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1.
Nucleic Acids Res ; 47(16): 8720-8733, 2019 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-31276587

RESUMO

Expression of human mitochondrial DNA is indispensable for proper function of the oxidative phosphorylation machinery. The mitochondrial genome encodes 22 tRNAs, 2 rRNAs and 11 mRNAs and their post-transcriptional modification constitutes one of the key regulatory steps during mitochondrial gene expression. Cytosine-5 methylation (m5C) has been detected in mitochondrial transcriptome, however its biogenesis has not been investigated in details. Mammalian NOP2/Sun RNA Methyltransferase Family Member 2 (NSUN2) has been characterized as an RNA methyltransferase introducing m5C in nuclear-encoded tRNAs, mRNAs and microRNAs and associated with cell proliferation and differentiation, with pathogenic variants in NSUN2 being linked to neurodevelopmental disorders. Here we employ spatially restricted proximity labelling and immunodetection to demonstrate that NSUN2 is imported into the matrix of mammalian mitochondria. Using three genetic models for NSUN2 inactivation-knockout mice, patient-derived fibroblasts and CRISPR/Cas9 knockout in human cells-we show that NSUN2 is necessary for the generation of m5C at positions 48, 49 and 50 of several mammalian mitochondrial tRNAs. Finally, we show that inactivation of NSUN2 does not have a profound effect on mitochondrial tRNA stability and oxidative phosphorylation in differentiated cells. We discuss the importance of the newly discovered function of NSUN2 in the context of human disease.


Assuntos
5-Metilcitosina/metabolismo , Eczema/genética , Transtornos do Crescimento/genética , Deficiência Intelectual/genética , Metiltransferases/genética , Microcefalia/genética , Processamento Pós-Transcricional do RNA , RNA Mitocondrial/genética , RNA de Transferência/genética , Animais , Sistemas CRISPR-Cas , Eczema/metabolismo , Eczema/patologia , Facies , Fibroblastos/metabolismo , Fibroblastos/patologia , Edição de Genes , Técnicas de Inativação de Genes , Transtornos do Crescimento/metabolismo , Transtornos do Crescimento/patologia , Células HEK293 , Humanos , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Metilação , Metiltransferases/deficiência , Camundongos , Camundongos Knockout , Microcefalia/metabolismo , Microcefalia/patologia , Mitocôndrias/genética , Mitocôndrias/metabolismo , Conformação de Ácido Nucleico , Fosforilação Oxidativa , Cultura Primária de Células , Transporte Proteico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Mitocondrial/metabolismo , RNA de Transferência/metabolismo
2.
Pharm Res ; 36(9): 137, 2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31332533

RESUMO

PURPOSE: Pitt Hopkins Syndrome (PTHS) is a rare genetic disorder caused by mutations of a specific gene, transcription factor 4 (TCF4), located on chromosome 18. PTHS results in individuals that have moderate to severe intellectual disability, with most exhibiting psychomotor delay. PTHS also exhibits features of autistic spectrum disorders, which are characterized by the impaired ability to communicate and socialize. PTHS is comorbid with a higher prevalence of epileptic seizures which can be present from birth or which commonly develop in childhood. Attenuated or absent TCF4 expression results in increased translation of peripheral ion channels Kv7.1 and Nav1.8 which triggers an increase in after-hyperpolarization and altered firing properties. METHODS: We now describe a high throughput screen (HTS) of 1280 approved drugs and machine learning models developed from this data. The ion channels were expressed in either CHO (KV7.1) or HEK293 (Nav1.8) cells and the HTS used either 86Rb+ efflux (KV7.1) or a FLIPR assay (Nav1.8). RESULTS: The HTS delivered 55 inhibitors of Kv7.1 (4.2% hit rate) and 93 inhibitors of Nav1.8 (7.2% hit rate) at a screening concentration of 10 µM. These datasets also enabled us to generate and validate Bayesian machine learning models for these ion channels. We also describe a structure activity relationship for several dihydropyridine compounds as inhibitors of Nav1.8. CONCLUSIONS: This work could lead to the potential repurposing of nicardipine or other dihydropyridine calcium channel antagonists as potential treatments for PTHS acting via Nav1.8, as there are currently no approved treatments for this rare disorder.


Assuntos
Di-Hidropiridinas/farmacologia , Reposicionamento de Medicamentos/métodos , Hiperventilação/tratamento farmacológico , Deficiência Intelectual/tratamento farmacológico , Canal de Potássio KCNQ1/antagonistas & inibidores , Canal de Sódio Disparado por Voltagem NAV1.8/metabolismo , Bloqueadores dos Canais de Potássio/farmacologia , Bloqueadores dos Canais de Sódio/farmacologia , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia , Animais , Teorema de Bayes , Células CHO , Cricetulus , Di-Hidropiridinas/química , Facies , Células HEK293 , Humanos , Canal de Potássio KCNQ1/metabolismo , Aprendizado de Máquina , Bloqueadores dos Canais de Potássio/química , Bibliotecas de Moléculas Pequenas/química , Bloqueadores dos Canais de Sódio/química , Relação Estrutura-Atividade , Bloqueadores do Canal de Sódio Disparado por Voltagem/química
3.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(7): 727-730, 2019 Jul 10.
Artigo em Chinês | MEDLINE | ID: mdl-31302922

RESUMO

OBJECTIVE: To analyze the clinical and molecular genetics features of a family affected with Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS). METHODS: High-throughput sequencing was used to detect copy number variations (CNVs) and pathogenic variant within the whole exome of the affected child. RESULTS: No pathogenic CNV was found in the child, while exome sequencing identified a heterozygous c.3367_c.3370delAGAA (p.Arg1123Argfs*6) frameshifting variant in the exon 16 of the KAT6B gene. The same variant was not found in either parent. CONCLUSION: The c.3367_c.3370delAGAA (p.R1123Rfs*6) probably underlies the disease in the affected child. Above finding has facilitated genetic counseling and prenatal diagnosis for the family.


Assuntos
Blefarofimose/genética , Hipotireoidismo Congênito/genética , Variações do Número de Cópias de DNA , Cardiopatias Congênitas/genética , Histona Acetiltransferases/genética , Deficiência Intelectual/genética , Instabilidade Articular/genética , Criança , Facies , Feminino , Humanos , Mutação , Fenótipo , Gravidez
4.
Ann Otol Rhinol Laryngol ; 128(8): 721-727, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31307215

RESUMO

OBJECTIVES: To investigate the effectiveness of make-up therapy for patients with facial nerve palsy. METHODS: Seven female patients with facial nerve palsy who received specialist make-up therapy were enrolled. The objective of the make-up therapy was to obtain a symmetrical facial appearance. RESULTS: Overall score for the Facial Clinimetric Evaluation (FaCE) scale was significantly improved after make-up therapy. There was a tendency for symptoms of depression to be improved among patients after make-up therapy. CONCLUSION: Make-up therapy to improve the symmetry of facial appearance could afford a noninvasive and low-cost treatment for patients with facial nerve palsy, especially in terms of patient quality of life and psychological condition.


Assuntos
Técnicas Cosméticas , Cosméticos , Assimetria Facial/terapia , Doenças do Nervo Facial/complicações , Paralisia Facial/terapia , Adulto , Estudos de Coortes , Assimetria Facial/etiologia , Paralisia Facial/etiologia , Facies , Feminino , Humanos , Pessoa de Meia-Idade , Qualidade de Vida
5.
Zhongguo Dang Dai Er Ke Za Zhi ; 21(5): 468-473, 2019 May.
Artigo em Chinês | MEDLINE | ID: mdl-31104665

RESUMO

Mowat-Wilson syndrome (MWS) is a rare autosomal dominant genetic disease caused by zinc finger E-box-binding homeobox 2 (ZEB2) gene mutation and has various clinical manifestations including intellectual disability/global developmental delay, unusual facies and multiple congenital malformations. This article reports the clinical features and gene mutations of three children diagnosed with MWS by ZEB2 gene analysis. All three children had Hirschsprung disease and unusual facies. One child died of severe heart failure and pneumonia at the age of 4 months. Global developmental delay was not discovered by her parents due to her young age. The other two children had severe global developmental delay. All three children carried a de novo heterozygous nonsense mutation in the ZEB2 gene, among which c.756C>A (p.Y252X) had not been reported before. Such mutations produced truncated proteins and were highly pathogenic. MWS is presented with strong clinical and genetic heterogeneity. Clinicians should consider the possibility of MWS when a child has unusual facies of MWS, intellectual disability/global developmental delay and multiple congenital malformations. Gene detection helps to make a confirmed diagnosis.


Assuntos
Facies , Doença de Hirschsprung , Deficiência Intelectual , Microcefalia , Feminino , Proteínas de Homeodomínio , Humanos , Proteínas Repressoras
6.
J Autism Dev Disord ; 49(7): 3031-3035, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30968316

RESUMO

Myhre syndrome (MS) is a connective tissue disorder with multisystem involvement with or without intellectual disability. In most cases SMAD4 mutations are reported. To date, 55 individuals have been molecularly confirmed. Autism has been proposed among associate clinical features of MS but no standardized diagnosis was available in previous cases. We report a case of a 25-year-old man with a pathogenic heterozygous SMAD4 missense mutation affecting residue Arg496 (SMAD4:p.Arg496Cys). Clinical findings are consistent with MS, commorbid with affective disorder and High Functioning Autism Spectrum Disorder confirmed by a standardized assessment procedure. The thorough clinical assessment of cases with syndromes such as MS can extend our knowledge on both the phenotypic characteristics of the syndrome and the genetic basis of autism.


Assuntos
Transtorno do Espectro Autista , Criptorquidismo , Facies , Transtornos do Crescimento , Deformidades Congênitas da Mão , Deficiência Intelectual , Adulto , Comorbidade , Feminino , Humanos , Deficiência Intelectual/diagnóstico , Masculino , Mutação , Proteína Smad4
7.
J Hum Genet ; 64(5): 499-504, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30842599

RESUMO

The genotype-phenotype correlation in BRAF variant in cardio-facio-cutaneous (CFC) syndrome is not clearly defined. Here we report a case with a severe clinical phenotype and a novel BRAF variant, p.Leu485del. The present case showed severe intellectual disability, impaired awareness, hyperekplexia, involuntary movements, early onset refractory seizures, and delayed myelination on brain magnetic resonance imaging as well as a polycystic and dysplastic kidney, which are previously unreported anomalies in CFC or RAS/mitogen-activated protein kinase syndromes related to BRAF variant. CFC syndrome, especially caused by BRAF variant, should be included in the differential diagnosis of patients with developmental and epileptic encephalopathies and hyperekplexia. Furthermore, we need to keep in mind that missense variants or the deletion of Leucine-485 may be associated with severe symptoms.


Assuntos
Sequência de Aminoácidos , Displasia Ectodérmica/genética , Insuficiência de Crescimento/genética , Cardiopatias Congênitas/genética , Proteínas Proto-Oncogênicas B-raf/genética , Deleção de Sequência , Pré-Escolar , Displasia Ectodérmica/patologia , Facies , Insuficiência de Crescimento/patologia , Cardiopatias Congênitas/patologia , Humanos , Leucina , Masculino , Índice de Gravidade de Doença
8.
J Hum Genet ; 64(5): 445-458, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30846821

RESUMO

Seckel syndrome (SS) is a rare spectrum of congenital severe microcephaly and dwarfism. One SS-causative gene is Ataxia Telangiectasia and Rad3-Related Protein (ATR), and ATR (c.2101 A>G) mutation causes skipping of exon 9, resulting in a hypomorphic ATR defect. This mutation is considered the cause of an impaired response to DNA replication stress, the main function of ATR, contributing to the pathogenesis of microcephaly. However, the precise behavior and impact of this splicing defect in human neural progenitor cells (NPCs) is unclear. To address this, we established induced pluripotent stem cells (iPSCs) from fibroblasts carrying the ATR mutation and an isogenic ATR-corrected counterpart iPSC clone. SS-patient-derived iPSCs (SS-iPSCs) exhibited cell type-specific splicing; exon 9 was dominantly skipped in fibroblasts and iPSC-derived NPCs, but it was included in undifferentiated iPSCs and definitive endodermal cells. SS-iPSC-derived NPCs (SS-NPCs) showed distinct expression profiles from ATR non-mutated NPCs with negative enrichment of neuronal genesis-related gene sets. In SS-NPCs, abnormal mitotic spindles occurred more frequently than in gene-corrected counterparts, and the alignment of NPCs in the surface of the neurospheres was perturbed. Finally, we tested several splicing-modifying compounds and found that TG003, a CLK1 inhibitor, could pharmacologically rescue the exon 9 skipping in SS-NPCs. Treatment with TG003 restored the ATR kinase activity in SS-NPCs and decreased the frequency of abnormal mitotic events. In conclusion, our iPSC model revealed a novel effect of the ATR mutation in mitotic processes of NPCs and NPC-specific missplicing, accompanied by the recovery of neuronal defects using a splicing rectifier.


Assuntos
Processamento Alternativo , Proteínas Mutadas de Ataxia Telangiectasia , Nanismo , Facies , Células-Tronco Pluripotentes Induzidas , Microcefalia , Modelos Biológicos , Mutação , Proteínas Mutadas de Ataxia Telangiectasia/biossíntese , Proteínas Mutadas de Ataxia Telangiectasia/genética , Linhagem Celular , Nanismo/enzimologia , Nanismo/genética , Nanismo/patologia , Feminino , Humanos , Células-Tronco Pluripotentes Induzidas/enzimologia , Células-Tronco Pluripotentes Induzidas/patologia , Masculino , Microcefalia/enzimologia , Microcefalia/genética , Microcefalia/patologia
9.
Gene ; 699: 110-114, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-30844479

RESUMO

Tricho-hepatic-enteric syndrome (THES) is a genetically heterogeneous rare syndrome (OMIM: 222470 (THES1) and 614602 (THES2)) that typically presents in the neonatal period with intractable diarrhoea, intra-uterine growth retardation (IUGR), facial dysmorphism, and hair and skin changes. THES is associated with pathogenic variants in either TTC37 or SKIV2L; both are components of the human SKI complex, an RNA exosome cofactor. We report an 8 year old girl who was diagnosed with THES by the Undiagnosed Disease Program-WA with compound heterozygous pathogenic variants in SKIV2L. While THES was considered in the differential diagnosis, the absence of protracted diarrhoea delayed definitive diagnosis. We therefore suggest that SKIV2L testing should be considered in cases otherwise suggestive of THES, but without the characteristic diarrhoea. We expand the phenotypic spectrum while reviewing the current knowledge on SKIV2L.


Assuntos
Diarreia Infantil/diagnóstico , Diarreia Infantil/genética , Diarreia/diagnóstico , Diarreia/genética , Retardo do Crescimento Fetal/diagnóstico , Retardo do Crescimento Fetal/genética , Doenças do Cabelo/diagnóstico , Doenças do Cabelo/genética , DNA Helicases/genética , Facies , Heterozigoto , Humanos
10.
Hum Genet ; 138(3): 257-269, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30806792

RESUMO

Rubinstein-Taybi syndrome (RSTS) is an autosomal-dominant neurodevelopmental disease affecting 1:125,000 newborns characterized by intellectual disability, growth retardation, facial dysmorphisms and skeletal abnormalities. RSTS is caused by mutations in genes encoding for writers of the epigenetic machinery: CREBBP (~ 60%) or its homologous EP300 (~ 10%). No causative mutation is identified in up to 30% of patients. We performed whole-exome sequencing (WES) on eight RSTS-like individuals who had normal high-resolution array CGH testing and were CREBBP- and EP300-mutation -negative, to identify the molecular cause. In four cases, we identified putatively causal variants in three genes (ASXL1, KMT2D and KMT2A) encoding members of the epigenetic machinery known to be associated with the Bohring-Opitz, Kabuki and Wiedemann-Steiner syndromes. Each variant is novel, de novo, fulfills the ACMG criteria and is predicted to result in loss-of-function leading to haploinsufficiency of the epi-gene. In two of the remaining cases, homozygous/compound heterozygous variants in XYLT2 and PLCB4 genes, respectively, associated with spondyloocular and auriculocondylar 2 syndromes and in the latter an additional candidate variant in XRN2, a gene yet unrelated to any disease, were detected, but their pathogenicity remains uncertain. These results underscore the broad clinical spectrum of Mendelian disorders of the epigenetic apparatus and the high rate of WES disclosure of the genetic basis in cases which may pose a challenge for phenotype encompassing distinct syndromes. The overlapping features of distinct intellectual disability syndromes reflect common pathogenic molecular mechanisms affecting the complex regulation of balance between open and closed chromatin.


Assuntos
Estudos de Associação Genética , Síndrome de Rubinstein-Taybi/diagnóstico , Síndrome de Rubinstein-Taybi/genética , Sequenciamento Completo do Exoma , Proteína de Ligação a CREB/genética , Criança , Pré-Escolar , Hibridização Genômica Comparativa , Proteína p300 Associada a E1A/genética , Epigênese Genética , Facies , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Fenótipo
11.
Am J Case Rep ; 20: 175-178, 2019 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-30739122

RESUMO

BACKGROUND The Say-Barber-Biesecker-Young-Simpson (SBBYS) variant of Ohdo syndrome is characterized by congenital hypothyroidism, facial dysmorphism, postaxial polydactyly, and mental retardation. The SBBYS variant of Ohdo syndrome is extremely rare with only 19 cases previously reported in the literature. A case is presented of chronic otitis media associated with cholesteatoma in a six-year-old boy with the SBBYS variant of Ohdo syndrome. CASE REPORT A 6-year-old boy presented with perforation of the tympanic membrane and a cholesteatoma in the mesotympanic-attic region associated with chronic otitis media. The child had previously been diagnosed with the SBBYS variant of Ohdo syndrome. Following computed tomography (CT) and magnetic resonance imaging (MRI), tympanoplasty was performed with removal of the lesion. CONCLUSIONS This is the first case described in the literature of chronic otitis media associated with cholesteatoma in a patient with the SBBYS variant of Ohdo syndrome. This case demonstrates the importance of specialist otolaryngology referral for patient management.


Assuntos
Blefarofimose/complicações , Colesteatoma da Orelha Média/complicações , Hipotireoidismo Congênito/complicações , Cardiopatias Congênitas/complicações , Deficiência Intelectual/complicações , Instabilidade Articular/complicações , Otite Média/complicações , Criança , Colesteatoma da Orelha Média/diagnóstico por imagem , Doença Crônica , Facies , Humanos , Imagem por Ressonância Magnética , Masculino , Doenças Raras
12.
J Autism Dev Disord ; 49(5): 2184-2202, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30783897

RESUMO

The presence of multiple dysmorphic features in some children with autism spectrum disorder (ASD) might identify distinct ASD phenotypes and serve as potential markers for understanding causes and prognoses. To evaluate dysmorphology in ASD, children aged 3-6 years with ASD and non-ASD population controls (POP) from the Study to Explore Early Development were evaluated using a novel, systematic dysmorphology review approach. Separate analyses were conducted for non-Hispanic White, non-Hispanic Black, and Hispanic children. In each racial/ethnic group, ~ 17% of ASD cases were Dysmorphic compared with ~ 5% of POP controls. The ASD-POP differential was not explained by known genetic disorders or birth defects. In future epidemiologic studies, subgrouping ASD cases as Dysmorphic vs. Non-dysmorphic might help delineate risk factors for ASD.


Assuntos
Transtorno do Espectro Autista/diagnóstico , Anormalidades Craniofaciais/complicações , Facies , Fenótipo , Transtorno do Espectro Autista/classificação , Transtorno do Espectro Autista/complicações , Criança , Desenvolvimento Infantil , Pré-Escolar , Grupos Étnicos , Feminino , Humanos , Masculino
13.
Proc Natl Acad Sci U S A ; 116(9): 3662-3667, 2019 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-30808755

RESUMO

Kaufman oculocerebrofacial syndrome (KOS) is a recessive neurodevelopmental disorder characterized by intellectual disability and lack of speech. KOS is caused by inactivating mutations in UBE3B, but the underlying biological mechanisms are completely unknown. We found that loss of Ube3b in mice resulted in growth retardation, decreased grip strength, and loss of vocalization. The brains of Ube3b -/- mice had hypoplasia of the corpus callosum, enlarged ventricles, and decreased thickness of the somatosensory cortex. Ube3b -/- cortical neurons had abnormal dendritic morphology and synapses. We identified 22 UBE3B interactors and found that branched-chain α-ketoacid dehydrogenase kinase (BCKDK) is an in vivo UBE3B substrate. Since BCKDK targets several metabolic pathways, we profiled plasma and cortical metabolomes from Ube3b -/- mice. Nucleotide metabolism and the tricarboxylic acid cycle were among the pathways perturbed. Substrate-induced mitochondrial respiration was reduced in skeletal muscle but not in liver of Ube3b -/- mice. To assess the relevance of these findings to humans, we identified three KOS patients who had compound heterozygous UBE3B mutations. We discovered changes in metabolites from similar pathways in plasma from these patients. Collectively, our results implicate a disease mechanism in KOS, suggest that it is a metabolic encephalomyopathy, and provide an entry to targeted therapies.


Assuntos
Anormalidades do Olho/genética , Deficiência Intelectual/genética , Transtornos do Desenvolvimento da Linguagem/genética , Deformidades Congênitas dos Membros/genética , Microcefalia/genética , Proteínas Quinases/genética , Ubiquitina-Proteína Ligases/genética , Adolescente , Adulto , Animais , Encéfalo/fisiopatologia , Criança , Anormalidades do Olho/fisiopatologia , Facies , Humanos , Deficiência Intelectual/fisiopatologia , Transtornos do Desenvolvimento da Linguagem/fisiopatologia , Deformidades Congênitas dos Membros/fisiopatologia , Masculino , Redes e Vias Metabólicas , Camundongos , Camundongos Knockout , Microcefalia/fisiopatologia , Mutação , Fenótipo , Ubiquitina/genética
14.
Genes Brain Behav ; 18(4): e12553, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30786142

RESUMO

KBG syndrome is a neurodevelopmental disorder, caused by dominant mutations in ANKRD11, that is characterized by developmental delay/intellectual disability, mild craniofacial dysmorphisms, and short stature. Behavior and cognition have hardly been studied, but anecdotal evidence suggests higher frequencies of ADHD-symptoms and social-emotional impairments. In this study, the behavioral and cognitive profile of KBG syndrome will be investigated in order to examine if and how cognitive deficits contribute to behavioral difficulties. A total of 18 patients with KBG syndrome and a control group consisting of 17 patients with other genetic disorders with comparable intelligence levels, completed neuropsychological assessment. Age-appropriate tasks were selected, covering overall intelligence, attention, memory, executive functioning, social cognition and visuoconstruction. Results were compared using Cohen's d effect sizes. As to behavior, fewer difficulties in social functioning and slightly more attentional problems, hyperactivity, oppositional defiant behavior and conduct problems were found in the KBG syndrome group. Regarding cognitive functioning, inspection of the observed differences shows that patients with KBG syndrome showed lower scores on sustained attention, cognitive flexibility, and visuoconstruction. In contrast, the KBG syndrome group demonstrated higher scores on visual memory, social cognition and emotion recognition. The cognitive profile of KBG syndrome in this sample indicates problems in attention and executive functioning that may underlie the behavior profile which primarily comprises impulsive behavior. Contrary to expectations based on previous (case) reports, no deficits were found in social cognitive functioning. These findings are important for counseling purposes, for tailored education planning, and for the development of personalized intervention.


Assuntos
Anormalidades Múltiplas/fisiopatologia , Doenças do Desenvolvimento Ósseo/fisiopatologia , Cognição , Deficiência Intelectual/fisiopatologia , Fenótipo , Anormalidades Dentárias/fisiopatologia , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/psicologia , Adolescente , Adulto , Idoso , Atenção , Doenças do Desenvolvimento Ósseo/genética , Doenças do Desenvolvimento Ósseo/psicologia , Criança , Função Executiva , Facies , Feminino , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/psicologia , Inteligência , Masculino , Memória , Pessoa de Meia-Idade , Proteínas Repressoras/genética , Comportamento Social , Anormalidades Dentárias/genética , Anormalidades Dentárias/psicologia , Percepção Visual
16.
J Hum Genet ; 64(4): 271-280, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30670789

RESUMO

A decade ago, we described novel de novo submicroscopic deletions of chromosome 14q11.2 in three children with developmental delay, cognitive impairment, and similar dysmorphic features, including widely-spaced eyes, short nose with flat nasal bridge, long philtrum, prominent Cupid's bow of the upper lip, full lower lip, and auricular anomalies. We suggested that this constituted a new multiple congenital anomaly-intellectual disability syndrome due to defects in CHD8 and/or SUPT16H. The three patients in our original cohort were between 2 years and 3 years of age at the time. Here we present a fourth patient and clinical updates on our previous patients. To document the longitudinal course more fully, we integrate published reports of other patients and describe genotype-phenotype correlations among them. Children with the disorder present with developmental delay, intellectual disability, and/or autism spectrum disorder in addition to characteristic facies. Gastrointestinal and sleep problems are notable. The identification of multiple patients with the same genetic defect and characteristic clinical phenotype, confirms our suggestion that this is a syndromic disorder caused by haploinsufficiency or heterozygous loss of function of CHD8.


Assuntos
Proteínas de Ciclo Celular/genética , Proteínas de Ligação a DNA/genética , Deficiência Intelectual/genética , Transtornos do Neurodesenvolvimento/genética , Fatores de Transcrição/genética , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/fisiopatologia , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/fisiopatologia , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 14/genética , Facies , Feminino , Haploinsuficiência/genética , Heterozigoto , Humanos , Deficiência Intelectual/fisiopatologia , Masculino , Megalencefalia/genética , Megalencefalia/fisiopatologia , Transtornos do Neurodesenvolvimento/patologia
17.
Nat Med ; 25(1): 60-64, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30617323

RESUMO

Syndromic genetic conditions, in aggregate, affect 8% of the population1. Many syndromes have recognizable facial features2 that are highly informative to clinical geneticists3-5. Recent studies show that facial analysis technologies measured up to the capabilities of expert clinicians in syndrome identification6-9. However, these technologies identified only a few disease phenotypes, limiting their role in clinical settings, where hundreds of diagnoses must be considered. Here we present a facial image analysis framework, DeepGestalt, using computer vision and deep-learning algorithms, that quantifies similarities to hundreds of syndromes. DeepGestalt outperformed clinicians in three initial experiments, two with the goal of distinguishing subjects with a target syndrome from other syndromes, and one of separating different genetic subtypes in Noonan syndrome. On the final experiment reflecting a real clinical setting problem, DeepGestalt achieved 91% top-10 accuracy in identifying the correct syndrome on 502 different images. The model was trained on a dataset of over 17,000 images representing more than 200 syndromes, curated through a community-driven phenotyping platform. DeepGestalt potentially adds considerable value to phenotypic evaluations in clinical genetics, genetic testing, research and precision medicine.


Assuntos
Aprendizado Profundo , Facies , Doenças Genéticas Inatas/diagnóstico , Algoritmos , Genótipo , Humanos , Processamento de Imagem Assistida por Computador , Fenótipo , Síndrome
18.
BMC Med Genet ; 20(1): 16, 2019 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-30642272

RESUMO

BACKGROUND: KBG syndrome is a very rare autosomal dominant disorder, characterized by macrodontia, distinctive craniofacial findings, skeletal findings, post-natal short stature, and developmental delays, sometimes associated with seizures and EEG abnormalities. So far, there have been over 100 cases of KBG syndrome reported. CASE PRESENTATION: Here, we describe two sisters of a non-consanguineous family, both presenting generalized epilepsy with febrile seizures (GEFS+), and one with a more complex phenotype associated with mild intellectual disability, skeletal and dental anomalies. Whole exome sequencing (WES) analysis in all the family members revealed a heterozygous SCN9A mutation, p.(Lys655Arg), shared among the father and the two probands, and a novel de novo loss of function mutation in the ANKRD11 gene, p.(Tyr1715*), in the proband with the more complex phenotype. The reassessment of the phenotypic features confirmed that the patient fulfilled the proposed diagnostic criteria for KBG syndrome, although complicated by early-onset isolated febrile seizures. EEG abnormalities with or without seizures have been reported previously in some KBG cases. The shared variant, occurring in SCN9A, has been previously found in several individuals with GEFS+ and Dravet syndrome. CONCLUSIONS: This report describe a novel de novo variant in ANKRD11 causing a mild phenotype of KGB syndrome and further supports the association of monogenic pattern of SCN9A mutations with GEFS+. Our data expand the allelic spectrum of ANKRD11 mutations, providing the first Brazilian case of KBG syndrome. Furthermore, this study offers an example of how WES has been instrumental allowing us to better dissect the clinical phenotype under study, which is a multilocus variation aggregating in one proband, rather than a phenotypic expansion associated with a single genomic locus, underscoring the role of multiple rare variants at different loci in the etiology of clinical phenotypes making problematic the diagnostic path. The successful identification of the causal variant in a gene may not be sufficient, making it necessary to identify other variants that fully explain the clinical picture. The prevalence of blended phenotypes from multiple monogenic disorders is currently unknown and will require a systematic re-analysis of large WES datasets for proper diagnosis in daily practice.


Assuntos
Anormalidades Múltiplas/genética , Doenças do Desenvolvimento Ósseo/genética , Epilepsia Generalizada/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Deficiência Intelectual/genética , Mutação , Fenótipo , Proteínas Repressoras/genética , Convulsões Febris/genética , Anormalidades Dentárias/genética , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/etiologia , Anormalidades Múltiplas/fisiopatologia , Adolescente , Alelos , Doenças do Desenvolvimento Ósseo/diagnóstico por imagem , Doenças do Desenvolvimento Ósseo/etiologia , Doenças do Desenvolvimento Ósseo/fisiopatologia , Brasil , Eletroencefalografia , Epilepsia Generalizada/fisiopatologia , Facies , Feminino , Loci Gênicos , Heterozigoto , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/etiologia , Deficiência Intelectual/fisiopatologia , Canal de Sódio Disparado por Voltagem NAV1.7/genética , Linhagem , Convulsões Febris/fisiopatologia , Anormalidades Dentárias/diagnóstico por imagem , Anormalidades Dentárias/etiologia , Anormalidades Dentárias/fisiopatologia , Sequenciamento Completo do Exoma
20.
Pediatrics ; 143(1)2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30573661

RESUMO

Purpura fulminans is a rapidly progressive syndrome of intravascular thrombosis and hemorrhagic infarction of the skin. The most common infectious etiology is Neisseria meningitidis sepsis, and less commonly it has been documented as a complication of invasive Streptococcus pneumoniae In children who are otherwise healthy, splenic dysfunction is a significant predisposing factor for invasive pneumococcal infection. We present the case of a 10-month-old girl with a history of developmental delay, who developed an overwhelming infection complicated by purpura fulminans and was found to have previously undiagnosed Mowat-Wilson syndrome with anatomic asplenia. We propose screening patients with clinical features suggestive of Mowat-Wilson syndrome for asplenia to evaluate the need for additional preventive care.


Assuntos
Doença de Hirschsprung/diagnóstico , Deficiência Intelectual/diagnóstico , Microcefalia/diagnóstico , Infecções Pneumocócicas/diagnóstico , Púrpura Fulminante/diagnóstico , Streptococcus pneumoniae/isolamento & purificação , Amputação/métodos , Diagnóstico Diferencial , Facies , Feminino , Doença de Hirschsprung/complicações , Doença de Hirschsprung/cirurgia , Humanos , Lactente , Deficiência Intelectual/complicações , Deficiência Intelectual/cirurgia , Microcefalia/complicações , Microcefalia/cirurgia , Infecções Pneumocócicas/complicações , Infecções Pneumocócicas/cirurgia , Púrpura Fulminante/complicações , Púrpura Fulminante/cirurgia
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