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2.
Eur J Hum Genet ; 27(5): 738-746, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30679813

RESUMO

Determining pathogenicity of genomic variation identified by next-generation sequencing techniques can be supported by recurrent disruptive variants in the same gene in phenotypically similar individuals. However, interpretation of novel variants in a specific gene in individuals with mild-moderate intellectual disability (ID) without recognizable syndromic features can be challenging and reverse phenotyping is often required. We describe 24 individuals with a de novo disease-causing variant in, or partial deletion of, the F-box only protein 11 gene (FBXO11, also known as VIT1 and PRMT9). FBXO11 is part of the SCF (SKP1-cullin-F-box) complex, a multi-protein E3 ubiquitin-ligase complex catalyzing the ubiquitination of proteins destined for proteasomal degradation. Twenty-two variants were identified by next-generation sequencing, comprising 2 in-frame deletions, 11 missense variants, 1 canonical splice site variant, and 8 nonsense or frameshift variants leading to a truncated protein or degraded transcript. The remaining two variants were identified by array-comparative genomic hybridization and consisted of a partial deletion of FBXO11. All individuals had borderline to severe ID and behavioral problems (autism spectrum disorder, attention-deficit/hyperactivity disorder, anxiety, aggression) were observed in most of them. The most relevant common facial features included a thin upper lip and a broad prominent space between the paramedian peaks of the upper lip. Other features were hypotonia and hyperlaxity of the joints. We show that de novo variants in FBXO11 cause a syndromic form of ID. The current series show the power of reverse phenotyping in the interpretation of novel genetic variances in individuals who initially did not appear to have a clear recognizable phenotype.

3.
Biol Psychiatry ; 2018 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-29724491

RESUMO

BACKGROUND: In genome-wide screening studies for de novo mutations underlying autism and intellectual disability, mutations in the ADNP gene are consistently reported among the most frequent. ADNP mutations have been identified in children with autism spectrum disorder comorbid with intellectual disability, distinctive facial features, and deficits in multiple organ systems. However, a comprehensive clinical description of the Helsmoortel-Van der Aa syndrome is lacking. METHODS: We identified a worldwide cohort of 78 individuals with likely disruptive mutations in ADNP from January 2014 to October 2016 through systematic literature search, by contacting collaborators, and through direct interaction with parents. Clinicians filled in a structured questionnaire on genetic and clinical findings to enable correlations between genotype and phenotype. Clinical photographs and specialist reports were gathered. Parents were interviewed to complement the written questionnaires. RESULTS: We report on the detailed clinical characterization of a large cohort of individuals with an ADNP mutation and demonstrate a distinctive combination of clinical features, including mild to severe intellectual disability, autism, severe speech and motor delay, and common facial characteristics. Brain abnormalities, behavioral problems, sleep disturbance, epilepsy, hypotonia, visual problems, congenital heart defects, gastrointestinal problems, short stature, and hormonal deficiencies are common comorbidities. Strikingly, individuals with the recurrent p.Tyr719* mutation were more severely affected. CONCLUSIONS: This overview defines the full clinical spectrum of individuals with ADNP mutations, a specific autism subtype. We show that individuals with mutations in ADNP have many overlapping clinical features that are distinctive from those of other autism and/or intellectual disability syndromes. In addition, our data show preliminary evidence of a correlation between genotype and phenotype.

5.
J Exp Med ; 213(7): 1163-74, 2016 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-27325888

RESUMO

Pseudo-TORCH syndrome (PTS) is characterized by microcephaly, enlarged ventricles, cerebral calcification, and, occasionally, by systemic features at birth resembling the sequelae of congenital infection but in the absence of an infectious agent. Genetic defects resulting in activation of type 1 interferon (IFN) responses have been documented to cause Aicardi-Goutières syndrome, which is a cause of PTS. Ubiquitin-specific peptidase 18 (USP18) is a key negative regulator of type I IFN signaling. In this study, we identified loss-of-function recessive mutations of USP18 in five PTS patients from two unrelated families. Ex vivo brain autopsy material demonstrated innate immune inflammation with calcification and polymicrogyria. In vitro, patient fibroblasts displayed severely enhanced IFN-induced inflammation, which was completely rescued by lentiviral transduction of USP18. These findings add USP18 deficiency to the list of genetic disorders collectively termed type I interferonopathies. Moreover, USP18 deficiency represents the first genetic disorder of PTS caused by dysregulation of the response to type I IFNs. Therapeutically, this places USP18 as a promising target not only for genetic but also acquired IFN-mediated CNS disorders.


Assuntos
Doenças Autoimunes do Sistema Nervoso , Encéfalo/imunologia , Calcinose , Endopeptidases/deficiência , Imunidade Inata , Interferon Tipo I/imunologia , Microglia/imunologia , Malformações do Sistema Nervoso , Transdução de Sinais , Doenças Autoimunes do Sistema Nervoso/genética , Doenças Autoimunes do Sistema Nervoso/imunologia , Doenças Autoimunes do Sistema Nervoso/patologia , Encéfalo/patologia , Calcinose/genética , Calcinose/imunologia , Calcinose/patologia , Endopeptidases/imunologia , Feminino , Humanos , Interferon Tipo I/genética , Masculino , Microglia/patologia , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/imunologia , Malformações do Sistema Nervoso/patologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia
6.
Genet Med ; 17(11): 843-53, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25719457

RESUMO

Two proα1(IV) chains, encoded by COL4A1, form trimers that contain, in addition, a proα2(IV) chain encoded by COL4A2 and are the major component of the basement membrane in many tissues. Since 2005, COL4A1 mutations have been known as an autosomal dominant cause of hereditary porencephaly. COL4A1 and COL4A2 mutations have been reported with a broader spectrum of cerebrovascular, renal, ophthalmological, cardiac, and muscular abnormalities, indicated as "COL4A1 mutation-related disorders." Genetic counseling is challenging because of broad phenotypic variation and reduced penetrance. At the Erasmus University Medical Center, diagnostic DNA analysis of both COL4A1 and COL4A2 in 183 index patients was performed between 2005 and 2013. In total, 21 COL4A1 and 3 COL4A2 mutations were identified, mostly in children with porencephaly or other patterns of parenchymal hemorrhage, with a high de novo mutation rate of 40% (10/24). The observations in 13 novel families harboring either COL4A1 or COL4A2 mutations prompted us to review the clinical spectrum. We observed recognizable phenotypic patterns and propose a screening protocol at diagnosis. Our data underscore the importance of COL4A1 and COL4A2 mutations in cerebrovascular disease, also in sporadic patients. Follow-up data on symptomatic and asymptomatic mutation carriers are needed for prognosis and appropriate surveillance.


Assuntos
Colágeno Tipo IV/genética , Estudos de Associação Genética , Mutação , Fenótipo , Alelos , Segmento Anterior do Olho/anormalidades , Encéfalo/patologia , Hemorragia Cerebral/diagnóstico , Hemorragia Cerebral/genética , Estudos de Coortes , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/genética , Oftalmopatias Hereditárias , Família , Ordem dos Genes , Loci Gênicos , Genótipo , Humanos , Leucomalácia Periventricular/diagnóstico , Leucomalácia Periventricular/genética , Imagem por Ressonância Magnética/métodos , Linhagem , Porencefalia/diagnóstico , Porencefalia/genética
7.
Am J Med Genet A ; 161A(6): 1376-80, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23613326

RESUMO

Thoracic aortic aneurysm and dissection (TAAD) are associated with connective tissue disorders like Marfan syndrome and Loeys-Dietz syndrome, caused by mutations in the fibrillin-1, the TGFß-receptor 1- and -2 genes, the SMAD3 and TGFß2 genes, but have also been ascribed to ACTA2 gene mutations in adults, spread throughout the gene. We report on a novel de novo c.535C>T in exon 6 leading to p.R179C aminoacid substitution in ACTA2 in a toddler girl with primary pulmonary hypertension, persistent ductus arteriosus, extensive cerebral white matter lesions, fixed dilated pupils, intestinal malrotation, and hypotonic bladder. Recently, de novo ACTA2 R179H substitutions have been associated with a similar phenotype and additional cerebral developmental defects including underdeveloped corpus callosum and vermis hypoplasia in a single patient. The patient here shows previously undescribed abnormal lobulation of the frontal lobes and position of the gyrus cinguli and rostral dysplasis of the corpus callosum; she died at the age of 3 years during surgery due to vascular fragility and rupture of the ductus arteriosus. Altogether these observations support a role of ACTA2 in brain development, especially related to the arginine at position 179. Although all previously reported patients with R179H substitution successfully underwent the same surgery at younger ages, the severe outcome of our patient warns against the devastating effects of the R179C substitution on vasculature.


Assuntos
Actinas/genética , Aneurisma da Aorta Torácica/genética , Permeabilidade do Canal Arterial/genética , Substituição de Aminoácidos , Aneurisma da Aorta Torácica/diagnóstico por imagem , Aneurisma da Aorta Torácica/cirurgia , Transtornos Cerebrovasculares/diagnóstico por imagem , Transtornos Cerebrovasculares/genética , Pré-Escolar , Corpo Caloso/diagnóstico por imagem , Corpo Caloso/cirurgia , Anormalidades do Sistema Digestório/genética , Permeabilidade do Canal Arterial/diagnóstico por imagem , Permeabilidade do Canal Arterial/cirurgia , Feminino , Estudos de Associação Genética , Genótipo , Heterozigoto , Humanos , Hipertensão Pulmonar , Volvo Intestinal/genética , Mutação de Sentido Incorreto , Midríase/genética , Fenótipo , Radiografia , Vasos Retinianos/patologia
8.
Eur J Med Genet ; 55(5): 323-31, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22564885

RESUMO

Incontinentia Pigmenti is a rare X-linked multisystem disorder with well described and pathognomonic skin manifestations. Neurological manifestations are found in 30% of IP patients, forming one of the major causes of morbidity and mortality of the condition. In this review, clinical and brain imaging data of 45 IP patients with a neurological phenotype are reviewed. Several clinical presentations could be identified, comprising seizures, infantile encephalopathy, acute disseminated encephalomyelitis and ischemic stroke. Most neurological features presented during the neonatal period. No patients presented during adolescence or at adult age. Seizures of different type are reported in about 20% of the patients at young age and seem to correlate with the degree of cerebrovascular damage. Brain MRI findings include periventricular and subcortical white matter disease, haemorrhagic changes, corpus callosum hypoplasia, cerebral atrophy and cerebellar hypoplasia. Ocular findings comprise a range of retinal vascular changes and optic atrophy, but also developmental defects like microphthalmia and cataract. Most findings may reflect changes following brain injury. Both (ischemic) vascular and inflammatory components may play a role in the cerebral and ocular phenotype. However, a role of disturbed apoptosis during development may also be a contributing factor.


Assuntos
Incontinência Pigmentar/patologia , Encéfalo/anormalidades , Encéfalo/patologia , Anormalidades do Olho/epidemiologia , Humanos , Incidência , Incontinência Pigmentar/epidemiologia , Incontinência Pigmentar/genética , Deficiência Intelectual/epidemiologia , Microcefalia/epidemiologia , Paralisia/epidemiologia , Fenótipo , Transtornos Psicomotores/epidemiologia , Convulsões/epidemiologia
9.
Eur J Hum Genet ; 20(8): 844-51, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22333902

RESUMO

Familial porencephaly, leukoencephalopathy and small-vessel disease belong to the spectrum of disorders ascribed to dominant mutations in the gene encoding for type IV collagen alpha-1 (COL4A1). Mice harbouring mutations in either Col4a1 or Col4a2 suffer from porencephaly, hydrocephalus, cerebral and ocular bleeding and developmental defects. We observed porencephaly and white matter lesions in members from two families that lack COL4A1 mutations. We hypothesized that COL4A2 mutations confer genetic predisposition to porencephaly, therefore we sequenced COL4A2 in the family members and characterized clinical, neuroradiological and biochemical phenotypes. Genomic sequencing of COL4A2 identified the heterozygous missense G1389R in exon 44 in one family and the c.3206delC change in exon 34 leading to frame shift and premature stop, in the second family. Fragmentation and duplication of epidermal basement membranes were observed by electron microscopy in a c.3206delC patient skin biopsy, consistent with abnormal collagen IV network. Collagen chain accumulation and endoplasmic reticulum (ER) stress have been proposed as cellular mechanism in COL4A1 mutations. In COL4A2 (3206delC) fibroblasts we detected increased rates of apoptosis and no signs of ER stress. Mutation phenotypes varied, including porencephaly, white matter lesions, cerebellar and optic nerve hypoplasia and unruptured carotid aneurysm. In the second family however, we found evidence for additional factors contributing to the phenotype. We conclude that dominant COL4A2 mutations are a novel major risk factor for familial cerebrovascular disease, including porencephaly and small-vessel disease with reduced penetrance and variable phenotype, which might also be modified by other contributing factors.


Assuntos
Encefalopatias/genética , Colágeno Tipo IV/genética , Predisposição Genética para Doença , Hemiplegia/genética , Aneurisma Intracraniano/genética , Mutação , Adolescente , Adulto , Animais , Apoptose/genética , Sequência de Bases , Membrana Basal/patologia , Membrana Basal/ultraestrutura , Encéfalo/patologia , Encefalopatias/diagnóstico , Criança , Pré-Escolar , Colágeno Tipo IV/deficiência , Consanguinidade , Estresse do Retículo Endoplasmático , Éxons , Feminino , Hemiplegia/diagnóstico , Heterozigoto , Humanos , Lactente , Aneurisma Intracraniano/diagnóstico , Imagem por Ressonância Magnética , Masculino , Camundongos , Camundongos Knockout , Linhagem , Porencefalia , Pele/patologia , Pele/ultraestrutura , Adulto Jovem
10.
Brain ; 133(Pt 3): 655-70, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20129935

RESUMO

Glucose transporter-1 deficiency syndrome is caused by mutations in the SLC2A1 gene in the majority of patients and results in impaired glucose transport into the brain. From 2004-2008, 132 requests for mutational analysis of the SLC2A1 gene were studied by automated Sanger sequencing and multiplex ligation-dependent probe amplification. Mutations in the SLC2A1 gene were detected in 54 patients (41%) and subsequently in three clinically affected family members. In these 57 patients we identified 49 different mutations, including six multiple exon deletions, six known mutations and 37 novel mutations (13 missense, five nonsense, 13 frame shift, four splice site and two translation initiation mutations). Clinical data were retrospectively collected from referring physicians by means of a questionnaire. Three different phenotypes were recognized: (i) the classical phenotype (84%), subdivided into early-onset (<2 years) (65%) and late-onset (18%); (ii) a non-classical phenotype, with mental retardation and movement disorder, without epilepsy (15%); and (iii) one adult case of glucose transporter-1 deficiency syndrome with minimal symptoms. Recognizing glucose transporter-1 deficiency syndrome is important, since a ketogenic diet was effective in most of the patients with epilepsy (86%) and also reduced movement disorders in 48% of the patients with a classical phenotype and 71% of the patients with a non-classical phenotype. The average delay in diagnosing classical glucose transporter-1 deficiency syndrome was 6.6 years (range 1 month-16 years). Cerebrospinal fluid glucose was below 2.5 mmol/l (range 0.9-2.4 mmol/l) in all patients and cerebrospinal fluid : blood glucose ratio was below 0.50 in all but one patient (range 0.19-0.52). Cerebrospinal fluid lactate was low to normal in all patients. Our relatively large series of 57 patients with glucose transporter-1 deficiency syndrome allowed us to identify correlations between genotype, phenotype and biochemical data. Type of mutation was related to the severity of mental retardation and the presence of complex movement disorders. Cerebrospinal fluid : blood glucose ratio was related to type of mutation and phenotype. In conclusion, a substantial number of the patients with glucose transporter-1 deficiency syndrome do not have epilepsy. Our study demonstrates that a lumbar puncture provides the diagnostic clue to glucose transporter-1 deficiency syndrome and can thereby dramatically reduce diagnostic delay to allow early start of the ketogenic diet.


Assuntos
Erros Inatos do Metabolismo dos Carboidratos , Transportador de Glucose Tipo 1/deficiência , Transportador de Glucose Tipo 1/genética , Adolescente , Adulto , Idade de Início , Erros Inatos do Metabolismo dos Carboidratos/diagnóstico , Erros Inatos do Metabolismo dos Carboidratos/genética , Erros Inatos do Metabolismo dos Carboidratos/terapia , Criança , Pré-Escolar , Dieta Cetogênica , Discinesias/diagnóstico , Discinesias/genética , Discinesias/terapia , Epilepsia/diagnóstico , Epilepsia/genética , Epilepsia/terapia , Feminino , Humanos , Lactente , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Deficiência Intelectual/terapia , Masculino , Mutação , Fenótipo , Estudos Retrospectivos , Síndrome , Adulto Jovem
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