Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 38
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
BMJ Open ; 9(7): e028928, 2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31289086

RESUMO

OBJECTIVES: (1) To explore professional and lay stakeholder views on the design and delivery of services in the area of consanguinity and genetic risk. (2) To identify principles on which there is sufficient consensus to warrant inclusion in a national guidance document. (3) To highlight differences of opinion that necessitate dialogue. (4) To identify areas where further research or development work is needed to inform practical service approaches. DESIGN: Delphi exercise. Three rounds and one consensus conference. SETTING: UK, national, web-based and face-to-face. PARTICIPANTS: Recruitment via email distribution lists and professional networks. 42 participants with varied professional and demographic backgrounds contributed to at least one round of the exercise. 29 people participated in statement ranking across both rounds 2 and 3. RESULTS: Over 700 individual statements were generated in round 1 and consolidated into 193 unique statements for ranking in round 2, with 60% achieving 80% or higher agreement. In round 3, 74% of statements achieved 80% or higher agreement. Consensus conference discussions resulted in a final set of 148 agreed statements, providing direction for both policy-makers and healthcare professionals. 13 general principles were agreed, with over 90% agreement on 12 of these. Remaining statements were organised into nine themes: national level leadership and coordination, local level leadership and coordination, training and competencies for healthcare and other professionals, genetic services, genetic literacy, primary care, referrals and coordination, monitoring and evaluation and research. Next steps and working groups were also identified. CONCLUSIONS: There is high agreement among UK stakeholders on the general principles that should shape policy and practice responses in this area: equity of access, cultural competence, coordinated inter-agency working, co-design and empowerment and embedded evaluation. The need for strong national leadership to ensure more efficient sharing of knowledge and promotion of more equitable and consistent responses across the country is emphasised.

2.
World Neurosurg ; 125: 271-272, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30794980

RESUMO

Labrune syndrome is a neurologic disorder that manifests as a progressive cerebral degeneration characterized by a radiologic triad of cerebral white matter disease (leukoencephalopathy), intracranial calcification, and cysts. The associated novel genetic mutation in SNORD118 has been recently identified. However, its significance in relation to the progression and severity of the disease is yet to be clarified. We present a 12-year-old boy with a 3-month history of headache that worsened 1 week before admission and was associated with nausea and vomiting, ataxia, and motor developmental delay. His head scans demonstrated widespread intracranial calcifications, cysts, leukoencephalopathy, and obstructive hydrocephalus. He had urgent endoscopic-assisted aspiration of the cerebellar cyst with insertion of a reservoir with resolution of the hydrocephalus and raised intracranial pressure symptoms. His genetic testing revealed a rare biallelic mutation with 2 variants in the gene SNORD118. The progressive form of this disease will be challenging for neurosurgeons.


Assuntos
Calcinose/diagnóstico por imagem , Calcinose/genética , Cistos do Sistema Nervoso Central/diagnóstico por imagem , Cistos do Sistema Nervoso Central/genética , Hidrocefalia/diagnóstico por imagem , Hidrocefalia/genética , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/genética , Mutação/genética , RNA Nucleolar Pequeno/genética , Calcinose/cirurgia , Cistos do Sistema Nervoso Central/cirurgia , Criança , Humanos , Hidrocefalia/cirurgia , Leucoencefalopatias/cirurgia , Masculino
3.
Clin Genet ; 95(4): 496-506, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30666632

RESUMO

Whole-exome sequencing has established IQSEC2 as a neurodevelopmental disability gene. The IQSEC2 variant phenotype includes developmental delay, intellectual disability, epilepsy, hypotonia, autism, developmental regression, microcephaly and stereotypies but is yet to be fully described. Presented here are 14 new patients with IQSEC2 variants. In addition to the established features, we observed: gait ataxia in 7 of 9 (77.8%), drooling in 9 of 14 (64.2%), early feeding difficulties in 7 of 14 (50%), structural brain abnormalities in 6 of 13 (46.2%), brachycephaly in 5 of 14 (35.7%), and scoliosis and paroxysms of laughter each in 4 of 14 (28.6%). We suggest that these are features of the IQSEC2-related disorder. Gastrostomy requirement, plagiocephaly, strabismus and cortical blindness, each seen in 2 of 14 (14.3%), may also be associated. Shared facial features were noted in 8 of 14 patients, and shared hair patterning was identified in 5 of 14 patients. This study further delineates the IQSEC2 phenotypic spectrum and supports the notion of an emerging IQSEC2 syndrome. We draw parallels between the IQSEC2-related disorder and the Angelman-/Rett-/Pitt-Hopkins syndrome group of conditions and recommend the addition of IQSEC2 to epilepsy and developmental delay gene panels. We observed discordant phenotypes in monozygotic twins and apparent gonadal mosaicism, which has implications for recurrence risk counselling in the IQSEC2-related disorder.

4.
Artigo em Inglês | MEDLINE | ID: mdl-30115503

RESUMO

Glucose transporter type 1 (GLUT1) deficiency syndrome is a well recognised genetic neurometabolic disorder typically presenting with progressive encephalopathy, acquired microcephaly and drug-resistant epilepsy. Imaging is normal in the majority. Here we describe a 5-month-old boy who presented with motor delay, myoclonic jerks and tonic-clonic seizures. His MRI brain scan revealed confluent symmetrical T2 hyperintense signal abnormality in both anterior frontal lobes and delayed myelination. Neurometabolic screen revealed low CSF glucose and lactate levels. A pathogenic de novo heterozygous mutation in SLC2A1 (c.275+1G > A) confirmed the diagnosis of GLUT1 deficiency. Ketogenic diet resulted in a dramatic termination of his seizures at 72 h. At 15 months, he continued to be seizure free with marked developmental catch up. Repeat imaging revealed a significant resolution of the previously seen changes. This case suggests that GLUT1 deficiency should be considered in the differential diagnosis of infants with suspected genetic leukoencephalopathies with important treatment implications.

5.
Am J Hum Genet ; 103(2): 305-316, 2018 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-30057029

RESUMO

Next-generation sequencing combined with international data sharing has enormously facilitated identification of new disease-associated genes and mutations. This is particularly true for genetically extremely heterogeneous entities such as neurodevelopmental disorders (NDDs). Through exome sequencing and world-wide collaborations, we identified and assembled 20 individuals with de novo variants in FBXO11. They present with mild to severe developmental delay associated with a range of features including short (4/20) or tall (2/20) stature, obesity (5/20), microcephaly (4/19) or macrocephaly (2/19), behavioral problems (17/20), seizures (5/20), cleft lip or palate or bifid uvula (3/20), and minor skeletal anomalies. FBXO11 encodes a member of the F-Box protein family, constituting a subunit of an E3-ubiquitin ligase complex. This complex is involved in ubiquitination and proteasomal degradation and thus in controlling critical biological processes by regulating protein turnover. The identified de novo aberrations comprise two large deletions, ten likely gene disrupting variants, and eight missense variants distributed throughout FBXO11. Structural modeling for missense variants located in the CASH or the Zinc-finger UBR domains suggests destabilization of the protein. This, in combination with the observed spectrum and localization of identified variants and the lack of apparent genotype-phenotype correlations, is compatible with loss of function or haploinsufficiency as an underlying mechanism. We implicate de novo missense and likely gene disrupting variants in FBXO11 in a neurodevelopmental disorder with variable intellectual disability and various other features.

6.
Prenat Diagn ; 38(1): 33-43, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29096039

RESUMO

OBJECTIVE: Rare genetic disorders resulting in prenatal or neonatal death are genetically heterogeneous, but testing is often limited by the availability of fetal DNA, leaving couples without a potential prenatal test for future pregnancies. We describe our novel strategy of exome sequencing parental DNA samples to diagnose recessive monogenic disorders in an audit of the first 50 couples referred. METHOD: Exome sequencing was carried out in a consecutive series of 50 couples who had 1 or more pregnancies affected with a lethal or prenatal-onset disorder. In all cases, there was insufficient DNA for exome sequencing of the affected fetus. Heterozygous rare variants (MAF < 0.001) in the same gene in both parents were selected for analysis. Likely, disease-causing variants were tested in fetal DNA to confirm co-segregation. RESULTS: Parental exome analysis identified heterozygous pathogenic (or likely pathogenic) variants in 24 different genes in 26/50 couples (52%). Where 2 or more fetuses were affected, a genetic diagnosis was obtained in 18/29 cases (62%). In most cases, the clinical features were typical of the disorder, but in others, they result from a hypomorphic variant or represent the most severe form of a variable phenotypic spectrum. CONCLUSION: We conclude that exome sequencing of parental samples is a powerful strategy with high clinical utility for the genetic diagnosis of lethal or prenatal-onset recessive disorders. © 2017 The Authors Prenatal Diagnosis published by John Wiley & Sons Ltd.


Assuntos
Anormalidades Congênitas/genética , Doenças Genéticas Inatas/diagnóstico , Pais , Diagnóstico Pré-Natal/métodos , Sequenciamento Completo do Exoma , Feminino , Genes Recessivos , Humanos , Masculino , Gravidez
7.
Hum Mol Genet ; 26(19): 3713-3721, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-28934384

RESUMO

SHORT syndrome is a rare, recognizable syndrome resulting from heterozygous mutations in PIK3R1 encoding a regulatory subunit of phosphoinositide-3-kinase (PI3K). The condition is characterized by short stature, intrauterine growth restriction, lipoatrophy and a facial gestalt involving a triangular face, deep set eyes, low hanging columella and small chin. PIK3R1 mutations in SHORT syndrome result in reduced signaling through the PI3K-AKT-mTOR pathway. We performed whole exome sequencing for an individual with clinical features of SHORT syndrome but negative for PIK3R1 mutation and her parents. A rare de novo variant in PRKCE was identified. The gene encodes PKCε and, as such, the AKT-mTOR pathway function was assessed using phospho-specific antibodies with patient lymphoblasts and following ectopic expression of the mutant in HEK293 cells. Kinase analysis showed that the variant resulted in a partial loss-of-function. Whilst interaction with PDK1 and the mTORC2 complex component SIN1 was preserved in the mutant PKCε, it bound to SIN1 with a higher affinity than wild-type PKCε and the dynamics of mTORC2-dependent priming of mutant PKCε was altered. Further, mutant PKCε caused impaired mTORC2-dependent pAKT-S473 following rapamycin treatment. Reduced pFOXO1-S256 and pS6-S240/244 levels were also observed in the patient LCLs. To date, mutations in PIK3R1 causing impaired PI3K-dependent AKT activation are the only known cause of SHORT syndrome. We identify a SHORT syndrome child with a novel partial loss-of-function defect in PKCε. This variant causes impaired AKT activation via compromised mTORC2 complex function.


Assuntos
Transtornos do Crescimento/genética , Hipercalcemia/genética , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Doenças Metabólicas/genética , Nefrocalcinose/genética , Proteína Quinase C-épsilon/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Adolescente , Nanismo/genética , Feminino , Transtornos do Crescimento/metabolismo , Células HEK293 , Humanos , Hipercalcemia/metabolismo , Doenças Metabólicas/metabolismo , Mutação , Nefrocalcinose/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosforilação , Proteína Quinase C-épsilon/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
9.
Am J Hum Genet ; 101(2): 300-310, 2017 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-28777935

RESUMO

Massively parallel sequencing has revealed many de novo mutations in the etiology of developmental and epileptic encephalopathies (EEs), highlighting their genetic heterogeneity. Additional candidate genes have been prioritized in silico by their co-expression in the brain. Here, we evaluate rare coding variability in 20 candidates nominated with the use of a reference gene set of 51 established EE-associated genes. Variants within the 20 candidate genes were extracted from exome-sequencing data of 42 subjects with EE and no previous genetic diagnosis. We identified 7 rare non-synonymous variants in 7 of 20 genes and performed Sanger sequence validation in affected probands and parental samples. De novo variants were found only in SLC1A2 (aka EAAT2 or GLT1) (c.244G>A [p.Gly82Arg]) and YWHAG (aka 14-3-3γ) (c.394C>T [p.Arg132Cys]), highlighting the potential cause of EE in 5% (2/42) of subjects. Seven additional subjects with de novo variants in SLC1A2 (n = 1) and YWHAG (n = 6) were subsequently identified through online tools. We identified a highly significant enrichment of de novo variants in YWHAG, establishing their role in early-onset epilepsy, and we provide additional support for the prior assignment of SLC1A2. Hence, in silico modeling of brain co-expression is an efficient method for nominating EE-associated genes to further elucidate the disorder's etiology and genotype-phenotype correlations.


Assuntos
Proteínas 14-3-3/genética , Predisposição Genética para Doença , Proteínas de Transporte de Glutamato da Membrana Plasmática/genética , Espasmos Infantis/genética , Adolescente , Adulto , Sequência de Aminoácidos , Criança , Exoma/genética , Feminino , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Masculino , Fenótipo , Adulto Jovem
10.
Hum Mol Genet ; 26(3): 519-526, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-28053047

RESUMO

Haploinsufficiency in DYRK1A is associated with a recognizable developmental syndrome, though the mechanism of action of pathogenic missense mutations is currently unclear. Here we present 19 de novo mutations in this gene, including five missense mutations, identified by the Deciphering Developmental Disorder study. Protein structural analysis reveals that the missense mutations are either close to the ATP or peptide binding-sites within the kinase domain, or are important for protein stability, suggesting they lead to a loss of the protein's function mechanism. Furthermore, there is some correlation between the magnitude of the change and the severity of the resultant phenotype. A comparison of the distribution of the pathogenic mutations along the length of DYRK1A with that of natural variants, as found in the ExAC database, confirms that mutations in the N-terminal end of the kinase domain are more disruptive of protein function. In particular, pathogenic mutations occur in significantly closer proximity to the ATP and the substrate peptide than the natural variants. Overall, we suggest that de novo dominant mutations in DYRK1A account for nearly 0.5% of severe developmental disorders due to substantially reduced kinase function.


Assuntos
Transtorno Autístico/genética , Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Tirosina Quinases/genética , Transtorno Autístico/patologia , Deficiências do Desenvolvimento/fisiopatologia , Feminino , Haploinsuficiência/genética , Humanos , Deficiência Intelectual/patologia , Masculino , Mutação , Mutação de Sentido Incorreto , Linhagem , Fenótipo , Conformação Proteica , Proteínas Serina-Treonina Quinases/química , Proteínas Tirosina Quinases/química , Relação Estrutura-Atividade
11.
Nephron ; 134(2): 51-58, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27504842

RESUMO

Renal-related disease is the most common cause of tuberous sclerosis complex (TSC)-related death in adults, and renal angiomyolipomas can lead to complications that include chronic kidney disease (CKD) and hemorrhage. International TSC guidelines recommend mammalian target of rapamycin (mTOR) inhibitors as first-line therapy for management of asymptomatic, growing angiomyolipomas >3 cm in diameter. This review discusses data regarding patient outcomes that were used to develop current guidelines for embolization of renal angiomyolipomas and presents recent data on 2 available mTOR inhibitors - sirolimus and everolimus - in the treatment of angiomyolipoma. TSC-associated renal angiomyolipomas can recur after embolization. Both sirolimus and everolimus have shown effectiveness in reduction of angiomyolipoma volume, with an acceptable safety profile that includes preservation of renal function with long-term therapy. The authors propose a hypothesis for mTORC1 haploinsufficiency as an additional mechanism for CKD and propose that preventive therapy with mTOR inhibitors might have a role in reducing the number of angiomyolipoma-related deaths. Because mTOR inhibitors target the underlying pathophysiology of TSC, patients might benefit from treatment of multiple manifestations with one systemic therapy. Based on recent evidence, new guidelines should be considered that support the earlier initiation of mTOR inhibitor therapy for the management of renal angiomyolipomas to prevent future serious complications, rather than try to rescue patients after the complications have occurred.


Assuntos
Angiomiolipoma/complicações , Consenso , Neoplasias Renais/complicações , Guias de Prática Clínica como Assunto , Esclerose Tuberosa/complicações , Adulto , Angiomiolipoma/tratamento farmacológico , Angiomiolipoma/mortalidade , Angiomiolipoma/fisiopatologia , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/mortalidade , Neoplasias Renais/fisiopatologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Esclerose Tuberosa/mortalidade , Esclerose Tuberosa/fisiopatologia
12.
Mol Genet Genomic Med ; 4(4): 465-74, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27441201

RESUMO

BACKGROUND: Exome sequencing has led to the discovery of mutations in novel causative genes for epilepsy. One such gene is EEF1A2, encoding a neuromuscular specific translation elongation factor, which has been found to be mutated de novo in five cases of severe epilepsy. We now report on a further seven cases, each with a different mutation, of which five are newly described. METHODS: New cases were identified and sequenced through the Deciphering Developmental Disabilities project, via direct contact with neurologists or geneticists, or recruited via our website. RESULTS: All the mutations cause epilepsy and intellectual disability, but with a much wider range of severity than previously identified. All new cases share specific subtle facial dysmorphic features. Each mutation occurs at an evolutionarily highly conserved amino acid position indicating strong structural or functional selective pressure. CONCLUSIONS: EEF1A2 should be considered as a causative gene not only in cases of epileptic encephalopathy but also in children with less severe epilepsy and intellectual disability. The emergence of a possible discernible phenotype, a broad nasal bridge, tented upper lip, everted lower lip and downturned corners of the mouth may help in identifying patients with mutations in EEF1A2.

13.
Am J Hum Genet ; 98(5): 981-992, 2016 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-27108798

RESUMO

Gillespie syndrome (GS) is characterized by bilateral iris hypoplasia, congenital hypotonia, non-progressive ataxia, and progressive cerebellar atrophy. Trio-based exome sequencing identified de novo mutations in ITPR1 in three unrelated individuals with GS recruited to the Deciphering Developmental Disorders study. Whole-exome or targeted sequence analysis identified plausible disease-causing ITPR1 mutations in 10/10 additional GS-affected individuals. These ultra-rare protein-altering variants affected only three residues in ITPR1: Glu2094 missense (one de novo, one co-segregating), Gly2539 missense (five de novo, one inheritance uncertain), and Lys2596 in-frame deletion (four de novo). No clinical or radiological differences were evident between individuals with different mutations. ITPR1 encodes an inositol 1,4,5-triphosphate-responsive calcium channel. The homo-tetrameric structure has been solved by cryoelectron microscopy. Using estimations of the degree of structural change induced by known recessive- and dominant-negative mutations in other disease-associated multimeric channels, we developed a generalizable computational approach to indicate the likely mutational mechanism. This analysis supports a dominant-negative mechanism for GS variants in ITPR1. In GS-derived lymphoblastoid cell lines (LCLs), the proportion of ITPR1-positive cells using immunofluorescence was significantly higher in mutant than control LCLs, consistent with an abnormality of nuclear calcium signaling feedback control. Super-resolution imaging supports the existence of an ITPR1-lined nucleoplasmic reticulum. Mice with Itpr1 heterozygous null mutations showed no major iris defects. Purkinje cells of the cerebellum appear to be the most sensitive to impaired ITPR1 function in humans. Iris hypoplasia is likely to result from either complete loss of ITPR1 activity or structure-specific disruption of multimeric interactions.


Assuntos
Aniridia/etiologia , Aniridia/patologia , Ataxia Cerebelar/etiologia , Ataxia Cerebelar/patologia , Genes Dominantes/genética , Receptores de Inositol 1,4,5-Trifosfato/genética , Deficiência Intelectual/etiologia , Deficiência Intelectual/patologia , Mutação/genética , Adolescente , Adulto , Animais , Células Cultivadas , Criança , Feminino , Humanos , Receptores de Inositol 1,4,5-Trifosfato/química , Linfócitos/metabolismo , Linfócitos/patologia , Masculino , Camundongos , Microscopia Confocal , Pessoa de Meia-Idade , Linhagem , Conformação Proteica
14.
Neurology ; 86(19): 1794-800, 2016 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-27029630

RESUMO

OBJECTIVE: The primary objective of this research was to characterize the movement disorders associated with FOXG1 mutations. METHODS: We identified patients with FOXG1 mutations who were referred to either a tertiary movement disorder clinic or tertiary epilepsy service and retrospectively reviewed medical records, clinical investigations, neuroimaging, and available video footage. We administered a telephone-based questionnaire regarding the functional impact of the movement disorders and perceived efficacy of treatment to the caregivers of one cohort of participants. RESULTS: We identified 28 patients with FOXG1 mutations, of whom 6 had previously unreported mutations. A wide variety of movement disorders were identified, with dystonia, choreoathetosis, and orolingual/facial dyskinesias most commonly present. Ninety-three percent of patients had a mixed movement disorder phenotype. In contrast to the phenotype classically described with FOXG1 mutations, 4 patients with missense mutations had a milder phenotype, with independent ambulation, spoken language, and normocephaly. Hyperkinetic involuntary movements were a major clinical feature in these patients. Of the symptomatic treatments targeted to control abnormal involuntary movements, most did not emerge as clearly beneficial, although 4 patients had a caregiver-reported response to levodopa. CONCLUSIONS: Abnormal involuntary movements are a major feature of FOXG1 mutations. Our study delineates the spectrum of movement disorders and confirms an expanding clinical phenotype. Symptomatic treatment may be considered for severe or disabling cases, although further research regarding potential treatment strategies is necessary.


Assuntos
Fatores de Transcrição Forkhead/genética , Transtornos dos Movimentos/genética , Mutação , Proteínas do Tecido Nervoso/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Transtornos dos Movimentos/tratamento farmacológico , Fenótipo , Estudos Retrospectivos , Centros de Atenção Terciária , Adulto Jovem
15.
Genet Med ; 18(11): 1143-1150, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-26986877

RESUMO

PURPOSE: Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) is an autosomal-dominant disorder characterized by optic atrophy and intellectual disability caused by loss-of-function mutations in NR2F1. We report 20 new individuals with BBSOAS, exploring the spectrum of clinical phenotypes and assessing potential genotype-phenotype correlations. METHODS: Clinical features of individuals with pathogenic NR2F1 variants were evaluated by review of medical records. The functional relevance of coding nonsynonymous NR2F1 variants was assessed with a luciferase assay measuring the impact on transcriptional activity. The effects of two start codon variants on protein expression were evaluated by western blot analysis. RESULTS: We recruited 20 individuals with novel pathogenic NR2F1 variants (seven missense variants, five translation initiation variants, two frameshifting insertions/deletions, one nonframeshifting insertion/deletion, and five whole-gene deletions). All the missense variants were found to impair transcriptional activity. In addition to visual and cognitive deficits, individuals with BBSOAS manifested hypotonia (75%), seizures (40%), autism spectrum disorder (35%), oromotor dysfunction (60%), thinning of the corpus callosum (53%), and hearing defects (20%). CONCLUSION: BBSOAS encompasses a broad range of clinical phenotypes. Functional studies help determine the severity of novel NR2F1 variants. Some genotype-phenotype correlations seem to exist, with missense mutations in the DNA-binding domain causing the most severe phenotypes.Genet Med 18 11, 1143-1150.


Assuntos
Transtorno do Espectro Autista/genética , Fator I de Transcrição COUP/genética , Estudos de Associação Genética , Atrofia Óptica/genética , Adolescente , Adulto , Transtorno do Espectro Autista/complicações , Transtorno do Espectro Autista/fisiopatologia , Criança , Pré-Escolar , Feminino , Deleção de Genes , Humanos , Masculino , Mutação de Sentido Incorreto , Atrofia Óptica/complicações , Atrofia Óptica/fisiopatologia , Linhagem
16.
Am J Med Genet A ; 167A(8): 1763-72, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25846194

RESUMO

Vascular Ehlers-Danlos syndrome (vEDS) is a heritable disorder of connective tissue caused by pathological variants in the COL3A1 gene, which encodes the α1 chain of type III collagen. Type III collagen is a major component of skin, arterial walls, and the gastrointestinal tract. Collagen III protein deficiency manifests as an increased risk of rupture, perforation, and dissection of these structures. The most disruptive gene variants affect the collagen helix via glycine substitutions or splice donor site mutations. The C-propeptide region of COL3A1 includes exons 49-52 and has a crucial role in initiating the C-terminal assembly of procollagen monomers in the early stages of collagen biosynthesis. Nineteen COL3A1 variants have previously been reported in these exons, of which four were associated with a severe vEDS phenotype. We identified two novel C-propeptide missense variants; p.Pro1440Leu, p.Arg1432Leu, and a non-stop mutation, c.4400A > T, p. (*1467Leuext*45). These variants produce variable phenotypes ranging from obvious acrogeria to classical or hypermobile EDS. A previously reported variant p.Lys1313Arg is of unknown clinical significance but likely benign, based on this study. Assigning disease pathogenicity remains complex, clinical phenotyping and crystal structure evidence being crucial. We briefly compare reported phenotypes for patients with missense variants in the C-propeptide domain for other human collagen disorders including COL1A1 and COL1A2 (osteogenesis imperfecta).


Assuntos
Colágeno Tipo III/genética , Fragmentos de Peptídeos/genética , Adulto , Colágeno Tipo III/química , Cristalografia por Raios X , Síndrome de Ehlers-Danlos/genética , Éxons , Feminino , Humanos , Masculino , Fragmentos de Peptídeos/química , Conformação Proteica
17.
Am J Med Genet A ; 167A(3): 461-75, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25604898

RESUMO

Type 2 collagen disorders encompass a diverse group of skeletal dysplasias that are commonly associated with orthopedic, ocular, and hearing problems. However, the frequency of many clinical features has never been determined. We retrospectively investigated the clinical, radiological, and genotypic data in a group of 93 patients with molecularly confirmed SEDC or a related disorder. The majority of the patients (80/93) had short stature, with radiological features of SEDC (n = 64), others having SEMD (n = 5), Kniest dysplasia (n = 7), spondyloperipheral dysplasia (n = 2), or Torrance-like dysplasia (n = 2). The remaining 13 patients had normal stature with mild SED, Stickler-like syndrome or multiple epiphyseal dysplasia. Over 50% of the patients had undergone orthopedic surgery, usually for scoliosis, femoral osteotomy or hip replacement. Odontoid hypoplasia was present in 56% (95% CI 38-74) and a correlation between odontoid hypoplasia and short stature was observed. Atlanto-axial instability, was observed in 5 of the 18 patients (28%, 95% CI 10-54) in whom flexion-extension films of the cervical spine were available; however, it was rarely accompanied by myelopathy. Myopia was found in 45% (95% CI 35-56), and retinal detachment had occurred in 12% (95% CI 6-21; median age 14 years; youngest age 3.5 years). Thirty-two patients complained of hearing loss (37%, 95% CI 27-48) of whom 17 required hearing aids. The ophthalmological features and possibly also hearing loss are often relatively frequent and severe in patients with splicing mutations. Based on clinical findings, age at onset and genotype-phenotype correlations in this cohort, we propose guidelines for the management and follow-up in this group of disorders.


Assuntos
Colágeno Tipo II/genética , Mutação , Osteocondrodisplasias/congênito , Fenótipo , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Estudos de Associação Genética , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Osteocondrodisplasias/diagnóstico por imagem , Osteocondrodisplasias/genética , Radiografia , Adulto Jovem
18.
Hum Mutat ; 34(1): 167-75, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22903760

RESUMO

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by mutations in the TSC1 or TSC2 genes. The TSC1 and TSC2 gene products, TSC1 and TSC2, form a complex that inhibits the mammalian target of rapamycin (mTOR) complex 1 (TORC1). Here, we investigate the effects of 78 TSC2 variants identified in individuals suspected of TSC, on the function of the TSC1-TSC2 complex. According to our functional assessment, 40 variants disrupted the TSC1-TSC2-dependent inhibition of TORC1. We classified 34 of these as pathogenic, three as probably pathogenic and three as possibly pathogenic. In one case, a likely effect on splicing as well as an effect on function was noted. In 15 cases, our functional assessment did not agree with the predictions of the SIFT amino acid substitution analysis software. Our data support the notion that different, nonterminating TSC2 mutations can have distinct effects on TSC1-TSC2 function, and therefore, on TSC pathology.


Assuntos
Mutação , Transdução de Sinais/genética , Esclerose Tuberosa/genética , Proteínas Supressoras de Tumor/genética , Substituição de Aminoácidos , Células HEK293 , Humanos , Immunoblotting , Alvo Mecanístico do Complexo 1 de Rapamicina , Complexos Multiproteicos/genética , Complexos Multiproteicos/metabolismo , Proteínas Quinases S6 Ribossômicas/genética , Proteínas Quinases S6 Ribossômicas/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Transfecção , Esclerose Tuberosa/metabolismo , Proteína 1 do Complexo Esclerose Tuberosa , Proteína 2 do Complexo Esclerose Tuberosa , Proteínas Supressoras de Tumor/metabolismo
19.
Am J Hum Genet ; 91(2): 358-64, 2012 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-22795537

RESUMO

Excessive growth of terminal hair around the elbows (hypertrichosis cubiti) has been reported both in isolation and in association with a variable spectrum of associated phenotypic features. We identified a cohort of six individuals with hypertrichosis cubiti associated with short stature, intellectual disability, and a distinctive facial appearance, consistent with a diagnosis of Wiedemann-Steiner syndrome (WSS). Utilizing a whole-exome sequencing approach, we identified de novo mutations in MLL in five of the six individuals. MLL encodes a histone methyltransferase that regulates chromatin-mediated transcription through the catalysis of methylation of histone H3K4. Each of the five mutations is predicted to result in premature termination of the protein product. Furthermore, we demonstrate that transcripts arising from the mutant alleles are subject to nonsense-mediated decay. These findings define the genetic basis of WSS, provide additional evidence for the role of haploinsufficency of histone-modification enzymes in multiple-congenital-anomaly syndromes, and further illustrate the importance of the regulation of histone modification in development.


Assuntos
Anormalidades Múltiplas/genética , Transtornos do Crescimento/genética , Hipertricose/congênito , Proteína de Leucina Linfoide-Mieloide/genética , Anormalidades Múltiplas/patologia , Sequência de Bases , Exoma/genética , Componentes do Gene , Transtornos do Crescimento/patologia , Haploinsuficiência/genética , Histona-Lisina N-Metiltransferase , Humanos , Hipertricose/genética , Hipertricose/patologia , Dados de Sequência Molecular , Mutação/genética , Análise de Sequência de DNA
20.
Nat Genet ; 44(6): 639-41, 2012 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-22544363

RESUMO

We show that haploinsufficiency of KANSL1 is sufficient to cause the 17q21.31 microdeletion syndrome, a multisystem disorder characterized by intellectual disability, hypotonia and distinctive facial features. The KANSL1 protein is an evolutionarily conserved regulator of the chromatin modifier KAT8, which influences gene expression through histone H4 lysine 16 (H4K16) acetylation. RNA sequencing studies in cell lines derived from affected individuals and the presence of learning deficits in Drosophila melanogaster mutants suggest a role for KANSL1 in neuronal processes.


Assuntos
Anormalidades Múltiplas/genética , Deleção Cromossômica , Proteínas Nucleares/genética , Idoso , Envelhecimento , Cromossomos Humanos Par 17 , Facies , Feminino , Haploinsuficiência , Humanos , Deficiência Intelectual/genética , Masculino , Pessoa de Meia-Idade , Mutação , Síndrome de Smith-Magenis , Síndrome
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA