo do Exoma
11.
Mol Genet Genomic Med ; 7(2): e00507, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30614210

RESUMO

BACKGROUND: Chromosome 22q11.2 is susceptible to genomic rearrangements and the most frequently reported involve deletions and duplications between low copy repeats LCR22A to LCR22D. Atypical nested deletions and duplications are rarer and can provide a valuable opportunity to investigate the dosage effects of a smaller subset of genes within the 22q11.2 genomic disorder region. METHODS: We describe thirteen individuals from six families, each with atypical nested duplications within the central 22q11.2 region between LCR22B and LCR22D. We then compared the molecular and clinical data for patients from this study and the few reported atypical duplication cases, to the cases with larger typical duplications between LCR22A and LCR22D. Further, we analyzed genes with the nested region to identify candidates highly enriched in human brain tissues. RESULTS: We observed that atypical nested duplications are heterogeneous in size, often familial, and associated with incomplete penetrance and highly variable clinical expressivity. We found that the nested atypical duplications are a possible risk factor for neurodevelopmental phenotypes, particularly for autism spectrum disorder (ASD), speech and language delay, and behavioral abnormalities. In addition, we analyzed genes within the nested region between LCR22B and LCR22D to identify nine genes (ZNF74, KLHL22, MED15, PI4KA, SERPIND1, CRKL, AIFM3, SLC7A4, and BCRP2) with enriched expression in the nervous system, each with unique spatiotemporal patterns in fetal and adult brain tissues. Interestingly, PI4KA is prominently expressed in the brain, and this gene is included either partially or completely in all of our subjects. CONCLUSION: Our findings confirm variable expressivity and incomplete penetrance for atypical nested 22q11.2 duplications and identify genes such as PI4KA to be directly relevant to brain development and disorder. We conclude that further work is needed to elucidate the basis of variable neurodevelopmental phenotypes and to exclude the presence of a second disorder. Our findings contribute to the genotype-phenotype data for atypical nested 22q11.2 duplications, with implications for genetic counseling.


Assuntos
Anormalidades Múltiplas/genética , Transtorno do Espectro Autista/genética , Duplicação Cromossômica/genética , Deficiências do Desenvolvimento/genética , Síndrome de DiGeorge/genética , Penetrância , Anormalidades Múltiplas/patologia , Adolescente , Adulto , Transtorno do Espectro Autista/patologia , Criança , Pré-Escolar , Cromossomos Humanos Par 22/genética , Deficiências do Desenvolvimento/patologia , Síndrome de DiGeorge/patologia , Feminino , Humanos , Masculino , Linhagem , Fenótipo , Duplicações Segmentares Genômicas , Síndrome
12.
J Mol Neurosci ; 67(3): 418-423, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30618027

RESUMO

In this report, we described a large Han-Chinese family which presents with various phenotypes from unaffected to manifested nystagmus in females. Infantile nystagmus (IN) is characterized by bilateral, involuntary, and periodic eyeball oscillation, occurring at birth or within the first 6 months. The most common inheritance pattern of IN is an X-linked form with incomplete penetrance among females, and the FERM domain containing 7 gene (FRMD7) is a main disease-causing gene. A combination of exome sequencing and Sanger sequencing, as well as detailed clinical examinations were performed on the Chinese IN family. An FRMD7 c.47T>C (p.Phe16Ser) variant was proposed as the disease-causing variant. Incomplete penetrance was found in females with the FRMD7 c.47T>C variant, and hemizygous male affected subjects presented more severe manifestations compared to heterozygous female affected subjects. These findings could enhance genetic counseling and antenatal diagnosis of IN.


Assuntos
Proteínas do Citoesqueleto/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Proteínas de Membrana/genética , Nistagmo Congênito/genética , Polimorfismo de Nucleotídeo Único , Adulto , Proteínas do Citoesqueleto/química , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Hemizigoto , Humanos , Masculino , Proteínas de Membrana/química , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Nistagmo Congênito/patologia , Linhagem , Penetrância
13.
Mol Genet Genomic Med ; 7(3): e541, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30623604

RESUMO

BACKGROUND: Heteroplasmic mitochondrial 3697G>A mutation has been associated with leber hereditary optic neuropathy (LHON), mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS), and LHON/MELAS overlap syndrome. However, homoplasmic m.3697G>A mutation was only found in a family with Leigh syndrome, and the phenotype and pathogenicity of this homoplasmic mutation still need to be investigated in new patients. METHODS: The clinical interviews were conducted in 12 individuals from a multiple-generation inherited family. Mutations were screened through exome next-generation sequencing and subsequently confirmed by PCR-restriction fragment length polymorphism. Mitochondrial complex activities and ATP production rate were measured by biochemical analysis. RESULTS: The male offspring with bilateral striatal necrosis (BSN) were characterized by severe spastic dystonia and complete penetrance, while the female offspring presented with mild symptom and low penetrance. All offspring carried homoplasmic mutation of NC_012920.1: m.3697G>A, p.(Gly131Ser). Biochemical analysis revealed an isolated defect of complex I, but the magnitude of the defect was higher in the male patients than that in the female ones. The ATP production rate also exhibited a similar pattern. However, no possible modifier genes on the X chromosome were identified. CONCLUSION: Homoplasmic m.3697G>A mutation could be associated with BSN, which expanded the clinical spectrum of m.3697G>A. Our preliminary investigations had not found the underlying modifiers to support the double hit hypothesis, while the high level of estrogens in the female patients might exert a potential compensatory effect on mutant cell metabolism.


Assuntos
DNA Mitocondrial/genética , Penetrância , Mutação Puntual , Degeneração Estriatonigral/genética , Humanos , Masculino , Linhagem , Fatores Sexuais , Degeneração Estriatonigral/diagnóstico por imagem , Degeneração Estriatonigral/patologia , Adulto Jovem
14.
Neuron ; 101(3): 429-443.e4, 2019 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-30578106

RESUMO

Normal vascular development includes the formation and specification of arteries, veins, and intervening capillaries. Vein of Galen malformations (VOGMs) are among the most common and severe neonatal brain arterio-venous malformations, shunting arterial blood into the brain's deep venous system through aberrant direct connections. Exome sequencing of 55 VOGM probands, including 52 parent-offspring trios, revealed enrichment of rare damaging de novo mutations in chromatin modifier genes that play essential roles in brain and vascular development. Other VOGM probands harbored rare inherited damaging mutations in Ephrin signaling genes, including a genome-wide significant mutation burden in EPHB4. Inherited mutations showed incomplete penetrance and variable expressivity, with mutation carriers often exhibiting cutaneous vascular abnormalities, suggesting a two-hit mechanism. The identified mutations collectively account for ∼30% of studied VOGM cases. These findings provide insight into disease biology and may have clinical implications for risk assessment.


Assuntos
Montagem e Desmontagem da Cromatina/genética , Mutação , Malformações da Veia de Galeno/genética , Efrinas/metabolismo , Feminino , Humanos , Masculino , Glicoproteínas de Membrana/genética , Metaloendopeptidases/genética , Linhagem , Penetrância , Receptor EphB4/genética , Transdução de Sinais , Malformações da Veia de Galeno/patologia
15.
Int J Cardiol ; 274: 263-270, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30454721

RESUMO

BACKGROUND: Variants in the desmoglein-2 (DSG2) gene account for a significant proportion of patients with Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC). The aim of this study was to evaluate the genetic epidemiology of DSG2 and the impact of a frequent homozygous DSG2 variant in East Asia. METHODS: Genetic screening of 14 ARVC related genes was performed in 118 unrelated index patients using next-generation sequencing. Following that, family screening, clinical evaluation and haplotype analysis were performed among eight probands who carry the same homozygous DSG2 variant. We also examined the histopathology and protein expression using immunofluorescence staining on the myocardial tissue of two probands undergoing heart transplant. RESULTS: Eighteen (15.2%) patients bear rare putatively deleterious variants in DSG2, among which 8 patients shared the homozygous DSG2 p.Phe531Cys variant. Family screening demonstrated that only homozygous variant carriers exhibited definite ARVC phenotype with 100% penetrance, while heterozygous variant carriers were either unaffected or only presented mild ARVC related symptoms in 25% relatives. Left ventricular involvement and bi-ventricular failure were common among homozygous p. Phe531Cys variant patients even at early age. Haplotype analysis demonstrated p. Phe531Cys was a founder variant in East Asia population with an allele frequency of 0.12%. CONCLUSIONS: We identified, for the first time, a homozygous founder variant of DSG2 in East Asia, which was at surprisingly high frequency of 8.47% among Chinese ARVC patients with a full penetrance. This result suggested an urgent demand of genetic counseling for the probands and their relatives with heterozygous variant.


Assuntos
Displasia Arritmogênica Ventricular Direita/genética , DNA/genética , Desmogleína 2/genética , Testes Genéticos/métodos , Insuficiência Cardíaca/genética , Mutação , Miocárdio/metabolismo , Adolescente , Adulto , Displasia Arritmogênica Ventricular Direita/epidemiologia , Displasia Arritmogênica Ventricular Direita/metabolismo , China/epidemiologia , Análise Mutacional de DNA , Extremo Oriente , Feminino , Frequência do Gene , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/metabolismo , Homozigoto , Humanos , Masculino , Miocárdio/patologia , Linhagem , Penetrância , Prevalência , Adulto Jovem
16.
G3 (Bethesda) ; 9(2): 425-437, 2019 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-30541930

RESUMO

Rod and cone photoreceptors are specialized retinal neurons that have a fundamental role in visual perception, capturing light and transducing it into a neuronal signal. Aberrant functioning of rod and/or cone photoreceptors can ultimately lead to progressive degeneration and eventually blindness. In man, many rod and rod-cone degenerative diseases are classified as forms of retinitis pigmentosa (RP). Dogs also have a comparable disease grouping termed progressive retinal atrophy (PRA). These diseases are generally due to single gene defects and follow Mendelian inheritance.We collected 51 DNA samples from Miniature Schnauzers affected by PRA (average age of diagnosis ∼3.9 ±1 years), as well as from 56 clinically normal controls of the same breed (average age ∼6.6 ±2.8 years). Pedigree analysis suggested monogenic autosomal recessive inheritance of PRA. GWAS and homozygosity mapping defined a critical interval in the first 4,796,806 bp of CFA15. Whole genome sequencing of two affected cases, a carrier and a control identified two candidate variants within the critical interval. One was an intronic SNV in HIVEP3, and the other was a complex structural variant consisting of the duplication of exon 5 of the PPT1 gene along with a conversion and insertion (named PPT1dci ). PPT1dci was confirmed homozygous in a cohort of 22 cases, and 12 more cases were homozygous for the CFA15 haplotype. Additionally, the variant was found homozygous in 6 non-affected dogs of age higher than the average age of onset. The HIVEP3 variant was found heterozygous (n = 4) and homozygous wild-type (n = 1) in cases either homozygous for PPT1dci or for the mapped CFA15 haplotype. We detected the wildtype and three aberrant PPT1 transcripts in isolated white blood cell mRNA extracted from a PRA case homozygous for PPT1dci , and the aberrant transcripts involved inclusion of the duplicated exon 5 and novel exons following the activation of cryptic splice sites. No neurological signs were detected among the dogs homozygous for the PPT1dci variant. Therefore, we propose PPT1dci as causative for a non-syndromic form of PRA (PRA PPT1 ) that shows incomplete penetrance in Miniature Schnauzers, potentially related to the presence of the wild-type transcript. To our knowledge, this is the first case of isolated retinal degeneration associated with a PPT1 variant.


Assuntos
Doenças do Cão/genética , Mutação , Degeneração Retiniana/genética , Tioléster Hidrolases/genética , Animais , Cães , Penetrância , Polimorfismo de Nucleotídeo Único , Processamento de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Degeneração Retiniana/veterinária , Tioléster Hidrolases/metabolismo
17.
BMC Res Notes ; 11(1): 911, 2018 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-30572950

RESUMO

OBJECTIVES: Leber's hereditary optic neuropathy (LHON) is a mitochondrial genetic disease characterized by a variable and reduced penetrance. Individuals carrying a primary LHON-causing mitochondrial DNA (mtDNA) mutation may either remain asymptomatic lifelong, as unaffected carriers, or develop sudden central visual loss that rapidly aggravates over some weeks. Over the years several genetic/environmental triggers able to modulate the risk of developing LHON have been proposed. We provided data supporting a possible correlation between LHON penetrance and the mtDNA copy number, a raw index of mitochondrial mass, whose increase could represent a compensatory response that cells implement to alleviate the pathogenic effect of the primary LHON-causing mtDNA mutations. DATA DESCRIPTION: We collected Italian and Spanish subjects harboring one of the three common LHON primary mutations, either in heteroplasmic or homoplasmic status. For each population we were able to discriminate between affected subjects presenting typical clinical tracts of LHON and LHON-causing mutation carriers showing no symptoms correlated with vision loss. Each subject has been characterized for the presence of a LHON primary mutation, for its status of homoplasmy or heteroplasmy, and for the mtDNA content per cell, expressed as relative mtDNA/nDNA ratio respect to controls. Additional clinical information is present for all the Italian subjects.


Assuntos
Variações do Número de Cópias de DNA/genética , DNA Mitocondrial/genética , Atrofia Óptica Hereditária de Leber/genética , Penetrância , Feminino , Heterozigoto , Humanos , Itália , Masculino , Mutação , Atrofia Óptica Hereditária de Leber/patologia , Atrofia Óptica Hereditária de Leber/fisiopatologia , Linhagem , Espanha
18.
PLoS Genet ; 14(12): e1007752, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30586411

RESUMO

The BRCA Challenge is a long-term data-sharing project initiated within the Global Alliance for Genomics and Health (GA4GH) to aggregate BRCA1 and BRCA2 data to support highly collaborative research activities. Its goal is to generate an informed and current understanding of the impact of genetic variation on cancer risk across the iconic cancer predisposition genes, BRCA1 and BRCA2. Initially, reported variants in BRCA1 and BRCA2 available from public databases were integrated into a single, newly created site, www.brcaexchange.org. The purpose of the BRCA Exchange is to provide the community with a reliable and easily accessible record of variants interpreted for a high-penetrance phenotype. More than 20,000 variants have been aggregated, three times the number found in the next-largest public database at the project's outset, of which approximately 7,250 have expert classifications. The data set is based on shared information from existing clinical databases-Breast Cancer Information Core (BIC), ClinVar, and the Leiden Open Variation Database (LOVD)-as well as population databases, all linked to a single point of access. The BRCA Challenge has brought together the existing international Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium expert panel, along with expert clinicians, diagnosticians, researchers, and database providers, all with a common goal of advancing our understanding of BRCA1 and BRCA2 variation. Ongoing work includes direct contact with national centers with access to BRCA1 and BRCA2 diagnostic data to encourage data sharing, development of methods suitable for extraction of genetic variation at the level of individual laboratory reports, and engagement with participant communities to enable a more comprehensive understanding of the clinical significance of genetic variation in BRCA1 and BRCA2.


Assuntos
Bases de Dados Genéticas , Genes BRCA1 , Genes BRCA2 , Variação Genética , Alelos , Neoplasias da Mama/genética , Bases de Dados Genéticas/ética , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Disseminação de Informação/ética , Disseminação de Informação/legislação & jurisprudência , Masculino , Mutação , Neoplasias Ovarianas/genética , Penetrância , Fenótipo , Fatores de Risco
19.
PLoS One ; 13(12): e0209504, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30586397

RESUMO

Birt-Hogg-Dubé syndrome (BHDS) is a genetic tumor syndrome characterized by lung cysts, pneumothorax, fibrofolliculomas and renal cell cancer. The diagnosis of BHDS is usually considered if kidney cancer occurs before age 50 years, is multifocal and/or bilateral or of the oncocytoma/hybrid oncocytoma-chromophobe type. Using a sample of 50 BHDS families with a total of 178 patients we analyzed how many kidney cancer patients fulfilled one or more of these criteria. Furthermore, we addressed the question if genotype-phenotype-correlations exist that can be used for risk stratification. Renal cell cancer occurred in 34/178 (19.1%) patients, and the reported male bias was not observed. Furthermore, most kidney malignancies occurred after the age of 50 years. Thus, the majority of tumors did not show the typical hallmarks of BHDS. A below-average tumor frequency (17.2%) was observed for the known mutational hotspot c.1285delC/dupC that was the cause of BHDS in 24% of families. Unexpected was the high tumor frequency (66.7%) associated with mutation c.887C>G within a single family, a finding that merits further exploration.


Assuntos
Síndrome de Birt-Hogg-Dubé/genética , Carcinoma de Células Renais/genética , Estudos de Associação Genética , Neoplasias Renais/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Supressoras de Tumor/genética , Adulto , Idoso , Carcinoma de Células Renais/epidemiologia , Feminino , Humanos , Neoplasias Renais/epidemiologia , Masculino , Pessoa de Meia-Idade , Mutação , Penetrância , Medição de Risco
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA