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1.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(8): 837-840, 2019 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-31400141

RESUMO

OBJECTIVE: To analyze the clinical and molecular genetic characteristics of patient with Kleefstra syndrome 1. METHODS: Clinical data, chromosomal karyotype and whole genome copy number variations (CNVs) of the patient were analyzed. RESULTS: The patient was found to have a karyotype of 45,XX,-9[4]/46,XX,r(9)(p24q34)[56]. Whole-genome CNVs detection revealed that she has carried a heterozygous deletion of approximately 670 kb at 9q34.3, which encompassed the entire EHMT1 gene. The region is strongly associated with Kleefstra syndrome (1/9q telomere deletion). In addition, the patient also had heterozygous deletion of 9pter, which may predispose to formation of ring chromosome 9. CONCLUSION: The child was diagnosed with Kleefstra syndrome type 1 in conjunct with ring chromosome 9.


Assuntos
Cromossomos Humanos Par 9/genética , Anormalidades Craniofaciais/genética , Cardiopatias Congênitas/genética , Deficiência Intelectual/genética , Cromossomos em Anel , Criança , Deleção Cromossômica , Variações do Número de Cópias de DNA , Feminino , Humanos
2.
Hum Genet ; 138(6): 601-611, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30968251

RESUMO

Facial shape differences are one of the most significant phenotypes in humans. It is affected largely by skull shape. However, research into the genetic basis of the craniofacial morphology has rarely been reported. The present study aimed to identify genetic variants influencing craniofacial morphology in northern Han Chinese through whole-exome sequencing (WES). Phenotypic data of the volunteers' faces and skulls were obtained through three-dimensional CT scan of the skull. A total of 48 phenotypes (35 facial and 13 cranial phenotypes) were used for the bioinformatics analysis. Four genetic loci were identified affecting the craniofacial shapes. The four candidate genes are RGPD3, IGSF3, SLC28A3, and USP40. Four single-nucleotide polymorphism (SNP) site mutations in RGPD3, IGSF3, and USP40 were significantly associated with the skull shape (p < 1×10-6), and three SNP site mutations in RGPD3, IGSF3, and SLC28A3 were significantly associated with the facial shape (p < 1×10-6). The rs62152530 site mutation in the RGPD3 gene may be closely associated with the nasal length, ear length, and alar width. The rs647711 site mutation in the IGSF3 gene may be closely associated with the nasal length, mandibular width, and width between the mental foramina. The rs10868138 site mutation in the SLC28A3 gene may be associated with the nasal length, alar width, width between tragus, and width between the mental foramina. The rs1048603 and rs838543 site mutations in the USP40 gene may be closely associated with the pyriform aperture width. Our findings provide useful genetic information for the determination of face morphology.


Assuntos
Ossos Faciais/metabolismo , Loci Gênicos/genética , Polimorfismo de Nucleotídeo Único , Crânio/metabolismo , Sequenciamento Completo do Exoma/métodos , Grupo com Ancestrais do Continente Asiático/genética , Sequência de Bases , China , Anormalidades Craniofaciais/etnologia , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/patologia , Ossos Faciais/anatomia & histologia , Predisposição Genética para Doença/etnologia , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Crânio/anatomia & histologia
3.
Medicina (Kaunas) ; 55(3)2019 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-30934652

RESUMO

The term congenital hypopigmentary disorders refers to a wide group of heterogeneous hereditary diseases, clinically characterized by inborn pigmentary defects of the iris, hair, and/or skin. They include Gray Hair Syndromes (GHSs), a rare group of autosomal recessive genodermatosis hallmarked by inborn silvery gray hair. GHSs encompass Griscelli, Chediak⁻Higashi, Elejalde, and Cross syndromes, which are all characterized by a broad spectrum of severe multisystem disorders, including neurological, ocular, skeletal, and immune system impairment. In this manuscript, we describe in detail the clinical, trichoscopic, and genetic features of a rare case of Griscelli syndrome; moreover, we provide an overview of all the GHSs known to date. Our report highlights how an accurate clinical examination with noninvasive methods, like trichoscopy, may play a crucial rule in diagnosis of rare and potentially lethal genetic syndromes such as Griscelli syndrome, in which timely diagnosis and therapy may modify the clinical course, quality of life, and likelihood of survival.


Assuntos
Transtornos da Pigmentação/diagnóstico , Transtornos da Pigmentação/genética , Doenças Raras/diagnóstico , Doenças Raras/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/imunologia , Anormalidades Múltiplas/patologia , Adulto , Síndrome de Chediak-Higashi/diagnóstico , Síndrome de Chediak-Higashi/genética , Síndrome de Chediak-Higashi/imunologia , Síndrome de Chediak-Higashi/patologia , Pré-Escolar , Anormalidades Craniofaciais/diagnóstico , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/imunologia , Anormalidades Craniofaciais/patologia , Diagnóstico Diferencial , Feminino , Cabelo/anormalidades , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/imunologia , Perda Auditiva Neurossensorial/patologia , Humanos , Hipertricose/induzido quimicamente , Iris/anormalidades , Masculino , Mutação , Síndromes Neurocutâneas/diagnóstico , Síndromes Neurocutâneas/genética , Síndromes Neurocutâneas/imunologia , Síndromes Neurocutâneas/patologia , Piebaldismo/diagnóstico , Piebaldismo/genética , Piebaldismo/imunologia , Piebaldismo/patologia , Transtornos da Pigmentação/imunologia , Transtornos da Pigmentação/patologia , Qualidade de Vida , Doenças Raras/imunologia , Doenças Raras/patologia , Anormalidades da Pele , Proteínas rab27 de Ligação ao GTP/genética
5.
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
6.
Genome Med ; 11(1): 12, 2019 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-30819258

RESUMO

BACKGROUND: Neurodevelopmental disorders are genetically and phenotypically heterogeneous encompassing developmental delay (DD), intellectual disability (ID), autism spectrum disorders (ASDs), structural brain abnormalities, and neurological manifestations with variants in a large number of genes (hundreds) associated. To date, a few de novo mutations potentially disrupting TCF20 function in patients with ID, ASD, and hypotonia have been reported. TCF20 encodes a transcriptional co-regulator structurally related to RAI1, the dosage-sensitive gene responsible for Smith-Magenis syndrome (deletion/haploinsufficiency) and Potocki-Lupski syndrome (duplication/triplosensitivity). METHODS: Genome-wide analyses by exome sequencing (ES) and chromosomal microarray analysis (CMA) identified individuals with heterozygous, likely damaging, loss-of-function alleles in TCF20. We implemented further molecular and clinical analyses to determine the inheritance of the pathogenic variant alleles and studied the spectrum of phenotypes. RESULTS: We report 25 unique inactivating single nucleotide variants/indels (1 missense, 1 canonical splice-site variant, 18 frameshift, and 5 nonsense) and 4 deletions of TCF20. The pathogenic variants were detected in 32 patients and 4 affected parents from 31 unrelated families. Among cases with available parental samples, the variants were de novo in 20 instances and inherited from 4 symptomatic parents in 5, including in one set of monozygotic twins. Two pathogenic loss-of-function variants were recurrent in unrelated families. Patients presented with a phenotype characterized by developmental delay, intellectual disability, hypotonia, variable dysmorphic features, movement disorders, and sleep disturbances. CONCLUSIONS: TCF20 pathogenic variants are associated with a novel syndrome manifesting clinical characteristics similar to those observed in Smith-Magenis syndrome. Together with previously described cases, the clinical entity of TCF20-associated neurodevelopmental disorders (TAND) emerges from a genotype-driven perspective.


Assuntos
Anormalidades Craniofaciais/genética , Deficiências do Desenvolvimento/genética , Mutação INDEL , Deficiência Intelectual/genética , Hipotonia Muscular/genética , Síndrome de Smith-Magenis/genética , Fatores de Transcrição/genética , Adolescente , Criança , Pré-Escolar , Anormalidades Craniofaciais/patologia , Deficiências do Desenvolvimento/patologia , Feminino , Humanos , Lactente , Deficiência Intelectual/patologia , Masculino , Hipotonia Muscular/patologia , Síndrome de Smith-Magenis/patologia , Fatores de Transcrição/metabolismo , Adulto Jovem
7.
Methods Mol Biol ; 1922: 407-452, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30838594

RESUMO

Rare genetic disorders are often challenging to diagnose. Anomalies of tooth number, shape, size, mineralized tissue structure, eruption, and resorption may exist as isolated symptoms or diseases but are often part of the clinical synopsis of numerous syndromes (Bloch-Zupan A, Sedano H, Scully C. Dento/oro/craniofacial anomalies and genetics, 1st edn. Elsevier, Boston, MA, 2012). Concerning amelogenesis imperfecta (AI), for example, mutations in a number of genes have been reported to cause isolated AI, including AMELX, ENAM, KLK4, MMP20, FAM83H, WDR72, C4orf26, SLC24A4, and LAMB3. In addition, many other genes such as DLX3, CNNM4, ROGDI, FAM20A, STIM1, ORAI1, and LTBP3 have been shown to be involved in developmental syndromes with enamel defects. The clinical presentation of the enamel phenotype (hypoplastic, hypomineralized, hypomature, or a combination of severities) alone does not allow a reliable prediction of possible causative genetic mutations. Understanding the potential genetic cause(s) of rare diseases is critical for overall health management of affected patient. One effective strategy to reach a genetic diagnosis is to sequence a selected gene panel chosen for a determined range of phenotypes. Here we describe a laboratory protocol to set up a specific gene panel for orodental diseases.


Assuntos
Anormalidades Craniofaciais/genética , Variação Genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Doenças Raras/genética , Anormalidades Dentárias/genética , Amelogênese Imperfeita/diagnóstico , Amelogênese Imperfeita/genética , Anormalidades Craniofaciais/diagnóstico , DNA/genética , Desenho de Equipamento , Sequenciamento de Nucleotídeos em Larga Escala/instrumentação , Humanos , Doenças Raras/diagnóstico , Anormalidades Dentárias/diagnóstico
8.
Mol Genet Genomic Med ; 7(4): e00569, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30729724

RESUMO

BACKGROUND: Mutations in mediator of RNA polymerase II transcription subunit 12 homolog (MED12, OMIM 300188) cause X-linked intellectual disability (XLID) disorders including FG, Lujan, and Ohdo syndromes. The Gli3-dependent Sonic Hedgehog (SHH) signaling pathway has been implicated in the original FG syndrome and Lujan syndrome. How are SHH-signaling defects related to the complex clinical phenotype of MED12-associated XLID syndromes are not fully understood. METHODS: Quantitative RT-PCR was used to study expression levels of three SHH-signaling genes in lymophoblast cell lines carrying four MED12 mutations from four unrelated XLID families. Genotype and phenotype correlation studies were performed on these mutations. RESULTS: Three newly identified and one novel MED12 mutations in six affected males from four unrelated XLID families were studied. Three mutations (c.2692A>G; p.N898D, c.3640C>T; p.R1214C, and c.3884G>A; p.R1295H) are located in the LS domain and one (c.617G>A; p.R206Q) is in the L domain of MED12. These mutations involve highly conserved amino acid residues and segregate with ID and related congenital malformations in respective probands families. Patients with the LS-domain mutations share many features of FG syndrome and some features of Lujan syndrome. The patient with the L-domain mutation presented with ID and predominant neuropsychiatric features but little dysmorphic features of either FG or Lujan syndrome. Transcript levels of three Gli3-dependent SHH-signaling genes, CREB5, BMP4, and NEUROG2, were determined by quantitative RT-PCR and found to be significantly elevated in lymphoblasts from patients with three mutations in the MED12-LS domain. CONCLUSIONS: These results support a critical role of MED12 in regulating Gli3-dependent SHH signaling and in developing ID and related congenital malformations in XLID syndromes. Differences in the expression profile of SHH-signaling genes potentially contribute to variability in clinical phenotypes in patients with MED12-related XLID disorders.


Assuntos
Anormalidades Craniofaciais/genética , Complexo Mediador/genética , Retardo Mental Ligado ao Cromossomo X/genética , Mutação de Sentido Incorreto , Adulto , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Proteína Morfogenética Óssea 4/genética , Proteína Morfogenética Óssea 4/metabolismo , Células Cultivadas , Anormalidades Craniofaciais/patologia , Proteína A de Ligação a Elemento de Resposta do AMP Cíclico/genética , Proteína A de Ligação a Elemento de Resposta do AMP Cíclico/metabolismo , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Humanos , Masculino , Complexo Mediador/química , Complexo Mediador/metabolismo , Retardo Mental Ligado ao Cromossomo X/patologia , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Linhagem , Domínios Proteicos , Transdução de Sinais
9.
PLoS Genet ; 15(2): e1007962, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30721228

RESUMO

Multiple syndromes share congenital heart and craniofacial muscle defects, indicating there is an intimate relationship between the adjacent cardiac and pharyngeal muscle (PM) progenitor fields. However, mechanisms that direct antagonistic lineage decisions of the cardiac and PM progenitors within the anterior mesoderm of vertebrates are not understood. Here, we identify that retinoic acid (RA) signaling directly promotes the expression of the transcription factor Nr2f1a within the anterior lateral plate mesoderm. Using zebrafish nr2f1a and nr2f2 mutants, we find that Nr2f1a and Nr2f2 have redundant requirements restricting ventricular cardiomyocyte (CM) number and promoting development of the posterior PMs. Cre-mediated genetic lineage tracing in nr2f1a; nr2f2 double mutants reveals that tcf21+ progenitor cells, which can give rise to ventricular CMs and PM, more frequently become ventricular CMs potentially at the expense of posterior PMs in nr2f1a; nr2f2 mutants. Our studies reveal insights into the molecular etiology that may underlie developmental syndromes that share heart, neck and facial defects as well as the phenotypic variability of congenital heart defects associated with NR2F mutations in humans.


Assuntos
Fator II de Transcrição COUP/metabolismo , Proteínas de Ligação a DNA/metabolismo , Miócitos Cardíacos/metabolismo , Músculos Faríngeos/metabolismo , Fatores de Transcrição/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Animais , Animais Geneticamente Modificados , Padronização Corporal/genética , Fator II de Transcrição COUP/genética , Linhagem da Célula/genética , Anormalidades Craniofaciais/embriologia , Anormalidades Craniofaciais/genética , Proteínas de Ligação a DNA/genética , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/metabolismo , Cardiopatias Congênitas/embriologia , Cardiopatias Congênitas/genética , Ventrículos do Coração/citologia , Ventrículos do Coração/embriologia , Ventrículos do Coração/metabolismo , Humanos , Mesoderma/citologia , Mesoderma/embriologia , Mesoderma/metabolismo , Modelos Animais , Mutação , Miócitos Cardíacos/citologia , Músculos Faríngeos/citologia , Músculos Faríngeos/embriologia , Regiões Promotoras Genéticas , Transdução de Sinais , Fatores de Transcrição/genética , Tretinoína/metabolismo , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/genética
11.
Int J Oncol ; 54(3): 797-806, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30628659

RESUMO

Fibroblast growth factors (FGFs) are diffusible polypeptides released by a variety of cell types. FGF8 subfamily members regulate embryonic development processes through controlling progenitor cell growth and differentiation, and are also functional in adults in tissue repair to maintain tissue homeostasis. FGF8 family members exhibit unique binding affinities with FGF receptors and tissue distribution patterns. Increasing evidence suggests that, by regulating multiple cellular signaling pathways, alterations in the FGF8 subfamily are involved in craniofacial development, odontogenesis, tongue development and salivary gland branching morphogenesis. Aberrant FGF signaling transduction, caused by mutations as well as abnormal expression or isoform splicing, plays an important role in the development of oral diseases. Targeting FGF8 subfamily members provides a new promising strategy for the treatment of oral diseases. The aim of this review was to summarize the aberrant regulations of FGF8 subfamily members and their potential implications in oral­maxillofacial diseases.


Assuntos
Anormalidades Craniofaciais/fisiopatologia , Desenvolvimento Embrionário/fisiologia , Fator 8 de Crescimento de Fibroblasto/fisiologia , Regulação da Expressão Gênica no Desenvolvimento , Animais , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/metabolismo , Transição Epitelial-Mesenquimal , Fator 8 de Crescimento de Fibroblasto/genética , Fator 8 de Crescimento de Fibroblasto/metabolismo , Humanos , Desenvolvimento Maxilofacial , Boca/embriologia , Transdução de Sinais
13.
PLoS One ; 14(1): e0210097, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30629636

RESUMO

BACKGROUND: GLI2 encodes for a transcription factor that controls the expression of several genes in the Hedgehog pathway. Mutations in GLI2 have been described as causative of a spectrum of clinical phenotypes, notably holoprosencephaly, hypopituitarism and postaxial polydactyl. METHODS: In order to identify causative genetic variant, we performed exome sequencing of a trio from an Italian family with multiple affected individuals presenting clinical phenotypes in the Culler-Jones syndrome spectrum. We performed a series of cell-based assays to test the functional properties of mutant GLI2. RESULTS: Here we report a novel deletion c.3493delC (p.P1167LfsX52) in the C-terminal activation domain of GLI2. Functional assays confirmed the pathogenicity of the identified variant and revealed a dominant-negative effect of mutant GLI2 on Hedgehog signalling. CONCLUSIONS: Our results highlight the variable clinical manifestation of GLI2 mutations and emphasize the value of functional characterisation of novel gene variants to assist genetic counselling and diagnosis.


Assuntos
Anormalidades Craniofaciais/genética , Dedos/anormalidades , Proteínas Hedgehog/metabolismo , Hipopituitarismo/genética , Proteínas Nucleares/genética , Polidactilia/genética , Dedos do Pé/anormalidades , Proteína Gli2 com Dedos de Zinco/genética , Animais , Criança , Feminino , Mutação da Fase de Leitura , Células HEK293 , Hormônio do Crescimento Humano/deficiência , Humanos , Hipopituitarismo/congênito , Masculino , Camundongos , Células NIH 3T3 , Linhagem , Adeno-Hipófise/anormalidades , Transdução de Sinais/genética , Síndrome
14.
Med Hypotheses ; 122: 180-183, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30593407

RESUMO

Many world-renowned scientists and artists had autism spectrum disorder (ASD). We suggest that the French mathematician and physicist Blaise Pascal (1623-1662) also had ASD. As a boy, he demonstrated his mastery of language, mathematics and science. He showed single-mindedness and obsessive interests in the pursuit of science in his younger years and later he pursued with religion with the same determination. Pascal neglected social interactions; he was cold and aloof and had an obsessive revulsion to any expression of emotional attachment. As shown by his funerary mask and the autopsy report Pascal had craniosynostosis (primary nonsyndromic oxycephaly) with atrophy of the right half of the face. Congenital facial asymmetry due to craniosynostosis has a genetic basis. This suggests that Pascal's facial deformity may betray his propensity to suffer from genetically determined diseases including ASD. Despite the intrinsic limitations of a diagnosis based only on biographical information, we surmise that Pascal had the three key symptoms (obsessive interests, difficulty in social relationship and problems in communicating) that characterize ASD individuals.


Assuntos
Transtorno do Espectro Autista/história , Craniossinostoses/história , Predisposição Genética para Doença , Matemática/história , Transtorno do Espectro Autista/genética , Comunicação , Comorbidade , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/história , Craniossinostoses/genética , Face , Pessoas Famosas , França , História do Século XVII , Humanos , Masculino , Comportamento Obsessivo , Crânio
15.
Proteomics Clin Appl ; 13(2): e1800135, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30548811

RESUMO

BACKGROUND: Progeria-like syndromes offer a unique insight into aging. Here the case of a boy affected with mandibuloacral dysplasia and compound heterozygous mutations in ZMPSTE24 is presented. METHODS: Capillary electrophoresis-mass spectroscopy is used for proteome analysis to analyze peptides previously found to be differentially regulated in chronic kidney disease (273 peptides defining the CKD273 classifier), coronary artery disease (238 peptides defining the CAD238 classifier), and aging (116 peptides defining the AGE116 classifier). RESULTS: No evidence of renal disease is identified. Although the boy has no overt cardiovascular disease other than a raised carotid intima media thickness relative to his age, a proteomic classifier for the diagnosis of coronary artery disease is mildly raised. The biological age based on the proteomic AGE116 classifier is 24 years compared to the chronological ages of 5 and 10 years. In contrast, a control group of healthy children has a significantly lower (p < 0.0001) calculated mean age of 13. CONCLUSION: Urinary proteomic analysis is effective in confirming advanced biological age and to identify early evidence of renal or cardiovascular damage. This case highlights the value of proteomic approaches in aging research and may represent a method for non-invasive monitoring of the effects of early aging.


Assuntos
Envelhecimento/genética , Doenças do Desenvolvimento Ósseo/genética , Anormalidades Craniofaciais/genética , Heterozigoto , Proteínas de Membrana/genética , Metaloendopeptidases/genética , Mutação , Proteômica , Criança , Pré-Escolar , Humanos
17.
PLoS Genet ; 14(12): e1007535, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30586385

RESUMO

The contactin-associated protein-like 2 (CNTNAP2) gene is a member of the neurexin superfamily. CNTNAP2 was first implicated in the cortical dysplasia-focal epilepsy (CDFE) syndrome, a recessive disease characterized by intellectual disability, epilepsy, language impairments and autistic features. Associated SNPs and heterozygous deletions in CNTNAP2 were subsequently reported in autism, schizophrenia and other psychiatric or neurological disorders. We aimed to comprehensively examine evidence for the role of CNTNAP2 in susceptibility to psychiatric disorders, by the analysis of multiple classes of genetic variation in large genomic datasets. In this study we used: i) summary statistics from the Psychiatric Genomics Consortium (PGC) GWAS for seven psychiatric disorders; ii) examined all reported CNTNAP2 structural variants in patients and controls; iii) performed cross-disorder analysis of functional or previously associated SNPs; and iv) conducted burden tests for pathogenic rare variants using sequencing data (4,483 ASD and 6,135 schizophrenia cases, and 13,042 controls). The distribution of CNVs across CNTNAP2 in psychiatric cases from previous reports was no different from controls of the database of genomic variants. Gene-based association testing did not implicate common variants in autism, schizophrenia or other psychiatric phenotypes. The association of proposed functional SNPs rs7794745 and rs2710102, reported to influence brain connectivity, was not replicated; nor did predicted functional SNPs yield significant results in meta-analysis across psychiatric disorders at either SNP-level or gene-level. Disrupting CNTNAP2 rare variant burden was not higher in autism or schizophrenia compared to controls. Finally, in a CNV mircroarray study of an extended bipolar disorder family with 5 affected relatives we previously identified a 131kb deletion in CNTNAP2 intron 1, removing a FOXP2 transcription factor binding site. Quantitative-PCR validation and segregation analysis of this CNV revealed imperfect segregation with BD. This large comprehensive study indicates that CNTNAP2 may not be a robust risk gene for psychiatric phenotypes.


Assuntos
Proteínas de Membrana/genética , Transtornos Mentais/genética , Proteínas do Tecido Nervoso/genética , Transtorno do Espectro Autista/genética , Transtorno Bipolar/genética , Anormalidades Craniofaciais/genética , Variações do Número de Cópias de DNA , Bases de Dados de Ácidos Nucleicos , Epilepsias Parciais/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Íntrons , Masculino , Malformações do Desenvolvimento Cortical/genética , Linhagem , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Esquizofrenia/genética , Deleção de Sequência
18.
Rom J Morphol Embryol ; 59(3): 985-988, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30534844

RESUMO

The co-occurrence in the same individual of two numerical chromosomal abnormalities (double aneuploidy) is a very rare condition, especially for autosomes. Clinical presentations are variable depending on the predominating aneuploidy. The authors present a rare case of a male infant with multiple congenital anomalies: craniofacial dysmorphism, short neck, agenesis of the corpus callosum, ventricular septal defect, bilateral broad hallux, large first interdigital space of the toes, plantar furrows, prominent calcaneus and right kidney agenesis. The karyotype identified 82% of mitosis with trisomy 8 (47,XY,+8) and 18% with trisomy 21 (47,XY,+21). The evolution was fatal because of eating difficulties, severe growth retardation and recurrent respiratory infections. He died at the age of five months. We report this case as a very rare double autosomal mosaicism, with a complete clinical and morphological description, as the first documented case in Romania.


Assuntos
Aneuploidia , Anormalidades Craniofaciais/genética , Trissomia/genética , Anormalidades Craniofaciais/patologia , Humanos , Recém-Nascido , Masculino , Mosaicismo , Trissomia/patologia
19.
Medicine (Baltimore) ; 97(50): e13644, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30558059

RESUMO

RATIONALE: Spondyloenchondrodysplasia (SPENCD) is an autosomal recessive skeletal dysplasia by biallelic mutations in ACP5 gene encoding tartrate-resistant acid phosphatase (TRAP). The extra-osseous phenotype of SPENCD is pleiotropic and involves neurological impairment and immune dysfunction. Dentofacial abnormalities and orofacial symptoms in SPENCD patients have been little discussed in the literature. PATIENTS CONCERNS: Herein we present clinical and radiological data regarding 2 siblings with SPENCD. Both patients exhibited short stature, cervical platyspondyly, growth disturbance with multiple skeletal deformities of the wrist, and systemic lupus erythematosus related autoimmunity. They experienced prolonged pain in the temporomandibular joint (TMJ) area and exhibited delayed dental development. One patient presented with midface hypoplasia, retrognathic mandible, and anterior openbite. Computed tomographic images demonstrated delayed spheno-occipital synchondrosis, obtuse cranial base angle, overdeveloped and anteriorly displaced sphenoidal sinuses, and compressed ethmoidal sinuses. DIAGNOSIS: The genetic analysis revealed heterozygous for a missense mutations at ACP5 in both probands. INTERVENTIONS: Routine follow-up with conservative treatment were conducted for 12 months. OUTCOMES: The elder sister's orofacial pain was relieved but the boy showed sustained masticatory and cervical muscle pain and TMJ arthralgia which had changed in accordance with systemic condition. No further teeth eruption or skeletal growth was observed in 2 siblings during the follow-up period. LESSONS: These findings extend the phenotypic spectrum of SPENCD and indicate that compromised endochondral ossification and the loss of TRAP activity may affect altered dentofacial development and orofacial symptoms.


Assuntos
Doenças Autoimunes , Tratamento Conservador/métodos , Anormalidades Craniofaciais , Lúpus Eritematoso Sistêmico , Osteocondrodisplasias , Fosfatase Ácida Resistente a Tartarato/genética , Articulação Temporomandibular , Adolescente , Assistência ao Convalescente , Artralgia/diagnóstico , Artralgia/etiologia , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Doenças Autoimunes/fisiopatologia , Anormalidades Craniofaciais/diagnóstico , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/imunologia , Anormalidades Craniofaciais/fisiopatologia , Feminino , Humanos , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/etiologia , Masculino , Mutação de Sentido Incorreto , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/genética , Osteocondrodisplasias/imunologia , Osteocondrodisplasias/fisiopatologia , Articulação Temporomandibular/diagnóstico por imagem , Articulação Temporomandibular/fisiopatologia , Tomografia Computadorizada por Raios X/métodos , Erupção Dentária
20.
BMC Neurol ; 18(1): 150, 2018 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-30236064

RESUMO

BACKGROUND: Noonan syndrome-like disorder with loose anagen hair-2 (NSLH2) is an extremely rare disease caused by a heterozygous mutation in the PPP1CB gene on chromosome 2p23. The syndrome causes not only numerous dysmorphic features but also hypotonia, developmental delay, and even intellectual disability. We report the first case of NSLH2 in Asia and the 16th in the world. Moreover, the first case of PPP1CB-related infantile spasms. The clinical and therapeutic significance is outlined in this paper. CASE PRESENTATION: We found a male infant presented with severe intractable epileptic spasms. Although certain clinical features of somatic dysmorphism were noted, numerous laboratory and neuroimaging studies failed to identify the cause. To determine the underlying etiology, whole-exome sequencing was conducted. We identified a de novo heterozygous mutation, NM_206876.1: c.548A > C (p.Glu183Ala), in the PPP1CB gene. His seizures were almost refractory to conventional antiepileptic drugs but relative seizure control was eventually achieved with a ketogenic diet. CONCLUSION: This result expands the clinical spectrum of NSLH2 and strengthens the association between the PPP1CB gene and epileptic seizures. Furthermore, we suggest that the ketogenic diet can offer seizure reduction in particular drug-resistant epilepsy syndromes. Additional studies are warranted to clarify the pathogenic mechanisms underlying this PPP1CB mutation in epileptic seizures.


Assuntos
Doenças do Recém-Nascido/genética , Proteína Fosfatase 1/genética , Espasmos Infantis/genética , Anormalidades Craniofaciais/genética , Deficiências do Desenvolvimento/genética , Dieta Cetogênica , Heterozigoto , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/genética , Masculino , Hipotonia Muscular/genética , Mutação , Neuroimagem , Espasmos Infantis/dietoterapia
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