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1.
J Hum Genet ; 64(6): 561-572, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30858506

RESUMO

Variants have been identified in the embryonic ectoderm development (EED) gene in seven patients with syndromic overgrowth similar to that observed in Weaver syndrome. Here, we present three additional patients with missense variants in the EED gene. All the missense variants reported to date (including the three presented here) have localized to one of seven WD40 domains of the EED protein, which are necessary for interaction with enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2). In addition, among the seven patients reported in the literature and the three new patients presented here, all of the reported pathogenic variants except one occurred at one of four amino acid residues in the EED protein. The recurrence of pathogenic variation at these loci suggests that these residues are functionally important (mutation hotspots). In silico modeling and calculations of the free energy changes resulting from these variants suggested that they not only destabilize the EED protein structure but also adversely affect interactions between EED, EZH2, and/or H3K27me3. These cases help demonstrate the mechanism(s) by which apparently deleterious variants in the EED gene might cause overgrowth and lend further support that amino acid residues in the WD40 domain region may be mutation hotspots.


Assuntos
Anormalidades Múltiplas/genética , Hipotireoidismo Congênito/genética , Anormalidades Craniofaciais/genética , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Deformidades Congênitas da Mão/genética , Histona-Lisina N-Metiltransferase/genética , Complexo Repressor Polycomb 2/genética , Anormalidades Múltiplas/etiologia , Anormalidades Múltiplas/fisiopatologia , Adolescente , Criança , Simulação por Computador , Hipotireoidismo Congênito/etiologia , Hipotireoidismo Congênito/fisiopatologia , Anormalidades Craniofaciais/etiologia , Anormalidades Craniofaciais/fisiopatologia , Proteína Potenciadora do Homólogo 2 de Zeste/química , Feminino , Deformidades Congênitas da Mão/etiologia , Deformidades Congênitas da Mão/fisiopatologia , Histona-Lisina N-Metiltransferase/química , Humanos , Masculino , Simulação de Dinâmica Molecular , Taxa de Mutação , Mutação de Sentido Incorreto/genética , Complexo Repressor Polycomb 2/química , Conformação Proteica , Repetições WD40/genética , Sequenciamento Completo do Exoma
2.
Int J Mol Sci ; 20(5)2019 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-30836598

RESUMO

Chromosome 16 is one of the most gene-rich chromosomes of our genome, and 10% of its sequence consists of segmental duplications, which give instability and predisposition to rearrangement by the recurrent mechanism of non-allelic homologous recombination. Microarray technologies have allowed for the analysis of copy number variations (CNVs) that can contribute to the risk of developing complex diseases. By array comparative genomic hybridization (CGH) screening of 1476 patients, we detected 27 cases with CNVs on chromosome 16. We identified four smallest regions of overlapping (SROs): one at 16p13.11 was found in seven patients; one at 16p12.2 was found in four patients; two close SROs at 16p11.2 were found in twelve patients; finally, six patients were found with atypical rearrangements. Although phenotypic variability was observed, we identified a male bias for Childhood Apraxia of Speech associated to 16p11.2 microdeletions. We also reported an elevated frequency of second-site genomic alterations, supporting the model of the second hit to explain the clinical variability associated with CNV syndromes. Our goal was to contribute to the building of a chromosome 16 disease-map based on disease susceptibility regions. The role of the CNVs of chromosome 16 was increasingly made clear in the determination of developmental delay. We also found that in some cases a second-site CNV could explain the phenotypic heterogeneity by a simple additive effect or a pejorative synergistic effect.


Assuntos
Anormalidades Múltiplas/genética , Cromossomos Humanos Par 16/genética , Hibridização Genômica Comparativa , Deficiências do Desenvolvimento/genética , Anormalidades Múltiplas/classificação , Anormalidades Múltiplas/fisiopatologia , Adolescente , Adulto , Criança , Pré-Escolar , Aberrações Cromossômicas , Deleção Cromossômica , Variações do Número de Cópias de DNA/genética , Deficiências do Desenvolvimento/classificação , Deficiências do Desenvolvimento/fisiopatologia , Feminino , Recombinação Homóloga/genética , Humanos , Lactente , Recém-Nascido , Cariótipo , Masculino , Fenótipo , Duplicações Segmentares Genômicas/genética , Adulto Jovem
3.
Cell Mol Gastroenterol Hepatol ; 7(2): 411-431, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30739867

RESUMO

BACKGROUND & AIMS: A generalized human pacemaking syndrome, chronic atrial and intestinal dysrhythmia (CAID) (OMIM 616201), is caused by a homozygous SGO1 mutation (K23E), leading to chronic intestinal pseudo-obstruction and arrhythmias. Because CAID patients do not show phenotypes consistent with perturbation of known roles of SGO1, we hypothesized that noncanonical roles of SGO1 drive the clinical manifestations observed. METHODS: To identify a molecular signature for CAID syndrome, we achieved unbiased screens in cell lines and gut tissues from CAID patients vs wild-type controls. We performed RNA sequencing along with stable isotope labeling with amino acids in cell culture. In addition, we determined the genome-wide DNA methylation and chromatin accessibility signatures using reduced representative bisulfite sequencing and assay for transposase-accessible chromatin with high-throughput sequencing. Functional studies included patch-clamp, quantitation of transforming growth factor-ß (TGF-ß) signaling, and immunohistochemistry in CAID patient gut biopsy specimens. RESULTS: Proteome and transcriptome studies converge on cell-cycle regulation, cardiac conduction, and smooth muscle regulation as drivers of CAID syndrome. Specifically, the inward rectifier current, an important regulator of cellular function, was disrupted. Immunohistochemistry confirmed overexpression of Budding Uninhibited By Benzimidazoles 1 (BUB1) in patients, implicating the TGF-ß pathway in CAID pathogenesis. Canonical TGF-ß signaling was up-regulated and uncoupled from noncanonical signaling in CAID patients. Reduced representative bisulfite sequencing and assay for transposase-accessible chromatin with high-throughput sequencing experiments showed significant changes of chromatin states in CAID, pointing to epigenetic regulation as a possible pathologic mechanism. CONCLUSIONS: Our findings point to impaired inward rectifier potassium current, dysregulation of canonical TGF-ß signaling, and epigenetic regulation as potential drivers of intestinal and cardiac manifestations of CAID syndrome. Transcript profiling and genomics data are as follows: repository URL: https://www.ncbi.nlm.nih.gov/geo; SuperSeries GSE110612 was composed of the following subseries: GSE110309, GSE110576, and GSE110601.


Assuntos
Anormalidades Múltiplas/genética , Proteínas de Ciclo Celular/metabolismo , Epigenômica , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Anormalidades Múltiplas/patologia , Anormalidades Múltiplas/fisiopatologia , Adulto , Metilação de DNA/genética , Derme/patologia , Fibroblastos/metabolismo , Perfilação da Expressão Gênica , Ontologia Genética , Humanos , Canais de Potássio/metabolismo , Proteoma/metabolismo , Reprodutibilidade dos Testes , Síndrome
4.
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
5.
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
6.
PLoS Genet ; 15(1): e1007879, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30653500

RESUMO

Variably expressive copy-number variants (CNVs) are characterized by extensive phenotypic heterogeneity of neuropsychiatric phenotypes. Approaches to identify single causative genes for these phenotypes within each CNV have not been successful. Here, we posit using multiple lines of evidence, including pathogenicity metrics, functional assays of model organisms, and gene expression data, that multiple genes within each CNV region are likely responsible for the observed phenotypes. We propose that candidate genes within each region likely interact with each other through shared pathways to modulate the individual gene phenotypes, emphasizing the genetic complexity of CNV-associated neuropsychiatric features.


Assuntos
Variações do Número de Cópias de DNA/genética , Estudos de Associação Genética , Heterogeneidade Genética , Predisposição Genética para Doença , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/fisiopatologia , Transtornos Cromossômicos/genética , Transtornos Cromossômicos/fisiopatologia , Duplicação Cromossômica/genética , Regulação da Expressão Gênica , Humanos , Fenótipo , Síndrome de Smith-Magenis/genética , Síndrome de Smith-Magenis/fisiopatologia , Síndrome de Sotos/genética , Síndrome de Sotos/fisiopatologia , Síndrome de Williams/genética , Síndrome de Williams/fisiopatologia
7.
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
9.
Pan Afr Med J ; 30: 219, 2018.
Artigo em Francês | MEDLINE | ID: mdl-30574238

RESUMO

Caudal regression syndrome is a rare malformative syndrome associated, to varying degrees, with agenesis of sacral and coccygeal vertebrae, lower limb shortening and gastrointestinal, genitourinary and cardiovascular abnormalities. Its relationship with gestational diabetes is well established, but its exact cause is poorly established. We here report a rare case of caudal regression syndrome in a 8-month old infant of diabetic mother with polymalformative syndrome and chronic constipation.


Assuntos
Anormalidades Múltiplas/diagnóstico , Constipação Intestinal/etiologia , Gravidez em Diabéticas/fisiopatologia , Anormalidades Múltiplas/etiologia , Anormalidades Múltiplas/fisiopatologia , Doença Crônica , Feminino , Humanos , Lactente , Masculino , Gravidez , Região Sacrococcígea/anormalidades , Síndrome
10.
BMJ Case Rep ; 20182018 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-29898907

RESUMO

Aortopulmonary window (APW) is rare a congenital heart disease accounting for 0.1%-0.2% of all congenital heart defects. The 35% of the APW has been associated with wide variety of other structural heart diseases such as ventricular septal defect, persistent ductus arteriosus, arch anomalies and coronary artery anomalies. To the best of our knowledge, only six cases of APW with pulmonary atresia with ventricular septal defect has been described in the literature. It resembles the type 1 truncus arteriosus, and differentiation from this condition is important prior to surgical correction. We present a case of 14-year-old girl child; she was diagnosed with APW with pulmonary atresia with ventricular septal defect and D transposition of great arteries with the help of echocardiography, cardiac catheterisation and cardiac CT.


Assuntos
Anormalidades Múltiplas/patologia , Defeito do Septo Aortopulmonar/patologia , Comunicação Interventricular/patologia , Atresia Pulmonar/patologia , Transposição dos Grandes Vasos/patologia , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/tratamento farmacológico , Anormalidades Múltiplas/fisiopatologia , Adolescente , Assistência ao Convalescente , Defeito do Septo Aortopulmonar/diagnóstico por imagem , Defeito do Septo Aortopulmonar/tratamento farmacológico , Defeito do Septo Aortopulmonar/fisiopatologia , Cateterismo Cardíaco/métodos , Ecocardiografia/métodos , Eletrocardiografia/métodos , Feminino , Comunicação Interventricular/diagnóstico por imagem , Comunicação Interventricular/tratamento farmacológico , Comunicação Interventricular/fisiopatologia , Humanos , Atresia Pulmonar/diagnóstico por imagem , Atresia Pulmonar/tratamento farmacológico , Atresia Pulmonar/fisiopatologia , Doenças Raras , Transposição dos Grandes Vasos/diagnóstico por imagem , Transposição dos Grandes Vasos/tratamento farmacológico , Transposição dos Grandes Vasos/fisiopatologia , Resultado do Tratamento
11.
BMJ Case Rep ; 20182018 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-29754141

RESUMO

Unilateral lung agenesis is a relatively rare congenital anomaly with a reported incidence of 1 in 15 000 births. It is frequently associated with other congenital malformations. Some of the sequelae of lung agenesis are potentially life-threatening. Here, we report a case of left lung agenesis in association with hiatal hernia and atrioventricular septal defect, a rare combination of anomalies which have not been described previously in the literature.


Assuntos
Anormalidades Múltiplas/diagnóstico por imagem , Defeitos dos Septos Cardíacos/diagnóstico por imagem , Hérnia Hiatal/diagnóstico por imagem , Herniorrafia/métodos , Pneumopatias/diagnóstico por imagem , Pulmão/anormalidades , Anormalidades Múltiplas/fisiopatologia , Anormalidades Múltiplas/terapia , Adulto , Feminino , Gastrostomia/métodos , Defeitos dos Septos Cardíacos/fisiopatologia , Defeitos dos Septos Cardíacos/terapia , Hérnia Hiatal/fisiopatologia , Hérnia Hiatal/terapia , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Pulmão/diagnóstico por imagem , Pulmão/fisiopatologia , Pneumopatias/fisiopatologia , Pneumopatias/terapia , Gravidez , Encaminhamento e Consulta , Fatores de Tempo , Resultado do Tratamento
13.
Mol Genet Genomic Med ; 6(3): 322-331, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29536651

RESUMO

BACKGROUND: Kabuki syndrome (KS) is a disorder characterized by multiple congenital anomalies affecting development and function of multiple systems. Over the years, researchers have attempted to characterize the neurobehavioral phenotype of KS in cohorts of patients enrolled on the basis of clinical assessment. The availability of molecular testing now allows for recruitment of patients with confirmed KS due to KMT2D and KDM6A. METHODS: The aims of the present study were to investigate the neuropsychological and behavioral profiles of individuals with molecularly confirmed diagnosis of KS, and determine the extent of heterogeneity occurring in these profiles between individuals with clinical diagnosis of KS with and without mutations in KMT2D. We also described performance of our cohort in any neuropsychological domain investigated. RESULTS: We documented a marked variation in the neuropsychological profile of subjects with clinical diagnosis of KS, even though a relatively homogeneous impairment in linguistic domains and motor skills was observed. No significant difference occurred between mutation-positive and mutation-negative groups. Phonological disorders and oromotor dysfunctions were also found, and adaptive functioning was characterized by low performance in daily living and in motor domain. CONCLUSION: The present study allowed identification of a distinctive neurobehavioral profile in a cohort of individuals affected by KS with or without molecularly confirmed diagnosis. These findings are expected to help clinicians define more accurately targeted protocols for individualized intervention.


Assuntos
Anormalidades Múltiplas/genética , Anormalidades Múltiplas/fisiopatologia , Face/anormalidades , Doenças Hematológicas/genética , Doenças Hematológicas/fisiopatologia , Doenças Vestibulares/genética , Doenças Vestibulares/fisiopatologia , Adolescente , Criança , Pré-Escolar , Cognição/fisiologia , Estudos de Coortes , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/fisiologia , Face/fisiopatologia , Feminino , Histona Desmetilases/genética , Histona Desmetilases/fisiologia , Humanos , Masculino , Destreza Motora/fisiologia , Mutação , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/fisiologia , Proteínas Nucleares/genética , Proteínas Nucleares/fisiologia , Fenótipo , Adulto Jovem
14.
Eur J Med Genet ; 61(6): 315-321, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29307790

RESUMO

Kabuki syndrome is mainly caused by dominant de-novo pathogenic variants in the KMT2D and KDM6A genes. The clinical features of this syndrome are highly variable, making the diagnosis of Kabuki-like phenotypes difficult, even for experienced clinical geneticists. Herein we present molecular genetic findings of causal genetic variation using array comparative genome hybridization and a Mendeliome analysis, utilizing targeted exome analysis focusing on regions harboring rare disease-causing variants in Kabuki-like patients which remained KMT2D/KDM6A-negative. The aCGH analysis revealed a pathogenic CNV in the 14q11.2 region, while targeted exome sequencing revealed pathogenic variants in genes associated with intellectual disability (HUWE1, GRIN1), including a gene coding for mandibulofacial dysostosis with microcephaly (EFTUD2). Lower values of the MLL2-Kabuki phenotypic score are indicative of Kabuki-like phenotype (rather than true Kabuki syndrome), where aCGH and Mendeliome analyses have high diagnostic yield. Based on our findings we conclude that for new patients with Kabuki-like phenotypes it is possible to choose a specific molecular testing approach that has the highest detection rate for a given MLL2-Kabuki score, thus fostering more precise patient diagnosis and improved management in these genetically- and phenotypically heterogeneous clinical entities.


Assuntos
Anormalidades Múltiplas/genética , Face/anormalidades , Heterogeneidade Genética , Genótipo , Doenças Hematológicas/genética , Fenótipo , Doenças Vestibulares/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/fisiopatologia , Criança , Pré-Escolar , Cromossomos Humanos Par 14 , Hibridização Genômica Comparativa , Proteínas de Ligação a DNA/genética , Exoma , Face/fisiopatologia , Feminino , Doenças Hematológicas/diagnóstico , Doenças Hematológicas/fisiopatologia , Sequenciamento de Nucleotídeos em Larga Escala , Histona Desmetilases/genética , Humanos , Deficiência Intelectual/genética , Masculino , Disostose Mandibulofacial/genética , Microcefalia/genética , Proteínas de Neoplasias/genética , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Fatores de Alongamento de Peptídeos/genética , Receptores de N-Metil-D-Aspartato/genética , Ribonucleoproteína Nuclear Pequena U5/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina-Proteína Ligases/genética , Doenças Vestibulares/diagnóstico , Doenças Vestibulares/fisiopatologia
15.
Brain Dev ; 40(4): 259-267, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29217415

RESUMO

OBJECTIVE: Arima syndrome (AS) is a rare disease and its clinical features mimic those of Joubert syndrome or Joubert syndrome-related diseases (JSRD). Recently, we clarified the AS diagnostic criteria and its severe phenotype. However, genetic evidence of AS remains unknown. We explored causative genes of AS and compared the clinical and genetic features of AS with the other JSRD. PATIENTS AND METHODS: We performed genetic analyses of 4 AS patients of 3 families with combination of whole-exome sequencing and Sanger sequencing. Furthermore, we studied cell biology with the cultured fibroblasts of 3 AS patients. RESULTS: All patients had a specific homozygous variant (c.6012-12T>A, p.Arg2004Serfs*7) or compound heterozygous variants (c.1711+1G>A; c.6012-12T>A, p.Gly570Aspfs*19;Arg2004Serfs*7) in centrosomal protein 290 kDa (CEP290) gene. These unique variants lead to abnormal splicing and premature termination. Morphological analysis of cultured fibroblasts from AS patients revealed a marked decrease of the CEP290-positive cell number with significantly longer cilium and naked and protruded ciliary axoneme without ciliary membrane into the cytoplasm. CONCLUSION: AS resulted in cilia dysfunction from centrosome disruption. The unique variant of CEP290 could be strongly linked to AS pathology. Here, we provided AS specific genetic evidence, which steers the structure and functions of centrosome that is responsible for normal ciliogenesis. This is the first report that has demonstrated the molecular basis of Arima syndrome.


Assuntos
Antígenos de Neoplasias/genética , Doenças Cerebelares/genética , Doenças Cerebelares/patologia , Coloboma/genética , Coloboma/patologia , Fibroblastos/patologia , Proteínas de Neoplasias/genética , Doenças Renais Policísticas/genética , Doenças Renais Policísticas/patologia , Anormalidades Múltiplas/patologia , Anormalidades Múltiplas/fisiopatologia , Adolescente , Adulto , Antígenos de Neoplasias/metabolismo , Células Cultivadas , Centrossomo/metabolismo , Centrossomo/patologia , Doenças Cerebelares/fisiopatologia , Cerebelo/anormalidades , Cerebelo/patologia , Cerebelo/fisiopatologia , Cílios/metabolismo , Cílios/patologia , Coloboma/fisiopatologia , Anormalidades do Olho/patologia , Anormalidades do Olho/fisiopatologia , Família , Feminino , Fibroblastos/metabolismo , Humanos , Imuno-Histoquímica , Doenças Renais Císticas/patologia , Doenças Renais Císticas/fisiopatologia , Microscopia Eletrônica de Transmissão , Peso Molecular , Mutação , Proteínas de Neoplasias/metabolismo , Doenças Renais Policísticas/fisiopatologia , Retina/anormalidades , Retina/patologia , Retina/fisiopatologia , Sequenciamento Completo do Exoma , Adulto Jovem
17.
Retina ; 38(9): 1725-1730, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29160785

RESUMO

PURPOSE: We report a novel finding on spectral domain optical coherence tomography in patients with choroideremia, which we describe as scleral pits (SCPs). METHODS: Cross-sectional observational case series of 36 patients with choroideremia, who underwent ophthalmic examination and multimodal imaging, including optical coherence tomography of the macula. Optical coherence tomography images were reviewed for SCP, which were defined as discrete tracts of hyporeflectivity that traverse the sclera with or without the involvement of Bruch membrane, retinal pigment epithelium, and retina. Unpaired two-tailed t-test with Welch correction was used for statistical analysis. RESULTS: Of the 36 patients, 19 had SCP in at least one eye. Scleral pits were confined to areas of advanced chorioretinal degeneration and never involved the foveola. Type 1 SCP affected only the sclera, whereas Type 2 SCP also involved the Bruch membrane and the retinal pigment epithelium. Type 3 SCP additionally had a full-thickness retinal defect. Patients with SCP were significantly older (51 ± 2 vs. 33 ± 4 years; P < 0.05) and had lower best-corrected visual acuity (20/160 vs. 20/30 or 0.9 ± 0.2 vs. 0.2 ± 0.07 logarithm of the minimum angle of resolution; P < 0.05) than patients without SCP. Patients with SCP had a greater myopic refractive error compared with patients without SCP (-2.6 ± 0.5 vs. -0.3 ± 0.5D; P < 0.05), but there was no significant correlation between the number of SCPs with refraction. Short posterior ciliary arteries were observed to enter the eye through one Type 3 SCP. CONCLUSION: Scleral pits are, to the best of our knowledge, a novel optical coherence tomography finding in advanced choroideremia that likely represents the abnormal juxtaposition of penetrating short posterior ciliary arteries with the retina.


Assuntos
Anormalidades Múltiplas/terapia , Corioide/irrigação sanguínea , Coroideremia/terapia , Fenda Labial/terapia , Fissura Palatina/terapia , Cistos/terapia , Terapia Genética/métodos , Lábio/anormalidades , Epitélio Pigmentado da Retina/patologia , Esclera/anormalidades , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/fisiopatologia , Adulto , Idoso , Lâmina Basilar da Corioide/patologia , Coroideremia/diagnóstico , Coroideremia/fisiopatologia , Fenda Labial/diagnóstico , Fenda Labial/fisiopatologia , Fissura Palatina/diagnóstico , Fissura Palatina/fisiopatologia , Estudos Transversais , Cistos/diagnóstico , Cistos/fisiopatologia , Feminino , Angiofluoresceinografia/métodos , Seguimentos , Humanos , Lábio/fisiopatologia , Masculino , Pessoa de Meia-Idade , Tomografia de Coerência Óptica/métodos , Acuidade Visual
18.
Bone ; 106: 187-193, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29051055

RESUMO

INTRODUCTION: Pierson syndrome is caused by a mutation of LAMB2, encoding for laminin ß2. Clinical phenotype is variable but usually associates congenital nephrotic syndrome (CNS) and ocular abnormalities. Neuromuscular impairment has also been described. METHODS: We report on a 15-year old girl, suffering from Pierson Syndrome, who developed severe bone deformations during puberty. This patient initially displayed CNS and microcoria, leading to the clinical diagnosis of Pierson syndrome. Genetic analysis revealed a truncating mutation and a splice site mutation of LAMB2. The patient received a renal transplantation (R-Tx) at the age of 3. After R-Tx, renal evolution was simple, the patient receiving low-dose corticosteroids, tacrolimus and mycophenolate mofetil. At the age of 12, bone deformations progressively appeared. At the time of bone impairment, renal function was subnormal (glomerular filtration rate using iohexol clearance 50mL/min per 1.73m2), and parameters of calcium/phosphate metabolism were normal (calcium 2.45mmol/L, phosphorus 1.30mmol/L, PTH 81ng/L, ALP 334U/L, 25OH-D 73nmol/L). Radiographs showed major deformations such as scoliosis, genu varum and diffuse epiphyseal abnormalities. A high resolution scanner (HR-pQCT) was performed, demonstrating a bone of "normal low" quantity and quality; major radial and cubital deformations were observed. Stainings of laminin ß2 were performed on bone and renal samples from the patient and healthy controls: as expected, laminin ß2 was expressed in the control kidney but not in the patient's renal tissue, and a similar pattern was observed in bone. CONCLUSION: This is the first case of skeletal impairment ever described in Pierson syndrome. Integrin α3ß1, receptor for laminin ß2, are found in podocytes and osteoblasts, and the observation of both the presence of laminin ß2 staining in healthy bone and its absence in the patient's bone raises the question of a potential role of laminin ß2 in bone physiology.


Assuntos
Anormalidades Múltiplas/metabolismo , Anormalidades Múltiplas/fisiopatologia , Anormalidades do Olho/metabolismo , Anormalidades do Olho/fisiopatologia , Laminina/metabolismo , Síndrome Nefrótica/metabolismo , Síndrome Nefrótica/fisiopatologia , Distúrbios Pupilares/metabolismo , Distúrbios Pupilares/fisiopatologia , Anormalidades Múltiplas/genética , Adolescente , Anormalidades do Olho/genética , Feminino , Humanos , Laminina/genética , Mutação , Síndrome Nefrótica/genética , Doenças Neuromusculares/genética , Doenças Neuromusculares/metabolismo , Doenças Neuromusculares/fisiopatologia , Distúrbios Pupilares/genética
19.
Clin Dysmorphol ; 27(2): 36-41, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29240611

RESUMO

Structural rearrangements of chromosome band 1p31p32 are rare, and their phenotypic consequences remain poorly delineated. Up to 12 patients with learning difficulties, developmental delay, multiple congenital anomalies and microdeletion of the chromosome band 1p31p32 have been described. Inheritance of this deletion has not been reported previously. We describe the inheritance of the 1p32 deletion and discuss the relevance of this deletion to the described phenotype. The differences in clinical and molecular characteristics between the proband and other published reports are reviewed. Patients were evaluated in Genetics Clinic with history, examination and investigation. The existing literature on interstitial deletions of 1p was reviewed. Here, we report on a three-generation family, where the index patient was an adult female with learning difficulty, dysmorphic features, microcephaly, ambiguous genitalia, congenital hip dislocation and brachydactyly in whom a maternally inherited 1.45 Mbp interstitial deletion was detected at 1p32.3. Both her mother and maternal grandmother have learning difficulties and dysmorphic features. There are 14 OMIM genes in the deleted region including LRP8 and DMRTB1. The NFIA gene is not deleted in this family. The first report of a familial 1p32 microdeletion in three generations of a family carrying the smallest reported a deletion involving this region and brachydactyly as a previously unreported feature.


Assuntos
Anormalidades Múltiplas/genética , Deleção Cromossômica , Deficiências do Desenvolvimento/genética , Microcefalia/genética , Anormalidades Múltiplas/fisiopatologia , Adulto , Cromossomos Humanos Par 1/genética , Hibridização Genômica Comparativa , Proteínas de Ligação a DNA/genética , Deficiências do Desenvolvimento/fisiopatologia , Feminino , Humanos , Proteínas Relacionadas a Receptor de LDL/genética , Masculino , Microcefalia/fisiopatologia , Linhagem , Fenótipo , Fatores de Transcrição/genética
20.
Pan Afr Med J ; 31: 93, 2018.
Artigo em Francês | MEDLINE | ID: mdl-31011394

RESUMO

Pycnodysostosis is a very rare genetic disease of the bone characterized by osteocondensation associated with dysmorphic syndrome and growth retardation. This study aims to highlight the phenotypic abnormalities, the radiological signs, the therapeutic and evolutionary features of pycnodysostosis in a 11-year old child. The child was referred by his dentist for clinical evaluation. He was born to first-degree consanguineous parents and had recurrent spontaneous fractures since the age of 3 years. Clinical examination showed dysmorphic syndrome characterized by frontal hump, persistent anterior fontanelle, micrognathia, finger deformities, dental malposition, curved nails, asymmetric chest, lumbar spine scoliosis with severe growth retardation (-4DS). Skeletal X-rays showed bony densification of the skull base, persistent anterior fontanelle, dental malposition, diaphysometaphyseal densification of the long bones mainly at the level of the lower limbs with malunions and tapered phalanges of the hands. Bone densitometry was normal. The diagnosis of pycnodysostosis was retained based on the clinical and radiological signs. Genetic counselling was proposed to the family as well as dental and orthopaedic treatment. Pycnodysostosis is a rare disorder; diagnosis is sometimes difficult and delayed posing diagnostic problem due to its resemblance with osteoporosis. Treatment is essentially based on fractures and dental caries prevention.


Assuntos
Anormalidades Múltiplas/diagnóstico , Fraturas Espontâneas/etiologia , Picnodisostose/diagnóstico , Anormalidades Múltiplas/fisiopatologia , Criança , Humanos , Masculino , Picnodisostose/fisiopatologia
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