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1.
BMC Med Genet ; 21(1): 193, 2020 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-33008324

RESUMO

BACKGROUND: Kabuki syndrome (KS) is a rare congenital condition with cardinal manifestations of typical facial features, developmental delays, skeletal anomalies, abnormal dermatoglyphic presentations, and mild to moderate intellectual disability. Pathogenic variants in two epigenetic modifier genes, KMT2D and KDM6A, are responsible for KS1 and KS2, respectively. CASE PRESENTATION: A Chinese girl had persistent neonatal hypoglycemia and Dandy-Walker variant. Whole-exome sequencing identified a novel single nucleotide deletion in KMT2D (NM_003482.3 c.12165del p.(Glu4056Serfs*10)) that caused frameshift and premature termination. The mutation was de novo. According to the American College of Medical Genetics and Genomics (ACMG) guidelines, this variant is considered pathogenic. The patient was diagnosed with KS by molecular testing. CONCLUSION: A single novel mutation in KMT2D was identified in a KS patients with hypoglycemia and Dandy-Walker variant in the neonatal stage. A molecular test was conducted to diagnose KS at an early stage.


Assuntos
Anormalidades Múltiplas/genética , Proteínas de Ligação a DNA/genética , Síndrome de Dandy-Walker/genética , Face/anormalidades , Doenças Hematológicas/genética , Hipoglicemia/genética , Proteínas de Neoplasias/genética , Deleção de Sequência , Doenças Vestibulares/genética , Anormalidades Múltiplas/diagnóstico , Sequência de Bases , Síndrome de Dandy-Walker/diagnóstico , Feminino , Testes Genéticos , Doenças Hematológicas/diagnóstico , Humanos , Hipoglicemia/diagnóstico , Recém-Nascido , Homologia de Sequência do Ácido Nucleico , Doenças Vestibulares/diagnóstico , Sequenciamento Completo do Exoma/métodos
2.
BMC Med Genet ; 21(1): 168, 2020 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-32838743

RESUMO

BACKGROUND: Loss of function mutations in the spermine synthase gene (SMS) have been reported to cause a rare X-linked intellectual disability known as Snyder-Robinson Syndrome (SRS). Besides intellectual disability, SRS is also characterized by reduced bone density, osteoporosis and facial dysmorphism. SRS phenotypes evolve with age from childhood to adulthood. METHODS: Whole exome sequencing was performed to know the causative gene/pathogenic variant. Later we confirmed the pathogenic variant through Sanger sequencing. Furthermore, we also performed the mutational analysis through HOPE SERVER and SWISS-MODEL. Also, radiographs were also obtained for affected individual to confirm the disease features. RESULTS: In this article, we report the first Pakistani family consisting of three patients with SRS and a novel missense pathogenic variant in the SMS gene (c.905 C > T p.(Ser302Leu)). In addition to the typical phenotypes, one patient presented with early-onset seizures. Clinical features, genetic and in-silico analysis linked the affected patients of the family with Snyder-Robinson and suggest that this novel mutation affects the spermine synthase activity. CONCLUSION: A novel missense variant in the SMS, c.905C > T p. (Ser302Leu), causing Snyder- Robinson Syndrome (SRS) is reported in three members of Pakistani Family.


Assuntos
Retardo Mental Ligado ao Cromossomo X/genética , Mutação de Sentido Incorreto/genética , Espermina Sintase/genética , Sequenciamento Completo do Exoma/métodos , Adolescente , Criança , Face/anormalidades , Saúde da Família , Feminino , Humanos , Masculino , Retardo Mental Ligado ao Cromossomo X/complicações , Osteoporose/complicações , Osteoporose/diagnóstico , Paquistão , Linhagem
3.
Medicine (Baltimore) ; 99(27): e20989, 2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32629715

RESUMO

BACKGROUND: Many genetic diseases are known to have distinctive facial phenotypes, which are highly informative to provide an opportunity for automated detection. However, the diagnostic performance of artificial intelligence to identify genetic diseases with facial phenotypes requires further investigation. The objectives of this systematic review and meta-analysis are to evaluate the diagnostic accuracy of artificial intelligence to identify the genetic diseases with face phenotypes and then find the best algorithm. METHODS: The systematic review will be conducted in accordance with the "Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols" guidelines. The following electronic databases will be searched: PubMed, Web of Science, IEEE, Ovid, Cochrane Library, EMBASE and China National Knowledge Infrastructure. Two reviewers will screen and select the titles and abstracts of the studies retrieved independently during the database searches and perform full-text reviews and extract available data. The main outcome measures include diagnostic accuracy, as defined by accuracy, recall, specificity, and precision. The descriptive forest plot and summary receiver operating characteristic curves will be used to represent the performance of diagnostic tests. Subgroup analysis will be performed for different algorithms aided diagnosis tests. The quality of study characteristics and methodology will be assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 tool. Data will be synthesized by RevMan 5.3 and Meta-disc 1.4 software. RESULTS: The findings of this systematic review and meta-analysis will be disseminated in a relevant peer-reviewed journal and academic presentations. CONCLUSION: To our knowledge, there have not been any systematic review or meta-analysis relating to diagnosis performance of artificial intelligence in identifying the genetic diseases with face phenotypes. The findings would provide evidence to formulate a comprehensive understanding of applications using artificial intelligence in identifying the genetic diseases with face phenotypes and add considerable value in the future of precision medicine. OSF REGISTRATION: DOI 10.17605/OSF.IO/P9KUH.


Assuntos
Face/anormalidades , Doenças Genéticas Inatas/diagnóstico , Aprendizado Profundo , Humanos , Desenvolvimento Maxilofacial/genética , Metanálise como Assunto , Fenótipo , Revisões Sistemáticas como Assunto
4.
Nat Commun ; 11(1): 3355, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32620778

RESUMO

Mammalian DNA methylation patterns are established by two de novo DNA methyltransferases, DNMT3A and DNMT3B, which exhibit both redundant and distinctive methylation activities. However, the related molecular basis remains undetermined. Through comprehensive structural, enzymology and cellular characterization of DNMT3A and DNMT3B, we here report a multi-layered substrate-recognition mechanism underpinning their divergent genomic methylation activities. A hydrogen bond in the catalytic loop of DNMT3B causes a lower CpG specificity than DNMT3A, while the interplay of target recognition domain and homodimeric interface fine-tunes the distinct target selection between the two enzymes, with Lysine 777 of DNMT3B acting as a unique sensor of the +1 flanking base. The divergent substrate preference between DNMT3A and DNMT3B provides an explanation for site-specific epigenomic alterations seen in ICF syndrome with DNMT3B mutations. Together, this study reveals distinctive substrate-readout mechanisms of the two DNMT3 enzymes, implicative of their differential roles during development and pathogenesis.


Assuntos
Ilhas de CpG/genética , DNA (Citosina-5-)-Metiltransferases/metabolismo , Metilação de DNA , Animais , Domínio Catalítico , Linhagem Celular , DNA (Citosina-5-)-Metiltransferases/genética , DNA (Citosina-5-)-Metiltransferases/ultraestrutura , Células-Tronco Embrionárias , Ensaios Enzimáticos , Epigênese Genética , Face/anormalidades , Humanos , Camundongos , Mutação , Doenças da Imunodeficiência Primária/genética , Relação Estrutura-Atividade , Especificidade por Substrato/genética , Difração de Raios X
6.
Int J Oral Maxillofac Surg ; 49(11): 1464-1469, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32249036

RESUMO

Hemifacial hyperplasia (HFH) is characterized by an increase in volume of all affected tissues of half of the face. It is present at birth, subsequently grows proportionally, and stops growing before adulthood. Unilateral condylar hyperplasia (UCH) consists of progressive asymmetric growth of the mandible and develops typically in early adulthood. Both disorders have an unknown aetiology. The overgrowth limited to one body part suggests somatic mosaicism, as this has been found in other similar localized overgrowth disorders. Often this includes a variant in a gene in the (PIK3CA)/PI3K/(PTEN)/AKT1/mTOR pathway. Here we report the case of an HFH patient with asymmetry present at birth, in whom a progressive growth pattern similar to UCH subsequently occurred, causing marked mandibular asymmetry. A condylectomy was successfully performed to stop the progressive growth. Somatic mosaicism for a mutation in PIK3CA was detected in the condylar tissue. This finding might indicate that both HFH and UCH can be caused by variants in genes in the (PIK3CA)/PI3K/(PTEN)/AKT1/mTOR pathway, similar to other disorders that result in asymmetrical bodily overgrowth.


Assuntos
Assimetria Facial , Côndilo Mandibular , Adulto , Face/anormalidades , Assimetria Facial/congênito , Assimetria Facial/genética , Assimetria Facial/patologia , Humanos , Hiperplasia/genética , Hiperplasia/patologia , Côndilo Mandibular/diagnóstico por imagem , Côndilo Mandibular/patologia
7.
Int J Pediatr Otorhinolaryngol ; 134: 110013, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32247220

RESUMO

BACKGROUND: Controversy exists on management of lymphatic malformations, with schools of thought advocating for observation, surgery or sclerotherapy. This study sought to examine outcomes after surgical resection of pediatric cervicofacial macrocystic lymphatic malformations (MLM). METHODS: Case series with planned data collection on pediatric patients with cervicofacial MLM who underwent surgical resection at a tertiary referral center for vascular anomalies from January 1995 to June 2016. For consistency in patient population analysis, patients who had pre-surgical sclerotherapy or had mixed or microcystic disease were excluded. The main outcome was complete response rate (CR) and long-term recurrence-free survival (RFS). RESULTS: Sixty-three patients who underwent excision of MLM were included, 52.4% were female, 77.8% Caucasian. The majority had de Serres stage I-III (96.8%) affecting the neck (71.4%). Patients were discharged the same day (28.6%), or had a 1 day median length-of-stay (interquartile range (IQR) = 2). Surgical complications included seroma/hematoma (9.5%), transient nerve weakness (facial nerve, sympathetic chain, or phrenic nerve, 6.3%), and infection (1.6%). On long-term follow-up (median: 12 months, IQR 1-43 months), a single surgery achieved CR in 90.5% of patients. RFS was achieved in 86% of patients in our observation period of up to 15 years. Most patients requiring a second intervention failed within 6-months of initial procedure (4/5 patients, 90%); associated factors included bilaterality, advanced staging, and partial response at first-follow-up (p = 0.0051, 0.0051, and <0.0001, respectively). CONCLUSIONS: Surgery is safe and effective as first line treatment for selected MLM. For stage I-III MLM CR and long-term RFS can be achieved with a single surgery. A direct and randomized comparison of treatment modalities is needed.


Assuntos
Face/anormalidades , Anormalidades Linfáticas/patologia , Anormalidades Linfáticas/cirurgia , Pescoço/anormalidades , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos , Escleroterapia , Centros de Atenção Terciária , Fatores de Tempo , Resultado do Tratamento
8.
Ann Clin Lab Sci ; 50(1): 140-145, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32161024

RESUMO

Coffin-Siris Syndrome (CSS) is a rare neurodevelopmental disorder characterized by intellectual disability, coarse facial features, hypoplastic digits/nails, and hypertrichosis. The genes causative of CSS mainly encode the SWI/SNF complex, which contributes to chromatin remodeling and regulates the access of transcriptional factors to specific gene sites. While ARID1B mutations account for a third of all CSS cases, the condition's phenotypic features vary widely. We document the case of a girl with CSS who presented with a variant facial appearance, global developmental delay with speech impairment, agenesis of the corpus callosum, funnel chest, and bilateral renal stones without hypertrichosis or hypoplasia of the fifth fingernail. Genetic analysis revealed that the patient had a novel heterozygous frameshift mutation c.2201dupG (p.Ser736Ilefs*27) on the ARID1B gene.


Assuntos
Anormalidades Múltiplas/etiologia , Proteínas de Ligação a DNA/genética , Face/anormalidades , Mutação da Fase de Leitura , Deformidades Congênitas da Mão/etiologia , Deficiência Intelectual/etiologia , Micrognatismo/etiologia , Pescoço/anormalidades , Fatores de Transcrição/genética , Anormalidades Múltiplas/patologia , Face/patologia , Feminino , Deformidades Congênitas da Mão/patologia , Humanos , Lactente , Deficiência Intelectual/patologia , Masculino , Micrognatismo/patologia , Pescoço/patologia , Prognóstico , República da Coreia
9.
Ann Thorac Surg ; 110(3): e185-e187, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32119854

RESUMO

A male infant with Kabuki syndrome had trivial congenital mitral regurgitation diagnosed at birth. At the age of 2 years and 9 months, the regurgitation worsened from mild to severe; thus, expedited surgical treatment was pursued. The primary operative finding was severe dysplastic two-leaflet disease. After completing chordal replacement as a conventional repair procedure, more-than-moderate central regurgitation caused by establishing a shallow coaptation between the anterior and posterior leaflets persisted. We report a successful case of mitral valve repair involving the novel option of interannular bridge for valvuloplasty to address congenital mitral regurgitation.


Assuntos
Face/anormalidades , Doenças Hematológicas/complicações , Anuloplastia da Valva Mitral , Insuficiência da Valva Mitral/congênito , Insuficiência da Valva Mitral/cirurgia , Doenças Vestibulares/complicações , Anormalidades Múltiplas , Pré-Escolar , Humanos , Masculino , Insuficiência da Valva Mitral/diagnóstico por imagem
11.
Int J Pediatr Otorhinolaryngol ; 133: 109920, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32092604

RESUMO

Craniofacial duplication is a rare congenital anomaly. A case of hemi-mandibular duplication with an accessory oral cavity is presented with along with first-time reported pre- and postnatal MRI, surgical approach and a literature review. MRI clearly depicts the ectopic tooth buds and parotid aplasia in this condition, features that are diagnostic of partial facial duplication. MRI is diagnostic for this condition and can be useful to avoid misdiagnosis of a facial mass.


Assuntos
Coristoma/diagnóstico por imagem , Face/anormalidades , Mandíbula/anormalidades , Glândula Parótida/anormalidades , Adulto , Face/diagnóstico por imagem , Feminino , Humanos , Recém-Nascido , Imagem por Ressonância Magnética , Mandíbula/diagnóstico por imagem , Glândula Parótida/diagnóstico por imagem , Dente , Ultrassonografia Pré-Natal
13.
Arch. Soc. Esp. Oftalmol ; 95(1): 38-41, ene. 2020. ilus, tab
Artigo em Espanhol | IBECS | ID: ibc-195316

RESUMO

El síndrome de Kabuki es una enfermedad genética rara debida a una mutación genética en los genes KMT2D y KDM6A, que afecta a múltiples órganos, entre ellos los ojos, en la mayoría de los pacientes. Las características clínicas más típicas son: facies peculiar, baja estatura, anormalidades esqueléticas y bajo coeficiente intelectual. Las manifestaciones oculares más frecuentes son el estrabismo, la ptosis y los defectos refractivos. Presentamos una serie de casos de 5 pacientes (3 mujeres), 4 de ellos con estrabismo en forma de esotropía, hiperacción de oblicuos inferiores e hipofunción de oblicuos superiores asociado a un síndrome V. Son pocos los casos publicados de síndrome de Kabuki que describan las afectaciones oftalmológicas y las estrabológicas. Podría ser conveniente la realización de resonancias magnéticas orbitarias para detectar cambios en los trayectos musculares que estén relacionados con la patología de los movimientos oculares encontrados


Kabuki syndrome is a rare genetic disorder, caused by mutation in the KMT2D or KDM6A genes, which affects several organs in the majority of patients, among which are the eyes. The most typical clinical characteristics are mental retardation, postnatal growth retardation, skeletal anomalies, and characteristic facial features. As the eyes are affected in most of the cases, ophthalmological examination is recommended for the early detection of ocular anomalies, in order to prevent visual impairment. The most frequent ocular signs are strabismus, ptosis, and refractive anomalies. A series of cases of Kabuki syndrome is described in five children, four of whom exhibited strabismus with esotropia, over action of inferior oblique muscles, and under action of superior oblique muscles associated with a V pattern. Most published papers do not report or might underestimate the ocular problems. It may be appropriate to perform orbital magnetic resonances in order to detect changes in the muscle paths that are related to the pathology of the eye movements found


Assuntos
Humanos , Masculino , Feminino , Pré-Escolar , Criança , Anormalidades Múltiplas/fisiopatologia , Face/anormalidades , Doenças Hematológicas/fisiopatologia , Transtornos da Motilidade Ocular/genética , Doenças Vestibulares/fisiopatologia , Anormalidades Múltiplas/genética , Astigmatismo/genética , Blefaroptose/genética , Proteínas de Ligação a DNA/genética , Face/fisiopatologia , Mutação da Fase de Leitura , Doenças Hematológicas/genética , Hiperopia/genética , Proteínas de Neoplasias/genética , Estrabismo/genética , Estrabismo/cirurgia , Doenças Vestibulares/genética
14.
An Bras Dermatol ; 95(1): 52-56, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31952993

RESUMO

BACKGROUND AND OBJECTIVES: Leprosy remains a leading cause of peripheral neuropathy and disability in the world. Primary objective of the study was to determine the incidence of deformities present at a time of diagnosis and new deformities that patients develop over follow up period. MATERIAL AND METHODS: An open, retrospective cohort study was performed at a tertiary medical center in western India. Recruitment phase of the study was of 2 years (2009-2010) followed by observation/follow up phase of 7 years till 31st December 2017. New patients with leprosy and released from treatment cases who presented with deformity as defined by WHO disability grade (1998) and subsequently developing new deformities during the follow up period of up to 7 years were included in the study. RESULTS: The study included 200 leprosy patients. Of the total 254 deformities, 168 (66.14%) deformities were noticed at the moment of diagnosis, 20 (7.87%) deformities occurred during the follow up phase. Of all patients, 21.25% had Grade 1 deformity and 6.31% had Grade 2 or more severe deformity. Deformities of hand were most common in 44.48%, followed by feet 39.76%, and face 15.74% respectively. LIMITATION OF STUDY: Mode of inclusion of patient was self-reporting during follow up phase so there is possible under reporting of the disabilities. CONCLUSION: New deformities continue to develop in certain forms of leprosy even after release from treatment. Long-term & regular follow up of patients who have been released from treatment is required.


Assuntos
Avaliação da Deficiência , Hanseníase/patologia , Hanseníase/fisiopatologia , Estudos Transversais , Progressão da Doença , Face/anormalidades , Feminino , Seguimentos , Deformidades Adquiridas do Pé/patologia , Deformidades Adquiridas do Pé/fisiopatologia , Deformidades Adquiridas da Mão/patologia , Deformidades Adquiridas da Mão/fisiopatologia , Humanos , Índia , Masculino , Registros Médicos , Nervos Periféricos/fisiopatologia , Estudos Retrospectivos , Índice de Gravidade de Doença , Fatores de Tempo
16.
Gene ; 731: 144360, 2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-31935506

RESUMO

Kabuki syndrome (KS) is a rare congenital disorder characterized by distinctive facies, postnatal growth deficiency, cardiac defects and skeletal anomalies. Studies have determined that pathogenic variants of the lysine-specific methyltransferase 2D (KMT2D) and lysine-specific demethylase 6A (KDM6A) genes are the major causes of KS. The two genes encode different histone-modifying enzymes that are found in the same protein complex that is critical for cell differentiation during development. Here we report the results from next-generation sequencing of genomic DNA from 13 patients who had a clinical diagnosis of KS based on facial dysmorphism and other KS-specific cardinal phenotypes. Nine of the 13 patients were confirmed to be carrying heterozygous pathogenic KMT2D variants, seven of which were truncating and two were missense substitutions. Overall, we uncovered 11 novel variants - nine in KMT2D and two in KDM6A. Seven of the novel variants (all KMT2D) were likely causative of the KS phenotype. Our study expands the number of naturally occurring KMT2D and KDM6A variants. The discovery of novel pathogenic variants will add to the knowledge on disease-causing variants and the relevance of missense variants in KS.


Assuntos
Anormalidades Múltiplas/genética , Anormalidades Congênitas/genética , Proteínas de Ligação a DNA/genética , Face/anormalidades , Doenças Hematológicas/genética , Histona Desmetilases/genética , Proteínas de Neoplasias/genética , Doenças Vestibulares/genética , Anormalidades Múltiplas/epidemiologia , Ásia Sudeste/epidemiologia , Criança , Pré-Escolar , Estudos de Coortes , Anormalidades Congênitas/epidemiologia , Análise Mutacional de DNA/métodos , Feminino , Doenças Hematológicas/epidemiologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação INDEL , Lactente , Recém-Nascido , Masculino , Mutação de Sentido Incorreto , Fenótipo , Análise de Sequência de DNA , Doenças Vestibulares/epidemiologia
17.
J Pediatr Hematol Oncol ; 42(3): e177-e180, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-30499906

RESUMO

Coffin-Siris syndrome (CSS) is a rare congenital disorder with variable clinical phenotype consisting of developmental delay and characteristic facial features. It is caused by mutations in the chromatin remodeling switch/sucrose nonfermenting complex. Although SWI/SNF genes are widely implicated in tumorigenesis, only 8 cases of neoplasm have been reported in patients with CSS. We report a case of anaplastic astrocytoma (WHO grade III) in an 18-month-old child with CSS due to a de novo germline missense SMARCE1 mutation. Additional molecular features of the tumor are described as well. The role of missense SMARCE1 mutations in tumor predisposition in children with CSS should be further investigated to better inform genetic counselling.


Assuntos
Anormalidades Múltiplas/genética , Astrocitoma/genética , Neoplasias Encefálicas/genética , Proteínas Cromossômicas não Histona/genética , Proteínas de Ligação a DNA/genética , Face/anormalidades , Deformidades Congênitas da Mão/genética , Deficiência Intelectual/genética , Micrognatismo/genética , Pescoço/anormalidades , Pré-Escolar , Feminino , Mutação em Linhagem Germinativa , Humanos , Mutação de Sentido Incorreto
18.
Eur J Med Genet ; 63(3): 103742, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31421288

RESUMO

THOC6 is a newly described causal gene for an autosomal recessive intellectual disability (ID) - Beaulieu Boycott Innes syndrome (BBIS) (OMIM # 613680). It is characterized by ID with dysmorphic facies, genitourinary, cardiac anomalies, and dentition problems. Here, we report the first two siblings of BBIS from the Indian subcontinent with previously unreported skeletal anomalies such as Sprengel shoulder, calcaneo valgus deformity, radioulnar dysostosis, and overlapping toes. Whole exome sequencing (WES) identified previously reported three missense variants (p.Trp100Arg, p.Val234Leu, p.Gly275Asp) in THOC6. THOC6 is a subunit of TRanscription and EXport (TREX) complex involved in mRNA transcription, processing, and nuclear export of spliced mRNAs and has a potential role in neurodevelopment. Till date, only 12 patients with BBIS have been reported. This report reviews the phenotypic and genetic data of known BBIS cases in addition to the new phenotypic features, thereby expanding the phenotype of this rare syndrome.


Assuntos
Anormalidades Múltiplas/genética , Deficiência Intelectual/genética , Proteínas de Ligação a RNA/genética , Criança , Pré-Escolar , Face/anormalidades , Estudos de Associação Genética , Cardiopatias Congênitas/genética , Humanos , Índia , Deficiência Intelectual/fisiopatologia , Masculino , Anormalidades Musculoesqueléticas/genética , Mutação de Sentido Incorreto , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Doenças Raras/genética , Irmãos , Anormalidades Dentárias/genética , Anormalidades Urogenitais/genética , Sequenciamento Completo do Exoma
19.
Eur J Med Genet ; 63(3): 103739, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31421289

RESUMO

The chromatin remodeling AT-Rich interaction domain containing 1B protein (ARID1B) also known as BAF-associated factor, 250-KD, B (BAF250B) codified by the ARID1B gene (MIM#614556), is a small subunit of the mammalian SWI/SNF or BAF complex, an ATP-dependent protein machinery which is able to activate or repress gene transcription, allowing protein access to histones through DNA relaxed conformation. ARID1B gene mutations have been associated with two hereditary syndromic conditions, namely Coffin-Siris (CSS, MIM#135900) and Nicolaides-Baraitser syndromes (NCBRS, MIM#601358), characterized by neurodevelopment delay, craniofacial dysmorphisms and skeletal anomalies. Furthermore, intellectual impairment and central nervous system (CNS) alterations, comprising abnormal corpus callosum, have been associated with mutations in this gene. Moreover, ARID1B anomalies resulted to be involved in neoplastic events and Hirschprung disease. Here we report on two monozygotic male twins, displaying clinical appearance strikingly resembling NCBRS and CSS phenotype, who resulted carriers of a novel 6q25.3 microdeletion, encompassing only part of the ARID1B gene. The deleted segment was not inherited from the only parent tested and afflicted the first exons of the gene, coding for protein disordered region. We also provide, for the first time, a review of previously published ARID1B mutated patients with NCBRS and CSS phenotype and a computer-assisted dysmorphology analysis of NCBRS and ARID1B related CSS individuals, through the Face2Gene suite, confirming the existence of highly overlapping facial gestalt of both conditions. The present findings indicate that ARID1B could be considered a contributing gene not only in CSS but also in NCBRS phenotype, although the main gene related to this latter condition is the SMARCA2 gene (MIM#600014), another component of the BAF complex. So, ARID1B study should be considered in such individuals.


Assuntos
Anormalidades Múltiplas/genética , Proteínas de Ligação a DNA/genética , Face/anormalidades , Deformidades Congênitas do Pé/genética , Deformidades Congênitas da Mão/genética , Hipotricose/genética , Deficiência Intelectual/genética , Micrognatismo/genética , Pescoço/anormalidades , Fatores de Transcrição/genética , Gêmeos Monozigóticos/genética , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/patologia , Anormalidades Múltiplas/fisiopatologia , Face/diagnóstico por imagem , Face/patologia , Face/fisiopatologia , Facies , Deformidades Congênitas do Pé/diagnóstico por imagem , Deformidades Congênitas do Pé/patologia , Deformidades Congênitas do Pé/fisiopatologia , Deformidades Congênitas da Mão/diagnóstico por imagem , Deformidades Congênitas da Mão/patologia , Deformidades Congênitas da Mão/fisiopatologia , Humanos , Hipotricose/diagnóstico por imagem , Hipotricose/patologia , Hipotricose/fisiopatologia , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/patologia , Deficiência Intelectual/fisiopatologia , Masculino , Micrognatismo/diagnóstico por imagem , Micrognatismo/patologia , Micrognatismo/fisiopatologia , Mutação de Sentido Incorreto , Pescoço/diagnóstico por imagem , Pescoço/patologia , Pescoço/fisiopatologia , Fenótipo , Processamento de RNA , Deleção de Sequência
20.
Genet Med ; 22(1): 181-188, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31363182

RESUMO

PURPOSE: Kabuki syndrome (KS) (OMIM 147920 and 300867) is a rare genetic disorder characterized by specific facial features, intellectual disability, and various malformations. Immunopathological manifestations seem prevalent and increase the morbimortality. To assess the frequency and severity of the manifestations, we measured the prevalence of immunopathological manifestations as well as genotype-phenotype correlations in KS individuals from a registry. METHODS: Data were for 177 KS individuals with KDM6A or KMT2D pathogenic variants. Questionnaires to clinicians were used to assess the presence of immunodeficiency and autoimmune diseases both on a clinical and biological basis. RESULTS: Overall, 44.1% (78/177) and 58.2% (46/79) of KS individuals exhibited infection susceptibility and hypogammaglobulinemia, respectively; 13.6% (24/177) had autoimmune disease (AID; 25.6% [11/43] in adults), 5.6% (10/177) with ≥2 AID manifestations. The most frequent AID manifestations were immune thrombocytopenic purpura (7.3% [13/177]) and autoimmune hemolytic anemia (4.0% [7/177]). Among nonhematological manifestations, vitiligo was frequent. Immune thrombocytopenic purpura was frequent with missense versus other types of variants (p = 0.027). CONCLUSION: The high prevalence of immunopathological manifestations in KS demonstrates the importance of systematic screening and efficient preventive management of these treatable and sometimes life-threatening conditions.


Assuntos
Doenças Autoimunes/epidemiologia , Proteínas de Ligação a DNA/genética , Face/anormalidades , Doenças Hematológicas/complicações , Histona Desmetilases/genética , Proteínas de Neoplasias/genética , Doenças da Imunodeficiência Primária/epidemiologia , Doenças Vestibulares/complicações , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/imunologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Doenças Hematológicas/genética , Doenças Hematológicas/imunologia , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Mutação , Prevalência , Sistema de Registros , Índice de Gravidade de Doença , Doenças Vestibulares/genética , Doenças Vestibulares/imunologia , Adulto Jovem
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