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1.
Nat Commun ; 10(1): 4630, 2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31604926

RESUMO

Mobile genetic Elements (MEs) are segments of DNA which can copy themselves and other transcribed sequences through the process of retrotransposition (RT). In humans several disorders have been attributed to RT, but the role of RT in severe developmental disorders (DD) has not yet been explored. Here we identify RT-derived events in 9738 exome sequenced trios with DD-affected probands. We ascertain 9 de novo MEs, 4 of which are likely causative of the patient's symptoms (0.04%), as well as 2 de novo gene retroduplications. Beyond identifying likely diagnostic RT events, we estimate genome-wide germline ME mutation rate and selective constraint and demonstrate that coding RT events have signatures of purifying selection equivalent to those of truncating mutations. Overall, our analysis represents a comprehensive interrogation of the impact of retrotransposition on protein coding genes and a framework for future evolutionary and disease studies.

2.
Lancet ; 393(10173): 747-757, 2019 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-30712880

RESUMO

BACKGROUND: Fetal structural anomalies, which are detected by ultrasonography, have a range of genetic causes, including chromosomal aneuploidy, copy number variations (CNVs; which are detectable by chromosomal microarrays), and pathogenic sequence variants in developmental genes. Testing for aneuploidy and CNVs is routine during the investigation of fetal structural anomalies, but there is little information on the clinical usefulness of genome-wide next-generation sequencing in the prenatal setting. We therefore aimed to evaluate the proportion of fetuses with structural abnormalities that had identifiable variants in genes associated with developmental disorders when assessed with whole-exome sequencing (WES). METHODS: In this prospective cohort study, two groups in Birmingham and London recruited patients from 34 fetal medicine units in England and Scotland. We used whole-exome sequencing (WES) to evaluate the presence of genetic variants in developmental disorder genes (diagnostic genetic variants) in a cohort of fetuses with structural anomalies and samples from their parents, after exclusion of aneuploidy and large CNVs. Women were eligible for inclusion if they were undergoing invasive testing for identified nuchal translucency or structural anomalies in their fetus, as detected by ultrasound after 11 weeks of gestation. The partners of these women also had to consent to participate. Sequencing results were interpreted with a targeted virtual gene panel for developmental disorders that comprised 1628 genes. Genetic results related to fetal structural anomaly phenotypes were then validated and reported postnatally. The primary endpoint, which was assessed in all fetuses, was the detection of diagnostic genetic variants considered to have caused the fetal developmental anomaly. FINDINGS: The cohort was recruited between Oct 22, 2014, and June 29, 2017, and clinical data were collected until March 31, 2018. After exclusion of fetuses with aneuploidy and CNVs, 610 fetuses with structural anomalies and 1202 matched parental samples (analysed as 596 fetus-parental trios, including two sets of twins, and 14 fetus-parent dyads) were analysed by WES. After bioinformatic filtering and prioritisation according to allele frequency and effect on protein and inheritance pattern, 321 genetic variants (representing 255 potential diagnoses) were selected as potentially pathogenic genetic variants (diagnostic genetic variants), and these variants were reviewed by a multidisciplinary clinical review panel. A diagnostic genetic variant was identified in 52 (8·5%; 95% CI 6·4-11·0) of 610 fetuses assessed and an additional 24 (3·9%) fetuses had a variant of uncertain significance that had potential clinical usefulness. Detection of diagnostic genetic variants enabled us to distinguish between syndromic and non-syndromic fetal anomalies (eg, congenital heart disease only vs a syndrome with congenital heart disease and learning disability). Diagnostic genetic variants were present in 22 (15·4%) of 143 fetuses with multisystem anomalies (ie, more than one fetal structural anomaly), nine (11·1%) of 81 fetuses with cardiac anomalies, and ten (15·4%) of 65 fetuses with skeletal anomalies; these phenotypes were most commonly associated with diagnostic variants. However, diagnostic genetic variants were least common in fetuses with isolated increased nuchal translucency (≥4·0 mm) in the first trimester (in three [3·2%] of 93 fetuses). INTERPRETATION: WES facilitates genetic diagnosis of fetal structural anomalies, which enables more accurate predictions of fetal prognosis and risk of recurrence in future pregnancies. However, the overall detection of diagnostic genetic variants in a prospectively ascertained cohort with a broad range of fetal structural anomalies is lower than that suggested by previous smaller-scale studies of fewer phenotypes. WES improved the identification of genetic disorders in fetuses with structural abnormalities; however, before clinical implementation, careful consideration should be given to case selection to maximise clinical usefulness. FUNDING: UK Department of Health and Social Care and The Wellcome Trust.


Assuntos
Cariótipo Anormal/estatística & dados numéricos , Anormalidades Congênitas/genética , Desenvolvimento Fetal/genética , Feto/anormalidades , Sequenciamento Completo do Exoma/estatística & dados numéricos , Cariótipo Anormal/embriologia , Aborto Eugênico/estatística & dados numéricos , Aborto Espontâneo/epidemiologia , Anormalidades Congênitas/diagnóstico , Anormalidades Congênitas/epidemiologia , Variações do Número de Cópias de DNA/genética , Feminino , Feto/diagnóstico por imagem , Humanos , Recém-Nascido , Nascimento Vivo/epidemiologia , Masculino , Medição da Translucência Nucal , Pais , Morte Perinatal/etiologia , Gravidez , Estudos Prospectivos , Natimorto/epidemiologia , Sequenciamento Completo do Exoma/métodos
3.
J Med Genet ; 55(2): 104-113, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29097605

RESUMO

BACKGROUND: De novo mutations in PURA have recently been described to cause PURA syndrome, a neurodevelopmental disorder characterised by severe intellectual disability (ID), epilepsy, feeding difficulties and neonatal hypotonia. OBJECTIVES: To delineate the clinical spectrum of PURA syndrome and study genotype-phenotype correlations. METHODS: Diagnostic or research-based exome or Sanger sequencing was performed in individuals with ID. We systematically collected clinical and mutation data on newly ascertained PURA syndrome individuals, evaluated data of previously reported individuals and performed a computational analysis of photographs. We classified mutations based on predicted effect using 3D in silico models of crystal structures of Drosophila-derived Pur-alpha homologues. Finally, we explored genotype-phenotype correlations by analysis of both recurrent mutations as well as mutation classes. RESULTS: We report mutations in PURA (purine-rich element binding protein A) in 32 individuals, the largest cohort described so far. Evaluation of clinical data, including 22 previously published cases, revealed that all have moderate to severe ID and neonatal-onset symptoms, including hypotonia (96%), respiratory problems (57%), feeding difficulties (77%), exaggerated startle response (44%), hypersomnolence (66%) and hypothermia (35%). Epilepsy (54%) and gastrointestinal (69%), ophthalmological (51%) and endocrine problems (42%) were observed frequently. Computational analysis of facial photographs showed subtle facial dysmorphism. No strong genotype-phenotype correlation was identified by subgrouping mutations into functional classes. CONCLUSION: We delineate the clinical spectrum of PURA syndrome with the identification of 32 additional individuals. The identification of one individual through targeted Sanger sequencing points towards the clinical recognisability of the syndrome. Genotype-phenotype analysis showed no significant correlation between mutation classes and disease severity.

4.
Am J Hum Genet ; 101(6): 1021-1033, 2017 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-29220674

RESUMO

ACTB encodes ß-actin, an abundant cytoskeletal housekeeping protein. In humans, postulated gain-of-function missense mutations cause Baraitser-Winter syndrome (BRWS), characterized by intellectual disability, cortical malformations, coloboma, sensorineural deafness, and typical facial features. To date, the consequences of loss-of-function ACTB mutations have not been proven conclusively. We describe heterozygous ACTB deletions and nonsense and frameshift mutations in 33 individuals with developmental delay, apparent intellectual disability, increased frequency of internal organ malformations (including those of the heart and the renal tract), growth retardation, and a recognizable facial gestalt (interrupted wavy eyebrows, dense eyelashes, wide nose, wide mouth, and a prominent chin) that is distinct from characteristics of individuals with BRWS. Strikingly, this spectrum overlaps with that of several chromatin-remodeling developmental disorders. In wild-type mouse embryos, ß-actin expression was prominent in the kidney, heart, and brain. ACTB mRNA expression levels in lymphoblastic lines and fibroblasts derived from affected individuals were decreased in comparison to those in control cells. Fibroblasts derived from an affected individual and ACTB siRNA knockdown in wild-type fibroblasts showed altered cell shape and migration, consistent with known roles of cytoplasmic ß-actin. We also demonstrate that ACTB haploinsufficiency leads to reduced cell proliferation, altered expression of cell-cycle genes, and decreased amounts of nuclear, but not cytoplasmic, ß-actin. In conclusion, we show that heterozygous loss-of-function ACTB mutations cause a distinct pleiotropic malformation syndrome with intellectual disability. Our biological studies suggest that a critically reduced amount of this protein alters cell shape, migration, proliferation, and gene expression to the detriment of brain, heart, and kidney development.


Assuntos
Anormalidades Múltiplas/genética , Actinas/genética , Deficiências do Desenvolvimento/genética , Haploinsuficiência/genética , Actinas/biossíntese , Adolescente , Adulto , Idoso , Animais , Ciclo Celular/genética , Proliferação de Células/genética , Criança , Pré-Escolar , Códon sem Sentido/genética , Coloboma/genética , Facies , Feminino , Mutação da Fase de Leitura/genética , Deleção de Genes , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/genética , Masculino , Malformações do Desenvolvimento Cortical/genética , Camundongos , Interferência de RNA , RNA Interferente Pequeno/genética , Adulto Jovem
5.
Am J Med Genet A ; 173(11): 3003-3012, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28944577

RESUMO

Exome sequencing in the context of developmental disorders is a useful technique, but variants found need to be interpreted in the context of detailed phenotypic information. Whole gene deletions and loss-of-function-mutations in the HNRNPU gene have been associated with intellectual disability and seizures in some patients. However, a unifying syndromic phenotype has not been previously elucidated. Here, we report a total of seven patients (six patients identified through the Wellcome Trust Deciphering Developmental Disorders study, with one additional patient), who have heterozygous de novo mutations in HNRNPU. These were found via trio-based exome sequencing. All but one of the mutations is predicted to cause loss-of-function. These patients have dysmorphic features in common, including prominent eyebrows, long palpebral fissures, overhanging columella, and thin upper lip. All patients have developmental delay and intellectual disability (ID), ranging from moderate to severe. Seizures are common from early childhood. These initially occur in the context of febrile episodes. This series demonstrates common phenotypic features, including emerging dysmorphism, associated with heterozygous HNRNPU mutations. This allows us to define a novel neurodevelopmental syndrome, with a likely mechanism of haploinsufficiency.


Assuntos
Deficiências do Desenvolvimento/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo U/genética , Deficiência Intelectual/genética , Transtornos do Neurodesenvolvimento/genética , Convulsões/genética , Adolescente , Adulto , Criança , Pré-Escolar , Deficiências do Desenvolvimento/fisiopatologia , Exoma , Feminino , Predisposição Genética para Doença , Haploinsuficiência/genética , Heterozigoto , Humanos , Lactente , Deficiência Intelectual/fisiopatologia , Masculino , Mutação , Transtornos do Neurodesenvolvimento/fisiopatologia , Fenótipo , Convulsões/fisiopatologia , Adulto Jovem
6.
J Med Genet ; 54(1): 64-72, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27572252

RESUMO

BACKGROUND: Disruptions of the FOXP2 gene, encoding a forkhead transcription factor, are the first known monogenic cause of a speech and language disorder. So far, mainly chromosomal rearrangements such as translocations or larger deletions affecting FOXP2 have been reported. Intragenic deletions or convincingly pathogenic point mutations in FOXP2 have up to date only been reported in three families. We thus aimed at a further characterisation of the mutational and clinical spectrum. METHODS: Chromosomal microarray testing, trio exome sequencing, multigene panel sequencing and targeted sequencing of FOXP2 were performed in individuals with variable developmental disorders, and speech and language deficits. RESULTS: We identified four different truncating mutations, two novel missense mutations within the forkhead domain and an intragenic deletion in FOXP2 in 14 individuals from eight unrelated families. Mutations occurred de novo in four families and were inherited from an affected parent in the other four. All index patients presented with various manifestations of language and speech impairment. Apart from two individuals with normal onset of speech, age of first words was between 4 and 7 years. Articulation difficulties such as slurred speech, dyspraxia, stuttering and poor pronunciation were frequently noted. Motor development was normal or only mildly delayed. Mild cognitive impairment was reported for most individuals. CONCLUSIONS: By identifying intragenic deletions or mutations in 14 individuals from eight unrelated families with variable developmental delay/cognitive impairment and speech and language deficits, we considerably broaden the mutational and clinical spectrum associated with aberrations in FOXP2.


Assuntos
Fatores de Transcrição Forkhead/genética , Transtornos da Linguagem/genética , Mutação de Sentido Incorreto/genética , Mutação Puntual/genética , Deleção de Sequência/genética , Distúrbios da Fala/genética , Deficiências do Desenvolvimento/genética , Humanos , Masculino , Linhagem , Fala/fisiologia
7.
Eur J Paediatr Neurol ; 20(2): 286-295, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26748598

RESUMO

INTRODUCTION: Next Generation Sequencing (NGS) is a useful tool in diagnosis of rare disorders but the interpretation of data can be challenging in clinical settings. We present results of extended studies on a family of multiple members with global developmental delay and learning disability, where another research group postulated the underlying cause to be a homozygous RABL6 missense variant. METHODS AND RESULTS: Using data from the Exome Variant Server, we show that missense RABL6 variants are unlikely to cause early onset rare developmental disorder. Protein structural analysis, cellular functional studies and reverse phenotyping proved that the condition in this family is due to a homozygous INPP5E mutation. An in-depth review of mutational and phenotypic spectrum associated with INPP5E demonstrated that mutations in this gene lead to a range of cilliopathy-phenotypes. DISCUSSION: We use this study as an example to demonstrate the importance of careful clinical evaluation of multiple family members, reverse phenotyping, considering the unknown phenotypic variability of rare diseases, utilizing publically available genomic databases and conducting appropriate bioinformatics and functional studies while interpreting results from NGS in uncertain cases. We emphasize that interpretation of NGS data is an iterative process and its dynamic nature should be explained to patients and families. Our study shows that developmental delay, intellectual disability, hypotonia and ocular motor apraxia are common in INPP5E-related disorders and considerable intra-familial phenotypic variability is possible. We have compiled the INPP5E mutational spectrum and provided novel insights into their molecular mechanisms.


Assuntos
Deficiências do Desenvolvimento/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Monoéster Fosfórico Hidrolases/genética , Feminino , Humanos , Masculino , Mutação , Proteínas Oncogênicas/genética , Linhagem , Fenótipo , Proteínas rab de Ligação ao GTP/genética
8.
Am J Med Genet A ; 170A(1): 170-5, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26395259

RESUMO

We present a Caucasian female, who was diagnosed at 13 years of age with Temple syndrome (formerly referred to as "maternal UPD 14 phenotype") due to an epigenetic loss of methylation at IG-DMR/MEG3-DMR at the chromosome 14q32 imprinted locus. Clinical features were typical and included intra-uterine growth retardation (IUGR), low birth weight, hypotonia, and poor feeding in the neonatal period; and failure to thrive and developmental delay--particularly in relation to speech--in early childhood. Premature puberty, with short stature and truncal obesity, but normal intelligence, were the key features in teenage years. To date only eight patients with Temple syndrome due to an epigenetic error have been described and the etiology of the methylation defect is currently undetermined. In view of a tendency towards central obesity, patients are at potential risk of early-onset type 2 diabetes mellitus, as well as cardiovascular disease and they, therefore, require appropriate monitoring.


Assuntos
Cromossomos Humanos Par 14/genética , Metilação de DNA/genética , Impressão Genômica/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Proteínas de Membrana/genética , RNA Longo não Codificante/genética , Dissomia Uniparental/genética , Anormalidades Múltiplas/genética , Adolescente , Deficiências do Desenvolvimento/genética , Feminino , Humanos , Fenótipo , Dissomia Uniparental/patologia
9.
Am J Hum Genet ; 97(4): 535-45, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-26387595

RESUMO

Heimler syndrome (HS) is a rare recessive disorder characterized by sensorineural hearing loss (SNHL), amelogenesis imperfecta, nail abnormalities, and occasional or late-onset retinal pigmentation. We ascertained eight families affected by HS and, by using a whole-exome sequencing approach, identified biallelic mutations in PEX1 or PEX6 in six of them. Loss-of-function mutations in both genes are known causes of a spectrum of autosomal-recessive peroxisome-biogenesis disorders (PBDs), including Zellweger syndrome. PBDs are characterized by leukodystrophy, hypotonia, SNHL, retinopathy, and skeletal, craniofacial, and liver abnormalities. We demonstrate that each HS-affected family has at least one hypomorphic allele that results in extremely mild peroxisomal dysfunction. Although individuals with HS share some subtle clinical features found in PBDs, the diagnosis was not suggested by routine blood and skin fibroblast analyses used to detect PBDs. In conclusion, our findings define HS as a mild PBD, expanding the pleiotropy of mutations in PEX1 and PEX6.


Assuntos
Adenosina Trifosfatases/genética , Amelogênese Imperfeita/genética , Fibroblastos/patologia , Perda Auditiva Neurossensorial/genética , Proteínas de Membrana/genética , Mutação/genética , Unhas Malformadas/genética , Peroxissomos/patologia , ATPases Associadas a Diversas Atividades Celulares , Adolescente , Adulto , Estudos de Casos e Controles , Células Cultivadas , Criança , Pré-Escolar , Feminino , Fibroblastos/metabolismo , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Linhagem , Peroxissomos/metabolismo , Fenótipo , Prognóstico , Taxa de Sobrevida , Adulto Jovem
10.
Am J Med Genet A ; 167A(2): 296-312, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25604658

RESUMO

Aicardi-Goutières syndrome is an inflammatory disease occurring due to mutations in any of TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR or IFIH1. We report on 374 patients from 299 families with mutations in these seven genes. Most patients conformed to one of two fairly stereotyped clinical profiles; either exhibiting an in utero disease-onset (74 patients; 22.8% of all patients where data were available), or a post-natal presentation, usually within the first year of life (223 patients; 68.6%), characterized by a sub-acute encephalopathy and a loss of previously acquired skills. Other clinically distinct phenotypes were also observed; particularly, bilateral striatal necrosis (13 patients; 3.6%) and non-syndromic spastic paraparesis (12 patients; 3.4%). We recorded 69 deaths (19.3% of patients with follow-up data). Of 285 patients for whom data were available, 210 (73.7%) were profoundly disabled, with no useful motor, speech and intellectual function. Chilblains, glaucoma, hypothyroidism, cardiomyopathy, intracerebral vasculitis, peripheral neuropathy, bowel inflammation and systemic lupus erythematosus were seen frequently enough to be confirmed as real associations with the Aicardi-Goutieres syndrome phenotype. We observed a robust relationship between mutations in all seven genes with increased type I interferon activity in cerebrospinal fluid and serum, and the increased expression of interferon-stimulated gene transcripts in peripheral blood. We recorded a positive correlation between the level of cerebrospinal fluid interferon activity assayed within one year of disease presentation and the degree of subsequent disability. Interferon-stimulated gene transcripts remained high in most patients, indicating an ongoing disease process. On the basis of substantial morbidity and mortality, our data highlight the urgent need to define coherent treatment strategies for the phenotypes associated with mutations in the Aicardi-Goutières syndrome-related genes. Our findings also make it clear that a window of therapeutic opportunity exists relevant to the majority of affected patients and indicate that the assessment of type I interferon activity might serve as a useful biomarker in future clinical trials.


Assuntos
Adenosina Desaminase/genética , Doenças Autoimunes do Sistema Nervoso/diagnóstico , Doenças Autoimunes do Sistema Nervoso/genética , RNA Helicases DEAD-box/genética , Exodesoxirribonucleases/genética , Proteínas Monoméricas de Ligação ao GTP/genética , Mutação , Malformações do Sistema Nervoso/diagnóstico , Malformações do Sistema Nervoso/genética , Fenótipo , Fosfoproteínas/genética , Ribonuclease H/genética , Estudos de Associação Genética , Genótipo , Humanos , Helicase IFIH1 Induzida por Interferon , Interferons/sangue , Interferons/líquido cefalorraquidiano , Pterinas/líquido cefalorraquidiano , Proteína 1 com Domínio SAM e Domínio HD
11.
Am J Med Genet A ; 167A(3): 587-91, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25604815

RESUMO

In 1987, Cole and Carpenter reported two unrelated infants with multiple fractures and deformities of bone, with a skeletal phenotype similar to severe osteogenesis imperfecta. In addition, these patients also had proptosis, blue sclerae, hydrocephalus, and a distinct facial gestalt. They were reported to be of normal intelligence. Radiologically, these patients had characteristic skeletal manifestations including craniosynostosis and deformities similar to severe progressive osteogenesis imperfecta. Since the first description, there have only been a few other reports of patients with a similar phenotype. Collagen studies performed in reported patients have been normal. The molecular basis of this syndrome has not been elucidated and the inheritance pattern is still unknown. We report on a child with Cole-Carpenter syndrome phenotype who has a homozygous c.118G>T mutation in exon 1 of the CRTAP gene. We describe the clinical features and correlate this with her molecular results. This is the first report towards elucidating the molecular basis of Cole-Carpenter syndrome.


Assuntos
Craniossinostoses/diagnóstico , Craniossinostoses/genética , Proteínas da Matriz Extracelular/genética , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/genética , Hidrocefalia/diagnóstico , Hidrocefalia/genética , Mutação , Osteogênese Imperfeita/diagnóstico , Osteogênese Imperfeita/genética , Osso e Ossos/anormalidades , Osso e Ossos/diagnóstico por imagem , Criança , Facies , Feminino , Estudos de Associação Genética , Homozigoto , Humanos , Fenótipo , Radiografia , Análise de Sequência de DNA
12.
Mol Genet Metab ; 113(4): 301-6, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25458521

RESUMO

Thiamine pyrophosphokinase (TPK) produces thiamine pyrophosphate, a cofactor for a number of enzymes, including pyruvate dehydrogenase and 2-ketoglutarate dehydrogenase. Episodic encephalopathy type thiamine metabolism dysfunction (OMIM 614458) due to TPK1 mutations is a recently described rare disorder. The mechanism of the disease, its phenotype and treatment are not entirely clear. We present two patients with novel homozygous TPK1 mutations (Patient 1 with p.Ser160Leu and Patient 2 with p.Asp222His). Unlike the previously described phenotype, Patient 2 presented with a Leigh syndrome like non-episodic early-onset global developmental delay, thus extending the phenotypic spectrum of the disorder. We, therefore, propose that TPK deficiency may be a better name for the condition. The two cases help to further refine the neuroradiological features of TPK deficiency and show that MRI changes can be either fleeting or progressive and can affect either white or gray matter. We also show that in some cases lactic acidosis can be absent and 2-ketoglutaric aciduria may be the only biochemical marker. Furthermore, we have established the assays for TPK enzyme activity measurement and thiamine pyrophosphate quantification in frozen muscle and blood. These tests will help to diagnose or confirm the diagnosis of TPK deficiency in a clinical setting. Early thiamine supplementation prevented encephalopathic episodes and improved developmental progression of Patient 1, emphasizing the importance of early diagnosis and treatment of TPK deficiency. We present evidence suggesting that thiamine supplementation may rescue TPK enzyme activity. Lastly, in silico protein structural analysis shows that the p.Ser160Leu mutation is predicted to interfere with TPK dimerization, which may be a novel mechanism for the disease.


Assuntos
Mutação , Doenças do Sistema Nervoso/genética , Tiamina Pirofosfoquinase/deficiência , Tiamina Pirofosfoquinase/genética , Acidose Láctica , Sequência de Aminoácidos , Criança , Pré-Escolar , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Modelos Moleculares , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças do Sistema Nervoso/metabolismo , Doenças do Sistema Nervoso/patologia , Fenótipo , Conformação Proteica , Multimerização Proteica , Tiamina Pirofosfoquinase/química , Tiamina Pirofosfoquinase/metabolismo , Tiamina/administração & dosagem , Tiamina/uso terapêutico , Tiamina Pirofosfato/metabolismo
13.
Am J Med Genet A ; 164A(7): 1713-33, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24782230

RESUMO

Somatic mutations in the phosphatidylinositol/AKT/mTOR pathway cause segmental overgrowth disorders. Diagnostic descriptors associated with PIK3CA mutations include fibroadipose overgrowth (FAO), Hemihyperplasia multiple Lipomatosis (HHML), Congenital Lipomatous Overgrowth, Vascular malformations, Epidermal nevi, Scoliosis/skeletal and spinal (CLOVES) syndrome, macrodactyly, and the megalencephaly syndrome, Megalencephaly-Capillary malformation (MCAP) syndrome. We set out to refine the understanding of the clinical spectrum and natural history of these phenotypes, and now describe 35 patients with segmental overgrowth and somatic PIK3CA mutations. The phenotypic data show that these previously described disease entities have considerable overlap, and represent a spectrum. While this spectrum overlaps with Proteus syndrome (sporadic, mosaic, and progressive) it can be distinguished by the absence of cerebriform connective tissue nevi and a distinct natural history. Vascular malformations were found in 15/35 (43%) and epidermal nevi in 4/35 (11%) patients, lower than in Proteus syndrome. Unlike Proteus syndrome, 31/35 (89%) patients with PIK3CA mutations had congenital overgrowth, and in 35/35 patients this was asymmetric and disproportionate. Overgrowth was mild with little postnatal progression in most, while in others it was severe and progressive requiring multiple surgeries. Novel findings include: adipose dysregulation present in all patients, unilateral overgrowth that is predominantly left-sided, overgrowth that affects the lower extremities more than the upper extremities and progresses in a distal to proximal pattern, and in the most severely affected patients is associated with marked paucity of adipose tissue in unaffected areas. While the current data are consistent with some genotype-phenotype correlation, this cannot yet be confirmed.


Assuntos
Estudos de Associação Genética , Fenótipo , Fosfatidilinositol 3-Quinases/genética , Tecido Adiposo/patologia , Adolescente , Adulto , Idade de Início , Criança , Pré-Escolar , Classe I de Fosfatidilinositol 3-Quinases , Feminino , Genótipo , Humanos , Hiperplasia/diagnóstico , Hiperplasia/genética , Lactente , Recém-Nascido , Lipoma/diagnóstico , Lipoma/genética , Masculino , Pessoa de Meia-Idade , Anormalidades Musculoesqueléticas/diagnóstico , Anormalidades Musculoesqueléticas/genética , Mutação , Nevo/diagnóstico , Nevo/genética , Especificidade de Órgãos/genética , Malformações Vasculares/diagnóstico , Malformações Vasculares/genética , Adulto Jovem
14.
Lancet Neurol ; 12(12): 1159-69, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24183309

RESUMO

BACKGROUND: Aicardi-Goutières syndrome (AGS) is an inflammatory disorder caused by mutations in any of six genes (TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR). The disease is severe and effective treatments are urgently needed. We investigated the status of interferon-related biomarkers in patients with AGS with a view to future use in diagnosis and clinical trials. METHODS: In this case-control study, samples were collected prospectively from patients with mutation-proven AGS. The expression of six interferon-stimulated genes (ISGs) was measured by quantitative PCR, and the median fold change, when compared with the median of healthy controls, was used to create an interferon score for each patient. Scores higher than the mean of controls plus two SD (>2·466) were designated as positive. Additionally, we collated historical data for interferon activity, measured with a viral cytopathic assay, in CSF and serum from mutation-positive patients with AGS. We also undertook neutralisation assays of interferon activity in serum, and looked for the presence of autoantibodies against a panel of interferon proteins. FINDINGS: 74 (90%) of 82 patients had a positive interferon score (median 12·90, IQR 6·14-20·41) compared with two (7%) of 29 controls (median 0·93, IQR 0·57-1·30). Of the eight patients with a negative interferon score, seven had mutations in RNASEH2B (seven [27%] of all 26 patients with mutations in this gene). Repeat sampling in 16 patients was consistent for the presence or absence of an interferon signature on 39 of 41 occasions. Interferon activity (tested in 147 patients) was negatively correlated with age (CSF, r=-0·604; serum, r=-0·289), and was higher in CSF than in serum in 104 of 136 paired samples. Neutralisation assays suggested that measurable antiviral activity was related to interferon α production. We did not record significantly increased concentrations of autoantibodies to interferon subtypes in patients with AGS, or an association between the presence of autoantibodies and interferon score or serum interferon activity. INTERPRETATION: AGS is consistently associated with an interferon signature, which is apparently sustained over time and can thus be used to differentiate patients with AGS from controls. If future studies show that interferon status is a reactive biomarker, the measurement of an interferon score might prove useful in the assessment of treatment efficacy in clinical trials. FUNDING: European Union's Seventh Framework Programme; European Research Council.


Assuntos
Adenosina Desaminase/genética , Doenças Autoimunes do Sistema Nervoso/metabolismo , Exodesoxirribonucleases/genética , Regulação da Expressão Gênica , Interferon Tipo I/fisiologia , Proteínas Monoméricas de Ligação ao GTP/genética , Malformações do Sistema Nervoso/metabolismo , Fosfoproteínas/genética , Ribonuclease H/genética , Adolescente , Adulto , Autoanticorpos/sangue , Doenças Autoimunes do Sistema Nervoso/genética , Biomarcadores , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Heterogeneidade Genética , Genótipo , Humanos , Lactente , Interferon Tipo I/sangue , Interferon Tipo I/líquido cefalorraquidiano , Interferon Tipo I/imunologia , Masculino , Mutação , Malformações do Sistema Nervoso/genética , Testes de Neutralização , Estudos Prospectivos , RNA Mensageiro/biossíntese , Proteínas de Ligação a RNA , Proteína 1 com Domínio SAM e Domínio HD , Regulação para Cima , Adulto Jovem
15.
Am J Hum Genet ; 89(5): 675-81, 2011 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-22077973

RESUMO

Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS or Ohdo syndrome) is a multiple anomaly syndrome characterized by severe intellectual disability, blepharophimosis, and a mask-like facial appearance. A number of individuals with SBBYSS also have thyroid abnormalities and cleft palate. The condition usually occurs sporadically and is therefore presumed to be due in most cases to new dominant mutations. In individuals with SBBYSS, a whole-exome sequencing approach was used to demonstrate de novo protein-truncating mutations in the highly conserved histone acetyltransferase gene KAT6B (MYST4/MORF)) in three out of four individuals sequenced. Sanger sequencing was used to confirm truncating mutations of KAT6B, clustering in the final exon of the gene in all four individuals and in a further nine persons with typical SBBYSS. Where parental samples were available, the mutations were shown to have occurred de novo. During mammalian development KAT6B is upregulated specifically in the developing central nervous system, facial structures, and limb buds. The phenotypic features seen in the Qkf mouse, a hypomorphic Kat6b mutant, include small eyes, ventrally placed ears and long first digits that mirror the human phenotype. This is a further example of how perturbation of a protein involved in chromatin modification might give rise to a multisystem developmental disorder.


Assuntos
Códon sem Sentido/genética , Hipotireoidismo Congênito/genética , Exoma/genética , Histona Acetiltransferases , Deficiência Intelectual/genética , Anormalidades Múltiplas/genética , Adulto , Animais , Blefarofimose/genética , Criança , Cromatina/metabolismo , Cromossomos Humanos Par 10/genética , Facies , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Cardiopatias Congênitas , Histona Acetiltransferases/deficiência , Histona Acetiltransferases/genética , Humanos , Mutação INDEL/genética , Instabilidade Articular , Masculino , Erros Inatos do Metabolismo/genética , Camundongos , Camundongos Transgênicos , Análise em Microsséries , Polimorfismo de Nucleotídeo Único/genética
16.
Am J Hum Genet ; 88(6): 767-777, 2011 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-21664999

RESUMO

Extreme corneal fragility and thinning, which have a high risk of catastrophic spontaneous rupture, are the cardinal features of brittle cornea syndrome (BCS), an autosomal-recessive generalized connective tissue disorder. Enucleation is frequently the only management option for this condition, resulting in blindness and psychosocial distress. Even when the cornea remains grossly intact, visual function could also be impaired by a high degree of myopia and keratoconus. Deafness is another common feature and results in combined sensory deprivation. Using autozygosity mapping, we identified mutations in PRDM5 in families with BCS. We demonstrate that regulation of expression of extracellular matrix components, particularly fibrillar collagens, by PRDM5 is a key molecular mechanism that underlies corneal fragility in BCS and controls normal corneal development and maintenance. ZNF469, encoding a zinc finger protein of hitherto undefined function, has been identified as a quantitative trait locus for central corneal thickness, and mutations in this gene have been demonstrated in Tunisian Jewish and Palestinian kindreds with BCS. We show that ZNF469 and PRDM5, two genes that when mutated cause BCS, participate in the same regulatory pathway.


Assuntos
Proteínas de Ligação a DNA/genética , Matriz Extracelular/genética , Fatores de Transcrição/genética , Criança , Análise Mutacional de DNA , Síndrome de Ehlers-Danlos/genética , Síndrome de Ehlers-Danlos/patologia , Matriz Extracelular/fisiologia , Anormalidades do Olho , Feminino , Humanos , Instabilidade Articular/congênito , Masculino , Mutação , Linhagem , Anormalidades da Pele
18.
Epilepsia ; 51(8): 1533-42, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20002144

RESUMO

PURPOSE: Valproic acid (VPA) is widely used clinically in epilepsy, bipolar disorder, and migraine. In experimental models, it has also been shown to have neuroprotective and antiepileptogenic effects. Its mechanisms of action in these diverse conditions are, however, unclear, but there is some evidence indicating an effect of VPA upon protein kinase A (PKA) activity. We, therefore, asked whether VPA modulates cyclic adenosine monophosphate (cAMP)/PKA-dependent synaptic plasticity and whether this mode of action could explain its anticonvulsant effect. METHODS: We first tested the effects of VPA on PKA-dependent synaptic plasticity at mossy fiber to CA3 synapses in rat hippocampus slices following very high-frequency stimulation or application of the adenylyl cyclase activator forskolin. Using biochemical assays, we then tested whether VPA had a direct effect on PKA activity or an indirect effect through modulating cAMP production. Lastly, VPA and inhibitors of adenylyl cyclase (SQ22536) and PKA (H89) were tested in in vitro models of epileptiform activity induced in hippocampal-entorhinal cortex slices using either pentylenetetrazol (2 mM) or low magnesium. RESULTS: VPA (1 mm) inhibited PKA-dependent long-term potentiation of mossy fiber to CA3 pyramidal cell transmission. However, VPA did not directly modulate PKA activity but rather inhibited the accumulation of cAMP. In acute in vitro seizure models, the anticonvulsant activity of VPA is not mediated through modulation of adenylyl cyclase or PKA. CONCLUSIONS: These results indicate that VPA through an action on cAMP accumulation can inhibit synaptic plasticity, but this cannot fully explain its anticonvulsant effect.


Assuntos
Anticonvulsivantes/farmacologia , Encéfalo , AMP Cíclico/metabolismo , Potenciação de Longa Duração/efeitos dos fármacos , Ácido Valproico/farmacologia , Análise de Variância , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/fisiologia , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Epilepsia/tratamento farmacológico , Epilepsia/metabolismo , Epilepsia/patologia , Isoquinolinas/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley , Sulfonamidas/farmacologia
19.
Vet J ; 176(3): 310-9, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17468024

RESUMO

Twenty-two dogs with idiopathic epilepsy which were pharmacoresistant to phenobarbitone and bromide were treated with levetiracetam as an add-on medication. Records of eight dogs were used retrospectively to determine a safe, efficient levetiracetam dosage. Fourteen dogs were entered into a prospective, open label, non-comparative study. After 2 months of levetiracetam oral treatment (10 mg/kg TID), 8/14 dogs responded significantly to the treatment and seizure frequency was reduced by 50%. In dogs that remained refractory, the dosage was increased to 20 mg/kg TID for 2 months. One further dog responded to levetiracetam treatment. Levetiracetam responders had a significant decrease in seizure frequency of 77% (7.9+/-5.2 to 1.8+/-1.7 seizures/month) and a decrease in seizure days per month of 68% (3.8+/-1.7 to 1.2+/-1.1 seizure days/month). However, 6/9 responders experienced an increase in seizure frequency and seizure days after 4-8 months continuing with the levetiracetam treatment at the last effective dosage. Levetiracetam was well tolerated by all dogs and sedation was the only side-effect reported in just one of the 14 dogs.


Assuntos
Anticonvulsivantes/uso terapêutico , Doenças do Cão/tratamento farmacológico , Epilepsia/veterinária , Piracetam/análogos & derivados , Animais , Anticonvulsivantes/efeitos adversos , Brometos/uso terapêutico , Cães , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Epilepsia/tratamento farmacológico , Feminino , Levetiracetam , Masculino , Fenobarbital/uso terapêutico , Piracetam/efeitos adversos , Piracetam/uso terapêutico , Estudos Retrospectivos , Resultado do Tratamento
20.
Am J Hum Genet ; 81(4): 713-25, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17846997

RESUMO

Aicardi-Goutieres syndrome (AGS) is a genetic encephalopathy whose clinical features mimic those of acquired in utero viral infection. AGS exhibits locus heterogeneity, with mutations identified in genes encoding the 3'-->5' exonuclease TREX1 and the three subunits of the RNASEH2 endonuclease complex. To define the molecular spectrum of AGS, we performed mutation screening in patients, from 127 pedigrees, with a clinical diagnosis of the disease. Biallelic mutations in TREX1, RNASEH2A, RNASEH2B, and RNASEH2C were observed in 31, 3, 47, and 18 families, respectively. In five families, we identified an RNASEH2A or RNASEH2B mutation on one allele only. In one child, the disease occurred because of a de novo heterozygous TREX1 mutation. In 22 families, no mutations were found. Null mutations were common in TREX1, although a specific missense mutation was observed frequently in patients from northern Europe. Almost all mutations in RNASEH2A, RNASEH2B, and RNASEH2C were missense. We identified an RNASEH2C founder mutation in 13 Pakistani families. We also collected clinical data from 123 mutation-positive patients. Two clinical presentations could be delineated: an early-onset neonatal form, highly reminiscent of congenital infection seen particularly with TREX1 mutations, and a later-onset presentation, sometimes occurring after several months of normal development and occasionally associated with remarkably preserved neurological function, most frequently due to RNASEH2B mutations. Mortality was correlated with genotype; 34.3% of patients with TREX1, RNASEH2A, and RNASEH2C mutations versus 8.0% RNASEH2B mutation-positive patients were known to have died (P=.001). Our analysis defines the phenotypic spectrum of AGS and suggests a coherent mutation-screening strategy in this heterogeneous disorder. Additionally, our data indicate that at least one further AGS-causing gene remains to be identified.


Assuntos
Doenças dos Gânglios da Base/genética , Adolescente , Adulto , Doenças dos Gânglios da Base/líquido cefalorraquidiano , Doenças dos Gânglios da Base/patologia , Encéfalo/patologia , Calcinose/genética , Calcinose/patologia , Pérnio/genética , Pérnio/patologia , Criança , Pré-Escolar , Análise Mutacional de DNA , Exodesoxirribonucleases/genética , Feminino , Humanos , Lactente , Recém-Nascido , Linfocitose/líquido cefalorraquidiano , Linfocitose/genética , Masculino , Dados de Sequência Molecular , Mutação , Fenótipo , Fosfoproteínas/genética , Ribonuclease H/genética , Síndrome
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