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1.
Am J Med Genet A ; 170(6): 1573-9, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27028100

RESUMO

Thanatophoric dysplasia is a type of short-limbed neonatal dwarfism that is usually lethal in the perinatal period. It is characterized by short limbs, a narrow, bell-shaped thorax, macrocephaly with a prominent forehead, and flattened vertebral bodies. These malformations result from autosomal dominant mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. In this report, we describe a novel FGFR3 insertion mutation in a fetus with shortened limbs, curved femurs, and a narrow thorax. The diagnosis of thanatophoric dysplasia type 1 was suspected clinically, and FGFR3 sequencing showed a c.742_743insTGT variant, which predicts p.R248delinsLC. In vivo studies in zebrafish demonstrated that this mutation resulted in the overexpression of zebrafish Fgfr3, leading to the over-activation of downstream signaling and dorsalized embryos. To date, no insertions or deletions in FGFR3 have been reported to cause thanatophoric dysplasia types 1 or 2; therefore, this represents the first report to describe such a mutation. © 2016 Wiley Periodicals, Inc.


Assuntos
Estudos de Associação Genética , Mutagênese Insercional , Fenótipo , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/deficiência , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Displasia Tanatofórica/diagnóstico , Displasia Tanatofórica/genética , Aborto Induzido , Alelos , Animais , Autopsia , Éxons , Feminino , Feto , Expressão Gênica , Genótipo , Humanos , Mutação , Gravidez , Peixe-Zebra
2.
Am J Med Genet A ; 164A(2): 516-21, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24311527

RESUMO

An adolescent female presented with intellectual disability, stimulus-induced drop episodes (SIDEs), facial characteristics that include wide set eyes, short nose with wide columella, full and everted lips with wide mouth and progressive skeletal changes: scoliosis, spondylolisthesis and pectus excavatum. These findings were suggestive of Coffin-Lowry syndrome (CLS), and this was confirmed by the identification of a novel mutation in RPS6KA3, a heterozygous one basepair duplication at nucleotide 1570 (c.1570dupA). This mutation occurs within the C-terminal kinase domain of the protein, and, therefore contradicts the previous report that SIDEs is only associated with premature truncation of the protein in the N-terminal kinase domain or upstream of this domain. As CLS is X-linked, it is unusual for a female to have such a classic phenotype.


Assuntos
Síndrome de Coffin-Lowry/diagnóstico , Síndrome de Coffin-Lowry/genética , Genótipo , Fenótipo , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Criança , Pré-Escolar , Análise Mutacional de DNA , Fácies , Feminino , Humanos , Lactente , Mutação , Domínios e Motivos de Interação entre Proteínas , Radiografia , Proteínas Quinases S6 Ribossômicas 90-kDa/química , Escoliose/diagnóstico por imagem , Escoliose/genética
3.
Am J Med Genet A ; 164A(9): 2391-7, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24924585

RESUMO

Cenani-Lenz syndrome (CLS) is an autosomal recessive skeletal dysplasia that results in malformations of the distal limb, renal anomalies, and characteristic facies. In 2010, this condition was found to be caused by mutations in LRP4, a member of the low-density lipoprotein family of receptors. LRP4 has been shown to antagonize LRP5/LRP6 activation of WNT and ß-catenin signaling. Loss of LRP4 function leads to excessive Wnt and ß-catenin signaling in the limb bud, which causes abnormal limb development. The large majority of patients with CLS reported in the literature have splicing and missense mutations, which result in syndactyly, oligodactyly, and minor renal malformations. More recently, a patient with CLS has been identified with a homozygous nonsense mutation and a more severe presentation of findings typically associated with this condition. Here we present two sibling fetuses with a prenatal lethal presentation of mesomelic limb reductions, oligosyndactyly, genitourinary malformation and compound heterozygosity for two novel truncating mutations in LRP4. These findings lend further support to the CLS genotype-phenotype correlation presented in recent publications.


Assuntos
Feto/anormalidades , Proteínas Relacionadas a Receptor de LDL/genética , Mutação/genética , Sindactilia/genética , Evolução Fatal , Feminino , Feto/diagnóstico por imagem , Humanos , Masculino , Linhagem , Mudanças Depois da Morte , Radiografia , Irmãos
4.
Mol Genet Metab ; 110(4): 484-9, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24144945

RESUMO

Congenital disorders of glycosylation are a group of metabolic disorders with an expansive and highly variable clinical presentation caused by abnormal glycosylation of proteins and lipids. Dolichol kinase (DOLK) catalyzes the final step in biosynthesis of dolichol phosphate (Dol-P), which is the oligosaccharide carrier required for protein N-glycosylation. Human DOLK deficiency, also known as DOLK-CDG or CDG-Im, results in a syndrome that has been reported to manifest with dilated cardiomyopathy of variable severity. A male neonate born to non-consanguineous parents of Palestinian origin presented with dysmorphic features, genital abnormalities, talipes equinovarus, and severe, refractory generalized seizures. Additional multi-systemic manifestations developed including dilated cardiomyopathy, hepatomegaly, severe insulin-resistant hyperglycemia, and renal failure, which were ultimately fatal at age 9months. Electrospray ionization mass spectrometric (ESI-MS) analysis of transferrin identified a type I congenital disorder of glycosylation; next-generation sequencing demonstrated homozygous p.Q483K DOLK mutations that were confirmed in patient fibroblasts to result in severely reduced substrate binding and catalytic activity. This patient expands the phenotype of DOLK-CDG to include anatomic malformations and multi-systemic dysfunction.


Assuntos
Cardiomiopatia Dilatada/patologia , Defeitos Congênitos da Glicosilação/patologia , Metabolismo dos Lipídeos/genética , Fosfotransferases (Aceptor do Grupo Álcool)/deficiência , Sequência de Aminoácidos , Cardiomiopatia Dilatada/complicações , Cardiomiopatia Dilatada/genética , Defeitos Congênitos da Glicosilação/complicações , Defeitos Congênitos da Glicosilação/genética , Defeitos Congênitos da Glicosilação/mortalidade , Dolicóis/metabolismo , Evolução Fatal , Glicosilação , Homozigoto , Humanos , Recém-Nascido , Masculino , Mutação , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo
5.
Am J Med Genet A ; 161A(6): 1432-5, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23613309

RESUMO

A male child with clinical features consistent with EEC/EECUT plus syndrome (ectrodactyly, ectodermal dysplasia, clefting, urinary tract abnormalities, and thymic abnormalities) including mild ectodermal abnormalities, ectrodactyly of hands and feet, cleft palate, bilateral hydronephrosis, and T cell lymphopenia is reported. He was noted to have T cell receptor excision circle (TREC) analysis below the cutoff for normal on newborn screening and T cell lymphopenia on further immunologic evaluation. A novel, presumably pathogenic de novo 3 bp deletion in exon 7 of TP63 (c.970_972delATT; NCBI Reference Sequence NM_003722.4) was identified. This observation provides supporting evidence for the association between TP63 mutations and EECUT plus syndrome. Clinicians caring for infants presenting with EEC spectrum disorders in the newborn period should also consider the possibility of T cell lymphopenia.


Assuntos
Fissura Palatina/genética , Displasia Ectodérmica/genética , Deformidades Congênitas dos Membros/genética , Linfopenia/genética , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , Sequência de Bases , Criança , Fenda Labial/diagnóstico , Fenda Labial/genética , Fissura Palatina/diagnóstico , Displasia Ectodérmica/diagnóstico , Éxons/genética , Genótipo , Humanos , Hidronefrose/diagnóstico , Hidronefrose/genética , Hibridização in Situ Fluorescente , Deformidades Congênitas dos Membros/diagnóstico , Linfopenia/diagnóstico , Masculino , Fenótipo , Deleção de Sequência , Linfócitos T/patologia
6.
Genet Med ; 13(3): 255-62, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21173700

RESUMO

PURPOSE: We report a male child who presented at 15 months with perianal abscesses and proctitis, progressing to transmural pancolitis with colocutaneous fistulae, consistent with a Crohn disease-like illness. The age and severity of the presentation suggested an underlying immune defect; however, despite comprehensive clinical evaluation, we were unable to arrive at a definitive diagnosis, thereby restricting clinical management. METHODS: We sought to identify the causative mutation(s) through exome sequencing to provide the necessary additional information required for clinical management. RESULTS: After sequencing, we identified 16,124 variants. Subsequent analysis identified a novel, hemizygous missense mutation in the X-linked inhibitor of apoptosis gene, substituting a tyrosine for a highly conserved and functionally important cysteine. X-linked inhibitor of apoptosis was not previously associated with Crohn disease but has a central role in the proinflammatory response and bacterial sensing through the NOD signaling pathway. The mutation was confirmed by Sanger sequencing in a licensed clinical laboratory. Functional assays demonstrated an increased susceptibility to activation-induced cell death and defective responsiveness to NOD2 ligands, consistent with loss of normal X-linked inhibitor of apoptosis protein function in apoptosis and NOD2 signaling. CONCLUSIONS: Based on this medical history, genetic and functional data, the child was diagnosed as having an X-linked inhibitor of apoptosis deficiency. Based on this finding, an allogeneic hematopoietic progenitor cell transplant was performed to prevent the development of life-threatening hemophagocytic lymphohistiocytosis, in concordance with the recommended treatment for X-linked inhibitor of apoptosis deficiency. At >42 days posttransplant, the child was able to eat and drink, and there has been no recurrence of gastrointestinal disease, suggesting this mutation also drove the gastrointestinal disease. This report describes the identification of a novel cause of inflammatory bowel disease. Equally importantly, it demonstrates the power of exome sequencing to render a molecular diagnosis in an individual patient in the setting of a novel disease, after all standard diagnoses were exhausted, and illustrates how this technology can be used in a clinical setting.


Assuntos
Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/genética , Análise de Sequência de DNA , Sequência de Aminoácidos , Éxons , Transplante de Células-Tronco Hematopoéticas , Humanos , Lactente , Doenças Inflamatórias Intestinais/terapia , Masculino , Dados de Sequência Molecular , Mutação , Alinhamento de Sequência , Resultado do Tratamento , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética
7.
Mol Genet Metab ; 100(1): 51-6, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20138557

RESUMO

Sanfilippo syndrome type B (mucopolysaccharidosis IIIB) is an autosomal recessive disease that is caused by a deficiency of the lysosomal enzyme alpha-N-acetylglucosaminidase (NAGLU). Over 100 different mutations in the NAGLU gene have been identified in Sanfilippo syndrome type B patients; however, no large deletions have been reported. Here we present the first case of a large homozygous intragenic NAGLU gene deletion identified in an affected child of consanguineous parents. Long range and multiplex PCR methods were used to characterize this deletion which encompasses exons 3 and 4 and is 1146 base pairs long. We propose that Alu element-mediated unequal homologous recombination between an Alu-Y in intron 2 and an Alu-Sx in intron 4 is the likely mechanism for this deletion, thereby contributing further insight into the molecular etiology of this disorder and providing additional evidence of its allelic heterogeneity.


Assuntos
Acetilglucosaminidase/genética , Mucopolissacaridose III/genética , Sequência de Bases , Criança , Consanguinidade , Feminino , Humanos , Lactente , Dados de Sequência Molecular , Mucopolissacaridose III/enzimologia , Linhagem , Deleção de Sequência
8.
BMJ Open ; 6(4): e009537, 2016 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-27130160

RESUMO

BACKGROUND: X linked intellectual disability (XLID) syndromes account for a substantial number of males with ID. Much progress has been made in identifying the genetic cause in many of the syndromes described 20-40 years ago. Next generation sequencing (NGS) has contributed to the rapid discovery of XLID genes and identifying novel mutations in known XLID genes for many of these syndromes. METHODS: 2 NGS approaches were employed to identify mutations in X linked genes in families with XLID disorders. 1 involved exome sequencing of genes on the X chromosome using the Agilent SureSelect Human X Chromosome Kit. The second approach was to conduct targeted NGS sequencing of 90 known XLID genes. RESULTS: We identified the same mutation, a c.12928 G>C transversion in the HUWE1 gene, which gives rise to a p.G4310R missense mutation in 2 XLID disorders: Juberg-Marsidi syndrome (JMS) and Brooks syndrome. Although the original families with these disorders were considered separate entities, they indeed overlap clinically. A third family was also found to have a novel HUWE1 mutation. CONCLUSIONS: As we identified a HUWE1 mutation in an affected male from the original family reported by Juberg and Marsidi, it is evident the syndrome does not result from a mutation in ATRX as reported in the literature. Additionally, our data indicate that JMS and Brooks syndromes are allelic having the same HUWE1 mutation.


Assuntos
Cromossomos Humanos X/genética , Surdez/genética , Transtornos do Crescimento/genética , Hipogonadismo/genética , Deficiência Intelectual Ligada ao Cromossomo X/genética , Espasticidade Muscular/genética , Ubiquitina-Proteína Ligases/genética , Adolescente , Adulto , Criança , Exoma , Fácies , Doenças Genéticas Ligadas ao Cromossomo X , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Deficiência Intelectual , Masculino , Megalencefalia , Pessoa de Meia-Idade , Mutação , Proteínas Supressoras de Tumor , Adulto Jovem
9.
Stroke ; 36(9): 1848-51, 2005 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16100023

RESUMO

BACKGROUND AND PURPOSE: Endothelial nitric oxide exerts a variety of protective effects on endothelial cells and blood vessels, and therefore the nitric oxide synthase 3 gene (NOS3) is a logical candidate gene for stroke susceptibility. METHODS: We used the population-based Stroke Prevention in Young Women case-control study to assess the association of five NOS3 polymorphisms in 110 cases (46% black) with ischemic stroke and 206 controls (38% black), 15 to 44 years of age. Polymorphisms included 3 single nucleotide polymorphisms (SNPs) in the promoter region (-1468 T>A, -922 G>A, -786 T>C), 1 SNP in exon 7 (G894T), and 1 insertion/deletion polymorphism within intron 4. RESULTS: Significant associations with both the -922 G>A and -786 T>C SNPs with ischemic stroke were observed in the black, but not the white, population. This association was attributable to an increased prevalence of the -922 A allele (OR=3.0, 95% CI=1.3 to 6.8; P=0.005) and the -786 T allele (OR=2.9, 95% CI=1.3 to 6.4; P=0.005) in cases versus controls. These 2 SNPs were in strong linkage disequilibrium (D'=1.0), making it impossible to determine, within the confines of this genetic study, whether 1 or both of these polymorphisms are functionally related to NOS3 expression. Two sets of haplotypes were also identified, 1 of which may confer an increased susceptibility to stroke in blacks, whereas the other appears to be protective. CONCLUSIONS: Promoter variants in NOS3 may be associated with ischemic stroke susceptibility among young black women.


Assuntos
Isquemia Encefálica/etnologia , Isquemia Encefálica/genética , Predisposição Genética para Doença , Óxido Nítrico Sintase Tipo III/genética , Polimorfismo Genético , Acidente Vascular Cerebral/etnologia , Acidente Vascular Cerebral/genética , Adolescente , Adulto , Alelos , População Negra , Estudos de Casos e Controles , Éxons , Feminino , Deleção de Genes , Variação Genética , Genótipo , Haplótipos , Humanos , Íntrons , Desequilíbrio de Ligação , Modelos Genéticos , Óxido Nítrico , Razão de Chances , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Risco , População Branca
10.
Curr Protoc Hum Genet ; 80: 9.5.1-9.5.19, 2014 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-24510684

RESUMO

The gene responsible for Fragile X syndrome, fragile X mental retardation-1 (FMR1), contains an unstable sequence of CGG trinucleotide repeats in its promoter region. Expansions of >200 trinucleotide repeats are considered full mutations and typically lead to abnormal methylation of the region, resulting in loss of FMR1 expression. Males with loss of FMR1 protein are expected to be affected by Fragile X syndrome, while females may or may not clinically manifest features of the condition. The protocols in this unit outline the complementary use of polymerase chain reaction (PCR) and methylation-sensitive Southern blot hybridization to accurately measure trinucleotide repeat size and methylation status. These protocols are also used to evaluate CGG repeat size in two adult-onset conditions known for their association with FMR1 premutation alleles, Fragile X Tremor/Ataxia (FXTAS) syndrome and Premature Ovarian Failure (POF).


Assuntos
Ataxia/diagnóstico , Ataxia/genética , Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/diagnóstico , Síndrome do Cromossomo X Frágil/genética , Testes Genéticos/métodos , Tremor/diagnóstico , Tremor/genética , Expansão das Repetições de Trinucleotídeos/genética , Composição de Bases/genética , Southern Blotting , Feminino , Deleção de Genes , Predisposição Genética para Doença , Humanos , Masculino , Reação em Cadeia da Polimerase/métodos , Insuficiência Ovariana Primária/diagnóstico , Regiões Promotoras Genéticas
12.
Genet Test Mol Biomarkers ; 16(6): 465-70, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22224633

RESUMO

AIMS: Most individuals with intellectual disability and/or autism are tested for Fragile X syndrome at some point in their lifetime. Greater than 99% of individuals with Fragile X have an expanded CGG trinucleotide repeat motif in the promoter region of the FMR1 gene, and diagnostic testing involves determining the size of the CGG repeat as well as methylation status when an expansion is present. RESULTS: Using a previously described triplet repeat-primed polymerase chain reaction, we have performed additional validation studies using two cohorts with previous diagnostic testing results available for comparison purposes. The first cohort (n=88) consisted of both males and females and had a high percentage of abnormal samples, while the second cohort (n=624) consisted of only females and was not enriched for expansion mutations. Data from each cohort were completely concordant with the results previously obtained during the course of diagnostic testing. CONCLUSIONS: This study further demonstrates the utility of using laboratory-developed triplet repeat-primed FMR1 testing in a clinical setting.


Assuntos
Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/diagnóstico , Expansão das Repetições de Trinucleotídeos/genética , Alelos , Estudos de Coortes , Feminino , Síndrome do Cromossomo X Frágil/genética , Humanos , Deficiência Intelectual , Masculino , Mutação , Reação em Cadeia da Polimerase/métodos , Fatores de Tempo
13.
Curr Protoc Hum Genet ; Chapter 9: Unit 9.5, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19806593

RESUMO

The gene responsible for Fragile X syndrome, fragile X mental retardation-1 (FMR1), contains an unstable sequence of CGG trinucleotide repeats in its promoter region. Expansions of >200 trinucleotide repeats are considered full mutations and typically lead to abnormal methylation of the region resulting in loss of FMR1 expression. Males with loss of FMR1 protein are expected to be affected by Fragile X syndrome while females may or may not clinically manifest features of the condition. The protocols in this unit outline the complementary use of polymerase chain reaction (PCR) and methylation-sensitive Southern blot hybridization to accurately measure trinucleotide repeat size and methylation status. These protocols are also used to evaluate CGG repeat size in two adult-onset conditions known for their association with FMR1 premutation alleles, Fragile X Tremor/Ataxia (FXTAS) syndrome and Premature Ovarian Failure (POF).


Assuntos
Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/genética , Southern Blotting , Feminino , Humanos , Masculino , Reação em Cadeia da Polimerase , Repetições de Trinucleotídeos
15.
J Allergy Clin Immunol ; 114(1): 80-7, 2004 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15241348

RESUMO

BACKGROUND: The role of variation in the IL4 gene in asthma and allergy susceptibility is controversial. This cytokine is important in IgE isotype switching and the regulation of allergic inflammation; however, published studies have not delineated the specific role of variation in this gene in allergic disorders. OBJECTIVE: We sought to identify single nucleotide polymorphisms (SNPs) in IL4 and to evaluate the association of SNPs and haplotypes with asthma and allergic phenotypes (total serum IgE) in white, African American, and Hispanic asthmatic populations. METHODS: Sixteen individuals were resequenced, and 19 SNPs were identified; 2 novel and 17 SNPs were previously reported. Eleven of the SNPs were used to evaluate association in the 3 groups. RESULTS: Nine polymorphisms were associated with total serum IgE levels in white subjects (.0012 < or = P < or =.034), and 5 of these were also associated with asthma in this population (.010 < or = P < or =.031). Three common haplotypes were observed, and all were associated with either high or low serum IgE levels in white subjects (.00008 < or = P < or =.004). Inspection of the haplotypes revealed that 3017 G/T in intron 2 was the only SNP concordant with serum IgE levels (G allele with lower levels and T allele with higher levels). CONCLUSIONS: After a comprehensive genetic evaluation, our data suggest that the 3017 G/T variant or the haplotype it identifies influences IL4's ability to modulate total serum IgE levels. Inconsistencies with previously reported IL4 associations might be due to population differences in allele frequencies, the extent of linkage disequilibrium with this SNP or haplotype, or both.


Assuntos
Asma/genética , Imunoglobulina E/genética , Interleucina-4/genética , Grupos Populacionais/genética , Adolescente , Adulto , Negro ou Afro-Americano/genética , Estudos de Casos e Controles , Criança , Feminino , Haplótipos/genética , Hispânico ou Latino/genética , Humanos , Hipersensibilidade/genética , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , População Branca/genética
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