RESUMO
Disease associated chromosomal rearrangements often have break points located within disease causing genes or in their vicinity. The purpose of this study is to characterize a balanced reciprocal translocation in a girl with intellectual disability and seizures by positional cloning and whole genome sequencing. The translocation was identification by G- banding and confirmed by WCP FISH. Fine mapping using BAC clones and whole genome sequencing using Oxford nanopore long read sequencing technology for a 1.46 X coverage of the genome was done. The positional cloning showed split signals with BAC RP11-943â¯J20. Long read sequencing analysis of chimeric reads carrying parts of chromosomes X and 20 helped to identify the breakpoints to be in intron 2 of ARHGEF9 gene on Xp11.1 and on 20p13 between RASSF2 and SLC23A2 genes. This is the first report of translocation which successfully delineated to single base resolution using Nanopore sequencing. The genotype-phenotype correlation is discussed.
Assuntos
Pontos de Quebra do Cromossomo , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 20/genética , Cromossomos Humanos X/genética , Translocação Genética , Pré-Escolar , Transtornos Cromossômicos/diagnóstico , Feminino , Testes Genéticos/métodos , Humanos , Fatores de Troca de Nucleotídeo Guanina Rho/genética , Análise de Sequência de DNA/métodos , Transportadores de Sódio Acoplados à Vitamina C/genética , Proteínas Supressoras de Tumor/genéticaRESUMO
Complex Camptosynpolydactyly is an autosomal recessive disorder characterized by complex hand deformities described earlier by us in a consanguineous family. We report on identification of mutations in BHLHA9 gene in this condition. Our results indicate that Complex Camptosynpolydactyly and Mesoaxial synostotic syndactyly with phalangeal reduction (MSSD) are likely to be allelic disorders. © 2016 Wiley Periodicals, Inc.
Assuntos
Alelos , Dedos/anormalidades , Deformidades Congênitas do Pé/diagnóstico , Deformidades Congênitas do Pé/genética , Estudos de Associação Genética , Deformidades Congênitas da Mão/diagnóstico , Deformidades Congênitas da Mão/genética , Mutação , Sinostose/genética , Dedos do Pé/anormalidades , Sequência de Aminoácidos , Consanguinidade , Feminino , Genótipo , Humanos , Recém-Nascido , Análise de Sequência com Séries de Oligonucleotídeos , Linhagem , Polidactilia , Polimorfismo de Nucleotídeo Único , Radiografia , Sindactilia/genética , Sinostose/diagnósticoRESUMO
We report on a sib pair of Indian origin presenting with intellectual disability, dysmorphism, and macrocephaly. Exome sequencing revealed a homozygous splice site HERC1 mutation in both probands. Functional analysis revealed use of an alternate splice site resulting in formation of a downstream stop codon and nonsense mediated decay. In the light of recent reports of HERC1 mutations in two families with a similar phenotypic presentation, this report reiterates the pathogenic nature and clinical consequences of HERC1 disruption. © 2016 Wiley Periodicals, Inc.
Assuntos
Predisposição Genética para Doença , Fatores de Troca do Nucleotídeo Guanina/genética , Deficiência Intelectual/genética , Megalencefalia/genética , Criança , Pré-Escolar , Face/fisiopatologia , Feminino , Homozigoto , Humanos , Deficiência Intelectual/fisiopatologia , Masculino , Megalencefalia/fisiopatologia , Mutação , Linhagem , Fenótipo , Sítios de Splice de RNA/genética , Ubiquitina-Proteína LigasesAssuntos
Agenesia do Corpo Caloso/genética , Catarata/genética , Malformações do Sistema Nervoso/genética , Proteínas/genética , Idade de Início , Agenesia do Corpo Caloso/diagnóstico por imagem , Agenesia do Corpo Caloso/mortalidade , Agenesia do Corpo Caloso/fisiopatologia , Proteínas Relacionadas à Autofagia , Autopsia , Catarata/diagnóstico por imagem , Catarata/mortalidade , Catarata/fisiopatologia , Feminino , Feto , Humanos , Proteínas de Membrana Lisossomal , Malformações do Sistema Nervoso/mortalidade , Malformações do Sistema Nervoso/fisiopatologia , Gravidez , Segundo Trimestre da Gravidez , Irmãos , Proteínas de Transporte VesicularRESUMO
BACKGROUND: Arecanut and smokeless tobacco usage is a major cause for oral submucous fibrosis (OSF) and its subsequent development to oral squamous cell carcinoma in South-east Asian population. Polymorphisms at N-acetyltransferase 2 locus, coding for an enzyme catalyzing acetylation of aromatic amines, might cause DNA adduct formation because of improper acetylation of these polyaromatic hydrocarbons. DNA repair enzymes remove these adduct to prevent malignancy. METHODS: In this hospital-based study, 100 controls and 88 OSF patients were genotyped at four polymorphic sites on NAT2 481 (C > T; silent), 590 (G > A; Arg197 > Gln), 803 (A > G; Lys268 > Arg), 857 (G > A; Gly286 > Glu) and two on XRCC1 18067 (C > T Arg 194 > Trp), 28152 (G > A Arg 399 > Gln), and one of XRCC3 26304 (C > T Thr 241 > Met) loci by PCR-RFLP to determine the risk of the disease. RESULTS: Heterozygous XRCC3 codon 241 [OR 2.07 (1.05-4.06)], homozygous variant of NAT C481T [OR 2.81 (1.09-7.21)], and both heterozygous and homozygous variants of NAT codon 268 and 286 [OR 2.31 (1.20-4.45) and 4.98 (1.87-13.14), and 6.12 (2.75-13.62) and 2.65 (1.04-6.72)] individually influenced susceptibility to OSF in the population. CONCLUSION: Gene-gene interaction analysis by multifactor dimensionality reduction (MDR) revealed that XRCC3 Thr 241 Met had the largest univariate effect followed by XRCC3 Thr 241 Met - NAT2 A857G in men that presents a highly synergistic interaction as one of the potential combinations of single nucleotide polymorphisms (SNPs) to increase the risk of OSF in men if exposed to arecanut or smokeless tobacco usage. These observations can speculate the impact of the studied SNPs on the etiology of OSF.
Assuntos
Arilamina N-Acetiltransferase/genética , Reparo do DNA/genética , Proteínas de Ligação a DNA/genética , Fibrose Oral Submucosa/genética , Polimorfismo Genético/genética , Adulto , Areca/efeitos adversos , Arginina/genética , Estudos de Casos e Controles , Códon/genética , Feminino , Predisposição Genética para Doença/genética , Ácido Glutâmico/genética , Glutamina/genética , Glicina/genética , Heterozigoto , Homozigoto , Humanos , Índia , Lisina/genética , Masculino , Metionina/genética , Redução Dimensional com Múltiplos Fatores , Fibrose Oral Submucosa/enzimologia , Polimorfismo de Fragmento de Restrição/genética , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Treonina/genética , Tabaco sem Fumaça/efeitos adversos , Triptofano/genética , Proteína 1 Complementadora Cruzada de Reparo de Raio-XAssuntos
Exoma/genética , Sequenciamento de Nucleotídeos em Larga Escala , Deficiência Intelectual/genética , Espasticidade Muscular/genética , Atrofia Óptica/genética , Ataxias Espinocerebelares/genética , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Pré-Escolar , Consanguinidade , Feminino , Humanos , Deficiência Intelectual/etiologia , Deficiência Intelectual/patologia , Espasticidade Muscular/etiologia , Espasticidade Muscular/patologia , Atrofia Óptica/etiologia , Atrofia Óptica/patologia , Radiografia , Ataxias Espinocerebelares/etiologia , Ataxias Espinocerebelares/patologiaRESUMO
BACKGROUND & OBJECTIVE: Screening for Fragile X syndrome (FRAXA), the most common genetic cause for mental retardation (MR), has mostly been carried out among MR patients. The present study was conducted to find out prevalence of FRAXA amongst children residing in the rural areas of West Bengal. METHODS: Demographic details including age, sex, nutritional status as well as birth, medical, and developmental histories, were collected amongst rural children (n=38,803) of West Bengal, India, over three years (2004-2007). Based on the records of scholastic backwardness, 179 children were short-listed and examined by a team of experts comprising of child psychiatrist, clinical psychologist, paediatrician and special educator. Blood samples were collected and molecular and cytogenetic studies were performed for identification of CGG repeats and determination of FMR1 gene promoter methylation. RESULTS: Of the selected 179 children, six were diagnosed as Down syndrome, one as cerebral palsy and 140 as non-syndromic MR. These 140 children with MR were grouped as mild (56), moderate (60), and severely (4) retarded based on IQ; children <5 yr were grouped as developmental delay (20). FRAXA was not detected in any of these children (frequency being 0% with 0-.02% confidence interval). Prevalence of MR was found to be low (about 4/1000 children). Down syndrome also had a lower frequency (0.15/1000 children). INTERPRETATION & CONCLUSION: The data obtained in the present study indicated that familial disorders like FRAXA were less frequent in the studied population.
Assuntos
Síndrome do Cromossomo X Frágil/epidemiologia , Criança , Pré-Escolar , Metilação de DNA , Feminino , Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/genética , Humanos , Índia/epidemiologia , Deficiência Intelectual/epidemiologia , Deficiência Intelectual/genética , Masculino , Programas de Rastreamento , Regiões Promotoras Genéticas , População Rural , Expansão das Repetições de TrinucleotídeosRESUMO
Intellectual disability (ID) is of major concern throughout the world, though in ~40% of cases etiology remains unknown (idiopathic ID or IID). Cognitive impairment and behavioral problems are of common occurrence in these subjects and dopamine is known to play an important role in regulating these traits. In the present study the role of functional polymorphisms in three dopaminergic genes, dopamine receptor D4 (DRD4: exon3 VNTR and rs1800955), dopamine transporter (DAT1: 3'UTR VNTR and intron8 VNTR) and catechol-O-methyl transferase (COMT: rs4680 and rs165599), was explored in IID. Probands (n=225), parents (n=298) and ethnically matched controls (n=175) were recruited following DSM-IV. Genotype data obtained was used for population- and family-based statistical analyses. Population-based analysis showed significant association of DRD4 exon3 VNTR 6R allele (P=0.01), DAT1 3'UTR VNTR lower repeat (6R and 7R) alleles (P<0.02) and intron8 VNTR 5R allele (P=0.0012) with IID. Stratified analysis revealed significant association of these alleles (P<0.05) with IID individuals exhibiting severe behavioral problems. On the other hand, preferential transmission of COMT rs4680 A allele and A-A haplotype (P<0.05) was observed specifically in male IID probands without any behavioral problem. Markers failed to show any significant epistatic interaction by MDR analysis. Alleles showing positive association were all reported to confer suboptimal activity to the transcribed proteins. Therefore, an alteration in dopaminergic neurotransmission could be predicted that may lead to impairments in cognition and behavioral problems.
Assuntos
Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Dopamina/genética , Predisposição Genética para Doença , Deficiência Intelectual/genética , Repetições Minissatélites/genética , Receptores de Dopamina D4/genética , Alelos , Catecol O-Metiltransferase/genética , Criança , Pré-Escolar , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Epistasia Genética/fisiologia , Éxons/fisiologia , Feminino , Genótipo , Haplótipos/fisiologia , Humanos , Deficiência Intelectual/etiologia , Masculino , Transtornos Mentais/genética , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único , Receptores de Dopamina D4/metabolismo , Análise de Sequência de DNARESUMO
Attention deficit hyperactivity disorder (ADHD) is a highly disabling, early onset childhood neurobehavioral disorder with a higher occurrence in boys as compared to girls. Pharmacological and molecular genetic studies have revealed the influence of dopaminergic and serotonergic systems in the etiology of the disorder. Monoamine oxidase A (MAOA) is a mitochondrial enzyme that regulates the dopaminergic signals in the pre-synaptic region. Polymorphism in the promoter region of the MAOA gene, which comprises of 30 bp repeats with repeat number varying between 2.5, 3.5, 4.5, and 5.5, has been shown to be associated with various neurobehavioral disorders including ADHD. This is the first study on Indian ADHD cases to validate an association between transmission of MAOA promoter polymorphism and risk of ADHD. We have analyzed the MAOA promoter polymorphism in a group of ADHD probands, their parents and ethnically matched controls by UNPHASED. Our findings indicate significant difference in the frequency of 3.5 repeat allele (P = 0.02) between cases and controls and preferential transmission of the short allele (3.5 repeat) from mothers to male ADHD probands (P = 0.005). We conclude that the short 3.5 repeat allele of the MAOA-u VNTR is probably associated with ADHD in our population and could be the reason for making boys prone to ADHD as compared to girls.