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Ann Neurol ; 83(6): 1105-1124, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29691892


OBJECTIVE: Comprehensive clinical characterization of congenital titinopathy to facilitate diagnosis and management of this important emerging disorder. METHODS: Using massively parallel sequencing we identified 30 patients from 27 families with 2 pathogenic nonsense, frameshift and/or splice site TTN mutations in trans. We then undertook a detailed analysis of the clinical, histopathological and imaging features of these patients. RESULTS: All patients had prenatal or early onset hypotonia and/or congenital contractures. None had ophthalmoplegia. Scoliosis and respiratory insufficiency typically developed early and progressed rapidly, whereas limb weakness was often slowly progressive, and usually did not prevent independent walking. Cardiac involvement was present in 46% of patients. Relatives of 2 patients had dilated cardiomyopathy. Creatine kinase levels were normal to moderately elevated. Increased fiber size variation, internalized nuclei and cores were common histopathological abnormalities. Cap-like regions, whorled or ring fibers, and mitochondrial accumulations were also observed. Muscle magnetic resonance imaging showed gluteal, hamstring and calf muscle involvement. Western blot analysis showed a near-normal sized titin protein in all samples. The presence of 2 mutations predicted to impact both N2BA and N2B cardiac isoforms appeared to be associated with greatest risk of cardiac involvement. One-third of patients had 1 mutation predicted to impact exons present in fetal skeletal muscle, but not included within the mature skeletal muscle isoform transcript. This strongly suggests developmental isoforms are involved in the pathogenesis of this congenital/early onset disorder. INTERPRETATION: This detailed clinical reference dataset will greatly facilitate diagnostic confirmation and management of patients, and has provided important insights into disease pathogenesis. Ann Neurol 2018;83:1105-1124.

Hum Mutat ; 38(5): 548-555, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28150386


The devastating clinical presentation of X-linked lissencephaly with abnormal genitalia (XLAG) is invariably caused by loss-of-function mutations in the Aristaless-related homeobox (ARX) gene. Mutations in this X-chromosome gene contribute to intellectual disability (ID) with co-morbidities including seizures and movement disorders such as dystonia in affected males. The detection of affected females with mutations in ARX is increasing. We present a family with multiple affected individuals, including two females. Two male siblings presenting with XLAG were deceased prior to full-term gestation or within the first few weeks of life. Of the two female siblings, one presented with behavioral disturbances, mild ID, a seizure disorder, and complete agenesis of the corpus callosum (ACC), similar to the mother's phenotype. A novel insertion mutation in Exon 2 of ARX was identified, c.982delCinsTTT predicted to cause a frameshift at p.(Q328Ffs* 37). Our finding is consistent with loss-of-function mutations in ARX causing XLAG in hemizygous males and extends the findings of ID and seizures in heterozygous females. We review the reported phenotypes of females with mutations in ARX and highlight the importance of screening ARX in male and female patients with ID, seizures, and in particular with complete ACC.

Estudos de Associação Genética , Proteínas de Homeodomínio/genética , Mutação , Fenótipo , Fatores de Transcrição/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Encéfalo/patologia , Criança , Pré-Escolar , Análise Mutacional de DNA , Éxons , Feminino , Genes Ligados ao Cromossomo X , Proteínas de Homeodomínio/metabolismo , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Linhagem , Fatores de Transcrição/metabolismo
Circ Cardiovasc Genet ; 9(6): 548-558, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27879313


BACKGROUND: The natural history of aortic diseases in patients with TGFBR1 or TGFBR2 mutations reported by different investigators has varied greatly. In particular, the current recommendations for the timing of surgical repair of the aortic root aneurysms may be overly aggressive. METHODS AND RESULTS: The Montalcino Aortic Consortium, which includes 15 centers worldwide that specialize in heritable thoracic aortic diseases, was used to gather data on 441 patients from 228 families, with 176 cases harboring a mutation in TGBR1 and 265 in TGFBR2. Patients harboring a TGFBR1 mutation have similar survival rates (80% survival at 60 years), aortic risk (23% aortic dissection and 18% preventive aortic surgery), and prevalence of extra-aortic features (29% hypertelorism, 53% cervical arterial tortuosity, and 27% wide scars) when compared with patients harboring a TGFBR2 mutation. However, TGFBR1 males had a greater aortic risk than females, whereas TGFBR2 males and females had a similar aortic risk. Additionally, aortic root diameter prior to or at the time of type A aortic dissection tended to be smaller in patients carrying a TGFBR2 mutation and was ≤45 mm in 6 women with TGFBR2 mutations, presenting with marked systemic features and low body surface area. Aortic dissection was observed in 1.6% of pregnancies. CONCLUSIONS: Patients with TGFBR1 or TGFBR2 mutations show the same prevalence of systemic features and the same global survival. Preventive aortic surgery at a diameter of 45 mm, lowered toward 40 in females with low body surface area, TGFBR2 mutation, and severe extra-aortic features may be considered.

Aorta Torácica , Doenças da Aorta/genética , Heterozigoto , Mutação , Complicações Cardiovasculares na Gravidez/genética , Proteínas Serina-Treonina Quinases/genética , Receptores de Fatores de Crescimento Transformadores beta/genética , Aorta Torácica/diagnóstico por imagem , Aorta Torácica/cirurgia , Doenças da Aorta/diagnóstico por imagem , Doenças da Aorta/mortalidade , Doenças da Aorta/cirurgia , Austrália/epidemiologia , Europa (Continente)/epidemiologia , Feminino , Predisposição Genética para Doença , Humanos , Japão/epidemiologia , Estimativa de Kaplan-Meier , Masculino , Fenótipo , Gravidez , Complicações Cardiovasculares na Gravidez/diagnóstico por imagem , Complicações Cardiovasculares na Gravidez/mortalidade , Complicações Cardiovasculares na Gravidez/cirurgia , Prevalência , Modelos de Riscos Proporcionais , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptor do Fator de Crescimento Transformador beta Tipo II , Sistema de Registros , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Resultado do Tratamento , Estados Unidos/epidemiologia , Procedimentos Cirúrgicos Vasculares
Am J Med Genet C Semin Med Genet ; 166C(3): 315-26, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25169753


Mutations in ADNP were recently identified as a frequent cause of syndromic autism, characterized by deficits in social communication and interaction and restricted, repetitive behavioral patterns. Based on its functional domains, ADNP is a presumed transcription factor. The gene interacts closely with the SWI/SNF complex by direct and experimentally verified binding of its C-terminus to three of its core components. A detailed and systematic clinical assessment of the symptoms observed in our patients allows a detailed comparison with the symptoms observed in other SWI/SNF disorders. While the mutational mechanism of the first 10 patients identified suggested a gain of function mechanism, an 11th patient reported here is predicted haploinsufficient. The latter observation may raise hope for therapy, as addition of NAP, a neuroprotective octapeptide named after the first three amino acids of the sequence NAPVSPIQ, has been reported by others to ameliorate some of the cognitive abnormalities observed in a knockout mouse model. It is concluded that detailed clinical and molecular studies on larger cohorts of patients are necessary to establish a better insight in the genotype phenotype correlation and in the mutational mechanism.

Transtorno Autístico/genética , Proteínas de Homeodomínio/genética , Mutação , Proteínas do Tecido Nervoso/genética , Anormalidades Múltiplas/genética , Animais , Transtorno Autístico/etiologia , Pré-Escolar , DNA Helicases/genética , DNA Helicases/metabolismo , Face/anormalidades , Deformidades Congênitas da Mão/genética , Haploinsuficiência/genética , Humanos , Lactente , Deficiência Intelectual/genética , Camundongos Knockout , Micrognatismo/genética , Pescoço/anormalidades , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Oligopeptídeos/farmacologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
Nat Genet ; 46(4): 380-4, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24531329


Despite the high heritability of autism spectrum disorders (ASD), characterized by persistent deficits in social communication and interaction and restricted, repetitive patterns of behavior, interests or activities, a genetic diagnosis can be established in only a minority of patients. Known genetic causes include chromosomal aberrations, such as the duplication of the 15q11-13 region, and monogenic causes, as in Rett and fragile-X syndromes. The genetic heterogeneity within ASD is striking, with even the most frequent causes responsible for only 1% of cases at the most. Even with the recent developments in next-generation sequencing, for the large majority of cases no molecular diagnosis can be established. Here, we report ten patients with ASD and other shared clinical characteristics, including intellectual disability and facial dysmorphisms caused by a mutation in ADNP, a transcription factor involved in the SWI/SNF remodeling complex. We estimate this gene to be mutated in at least 0.17% of ASD cases, making it one of the most frequent ASD-associated genes known to date.

Anormalidades Múltiplas/genética , Transtornos Globais do Desenvolvimento Infantil/genética , Proteínas Cromossômicas não Histona/genética , Proteínas de Homeodomínio/genética , Proteínas do Tecido Nervoso/genética , Fatores de Transcrição/genética , Sequência de Bases , Códon sem Sentido/genética , Exoma/genética , Mutação da Fase de Leitura/genética , Componentes do Gene , Humanos , Dados de Sequência Molecular , Reação em Cadeia da Polimerase em Tempo Real , Análise de Sequência de DNA
Mol Genet Metab ; 109(3): 289-95, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23680354


Brittle cornea syndrome (BCS; MIM 229200) is an autosomal recessive generalized connective tissue disorder caused by mutations in ZNF469 and PRDM5. It is characterized by extreme thinning and fragility of the cornea that may rupture in the absence of significant trauma leading to blindness. Keratoconus or keratoglobus, high myopia, blue sclerae, hyperelasticity of the skin without excessive fragility, and hypermobility of the small joints are additional features of BCS. Transcriptional regulation of extracellular matrix components, particularly of fibrillar collagens, by PRDM5 and ZNF469 suggests that they might be part of the same pathway, the disruption of which is likely to cause the features of BCS. In the present study, we have performed molecular analysis of a cohort of 23 BCS affected patients on both ZNF469 and PRDM5, including those who were clinically reported previously [1]; the clinical description of three additional patients is reported in detail. We identified either homozygous or compound heterozygous mutations in ZNF469 in 18 patients while, 4 were found to be homozygous for PRDM5 mutations. In one single patient a mutation in neither ZNF469 nor PRDM5 was identified. Furthermore, we report the 12 novel ZNF469 variants identified in our patient cohort, and show evidence that ZNF469 is a single exon rather than a two exon gene.

Síndrome de Ehlers-Danlos/genética , Éxons , Matriz Extracelular/genética , Regulação da Expressão Gênica , Mutação , Fatores de Transcrição/genética , Adolescente , Criança , Pré-Escolar , Análise Mutacional de DNA , Proteínas de Ligação a DNA/genética , Síndrome de Ehlers-Danlos/diagnóstico , Síndrome de Ehlers-Danlos/terapia , Anormalidades do Olho , Feminino , Genótipo , Humanos , Instabilidade Articular/congênito , Anormalidades da Pele