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2.
BMC Med Genet ; 20(1): 152, 2019 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-31488071

RESUMO

BACKGROUND: Consanguine families display a high degree of homozygosity which increases the risk of family members suffering from autosomal recessive disorders. Thus, homozygous mutations in monogenic obesity genes may be a more frequent cause of childhood obesity in a consanguineous population. METHODS: We identified 23 probands from 23 Pakistani families displaying autosomal recessive obesity. We have previously excluded mutations in MC4R, LEP and LEPR in all probands. Using a chip-based, target-region capture array, 31 genes involved in monogenic forms of obesity, were screened in all probands. RESULTS: We identified 31 rare non-synonymous possibly pathogenic variants (28 missense and three nonsense) within the 31 selected genes. All variants were heterozygous, thus no homozygous pathogenic variants were found. Two of the rare heterozygous nonsense variants identified (p.R75X and p.R481X) were found in BBS9 within one proband, suggesting that obesity is caused by compound heterozygosity. Sequencing of the parents supported the compound heterozygous nature of obesity as each parent was carrying one of the variants. Subsequent clinical investigation strongly indicated that the proband had Bardet-Biedl syndrome. CONCLUSIONS: Mutation screening in 31 genes among probands with severe early-onset obesity from Pakistani families did not reveal the presence of homozygous obesity causing variants. However, a compound heterozygote carrier of BBS9 mutations was identified, indicating that compound heterozygosity must not be overlooked when investigating the genetic etiology of severe childhood obesity in populations with a high degree of consanguinity.


Assuntos
Consanguinidade , Estudos de Associação Genética , Predisposição Genética para Doença/genética , Obesidade Pediátrica/genética , Síndrome de Bardet-Biedl/genética , Índice de Massa Corporal , Pré-Escolar , Códon sem Sentido , Feminino , Genótipo , Heterozigoto , Homozigoto , Humanos , Leptina/genética , Masculino , Mutação , Paquistão , Obesidade Pediátrica/fisiopatologia , Linhagem , Receptor Tipo 4 de Melanocortina/genética , Receptores para Leptina/genética
3.
BMC Med Genet ; 20(1): 145, 2019 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-31443639

RESUMO

BACKGROUND: Inherited palmoplantar keratodermas (PPKs) are clinically and genetically heterogeneous and phenotypically diverse group of genodermatoses characterized by hyperkeratosis of the palms and soles. More than 20 genes have been reported to be associated with PPKs including desmoglein 1 (DSG1) a key molecular component for epidermal adhesion and differentiation. Mal de Meleda (MDM) is a rare inherited autosomal recessive genodermatosis characterized by transgrediens PPK, associated with mutations in the secreted LY6/PLAUR domain containing 1 (SLURP1) gene. METHODS: This study describes clinical as well as genetic whole exome sequencing (WES) and di-deoxy sequencing investigations in two Pakistani families with a total of 12 individuals affected by PPK. RESULTS: WES identified a novel homozygous nonsense variant in SLURP1, and a novel heterozygous nonsense variant in DSG1, as likely causes of the conditions in each family. CONCLUSIONS: This study expands knowledge regarding the molecular basis of PPK, providing important information to aid clinical management in families with PPK from Pakistan.


Assuntos
Antígenos Ly/genética , Desmogleína 1/genética , Estudos de Associação Genética , Predisposição Genética para Doença/genética , Ceratodermia Palmar e Plantar/genética , Ativador de Plasminogênio Tipo Uroquinase/genética , Adolescente , Adulto , Criança , Códon sem Sentido , Grupos Étnicos , Feminino , Variação Genética , Genótipo , Heterozigoto , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Paquistão , Linhagem , Sequenciamento Completo do Exoma , Adulto Jovem
4.
BMC Med Genet ; 20(1): 120, 2019 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-31277601

RESUMO

BACKGROUND: Diamond-Blackfan anemia (DBA), a congenital pure red cell aplasia (PRCA), is characterized by normochromic macrocytic anemia, reticulocytopenia, and nearly absent erythroid progenitors in the bone marrow. DBA10, a subset of DBA, is an autosomal dominant disease caused by a mutation in RPS26. So far, there are 30 disease-causing variants in RPS26 being reported, however, only three of them are small insert mutations. CASE PRESENTATION: Here we report a three-month Chinese boy who presents with anemia from postnatal day 2. He was suspected to have Diamond-Blackfan anemia, according to the clinical result. Thus, whole-exome sequencing was performed for precise diagnosis. CONCLUSION: Here, a novel insert mutation c.96dupG in RPS26 was identified by whole-exome sequencing, which caused neonatal DBA in a Chinese boy. This is the first case report of a Chinese DBA10 patient who carries a small insertion in the RPS26 gene. These findings expand the mutation diversity of RPS26 and demonstrate the clinical presentations of the Chinese DBA10 patient.


Assuntos
Anemia de Diamond-Blackfan/genética , Códon sem Sentido/genética , Predisposição Genética para Doença/genética , Mutação INDEL , Proteínas Ribossômicas/genética , Anemia de Diamond-Blackfan/diagnóstico , Grupo com Ancestrais do Continente Asiático , Sequência de Bases , Estudos de Associação Genética , Humanos , Lactente , Masculino , Sequenciamento Completo do Exoma
5.
BMC Med Genet ; 20(1): 131, 2019 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-31349801

RESUMO

BACKGROUND: CHEK2 is involved in the DNA damage repair response Fanconi anemia (FA)-BRCA pathway. An increased risk for breast and other cancers has been documented in individuals who carry a single pathogenic CHEK2 variant. As for other genes involved in cancer predisposition, different types of pathogenic variants have been observed, including single nucleotide variations, short insertions/deletions, large genomic rearrangements and splicing variants. Splicing variants occurring in the splicing acceptor or donor site result in alternative mature mRNA produced and can cause intron retention, exon skipping, or creation of alternative 3' and 5' splice site. Thus, the pathogenicity of this type of alterations should always be explored experimentally and their effect in the mRNA and consequently the protein produced, should be defined. The aim of this study was the delineation of the effect of a splicing variant in the CHEK2 gene. CASE PRESENTATION: A healthy 28-year-old woman with a family history of breast and ovarian cancer was referred for genetic testing. The variant c.793-1G > A (rs730881687) was identified by Next Generation Sequencing (NGS) using a solution-based capture method, targeting 33 cancer predisposition genes (SeqCap EZ Probe library, Roche NimbleGen). Experimental analysis in patient-derived leukocytes using RT-PCR of mRNA followed by cDNA sequencing revealed the deletion of one base from the alternative transcript created (r.793del). This resulted in a frameshift leading to premature termination codon within exon 7 (p.(Asp265Thrfs*10)). CONCLUSIONS: This finding suggests that the CHEK2 splicing variant c.793-1G > A is a deleterious variant. Our case shows that RNA analysis is a valuable tool for uncharacterized splice site variants in individuals referred for testing and facilitates their personalized management.


Assuntos
Quinase do Ponto de Checagem 2/genética , Estudos de Associação Genética , Predisposição Genética para Doença/genética , Processamento de RNA , Adulto , Processamento Alternativo , Sequência de Bases , Neoplasias da Mama/genética , Códon sem Sentido , Éxons , Anemia de Fanconi/genética , Feminino , Testes Genéticos , Humanos , Íntrons , Neoplasias Ovarianas/genética , Linhagem , RNA Mensageiro/genética , Análise de Sequência de DNA
6.
Nat Commun ; 10(1): 2655, 2019 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-31201320

RESUMO

CDKL5 deficiency disorder (CDD) is characterized by epilepsy, intellectual disability, and autistic features, and CDKL5-deficient mice exhibit a constellation of behavioral phenotypes reminiscent of the human disorder. We previously found that CDKL5 dysfunction in forebrain glutamatergic neurons results in deficits in learning and memory. However, the pathogenic origin of the autistic features of CDD remains unknown. Here, we find that selective loss of CDKL5 in GABAergic neurons leads to autistic-like phenotypes in mice accompanied by excessive glutamatergic transmission, hyperexcitability, and increased levels of postsynaptic NMDA receptors. Acute, low-dose inhibition of NMDAR signaling ameliorates autistic-like behaviors in GABAergic knockout mice, as well as a novel mouse model bearing a CDD-associated nonsense mutation, CDKL5 R59X, implicating the translational potential of this mechanism. Together, our findings suggest that enhanced NMDAR signaling and circuit hyperexcitability underlie autistic-like features in mouse models of CDD and provide a new therapeutic avenue to treat CDD-related symptoms.


Assuntos
Síndromes Epilépticas/patologia , Neurônios GABAérgicos/patologia , Proteínas Serina-Treonina Quinases/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Transdução de Sinais/genética , Espasmos Infantis/patologia , Animais , Comportamento Animal/efeitos dos fármacos , Códon sem Sentido , Modelos Animais de Doenças , Síndromes Epilépticas/tratamento farmacológico , Síndromes Epilépticas/genética , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Feminino , Humanos , Masculino , Memantina/farmacologia , Memantina/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Prosencéfalo/citologia , Prosencéfalo/efeitos dos fármacos , Prosencéfalo/patologia , Proteínas Serina-Treonina Quinases/deficiência , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Espasmos Infantis/tratamento farmacológico , Espasmos Infantis/genética , Resultado do Tratamento
7.
PLoS Genet ; 15(6): e1008180, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31170158

RESUMO

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system characterized by myelin loss and neuronal dysfunction. Although the majority of patients do not present familial aggregation, Mendelian forms have been described. We performed whole-exome sequencing analysis in 132 patients from 34 multi-incident families, which nominated likely pathogenic variants for MS in 12 genes of the innate immune system that regulate the transcription and activation of inflammatory mediators. Rare missense or nonsense variants were identified in genes of the fibrinolysis and complement pathways (PLAU, MASP1, C2), inflammasome assembly (NLRP12), Wnt signaling (UBR2, CTNNA3, NFATC2, RNF213), nuclear receptor complexes (NCOA3), and cation channels and exchangers (KCNG4, SLC24A6, SLC8B1). These genes suggest a disruption of interconnected immunological and pro-inflammatory pathways as the initial event in the pathophysiology of familial MS, and provide the molecular and biological rationale for the chronic inflammation, demyelination and neurodegeneration observed in MS patients.


Assuntos
Predisposição Genética para Doença , Inflamação/genética , Esclerose Múltipla/genética , Transcriptoma/genética , Adulto , Códon sem Sentido , Doenças Desmielinizantes/genética , Doenças Desmielinizantes/patologia , Exoma/genética , Feminino , Humanos , Inflamação/metabolismo , Inflamação/patologia , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Bainha de Mielina/genética , Bainha de Mielina/patologia , Degeneração Neural/genética , Degeneração Neural/patologia , Neurônios/metabolismo , Neurônios/patologia , Linhagem , Sequenciamento Completo do Exoma , Adulto Jovem
8.
Genet Test Mol Biomarkers ; 23(6): 428-432, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31081706

RESUMO

Background: Autosomal recessive congenital ichthyoses (ARCI) are a group of rare nonsyndromic genodermatoses characterized by generalized scaly appearance of the epidermis with markedly impaired cutaneous barriers owing to defects in keratinization related genes. In this study, we ascertained a consanguineous Pakistani family affected with ARCI. Aims: To investigate genetic defect underlying disease phenotype in the affected family. Methods: All available members of the family (affected and unaffected) were sampled. Whole exome sequencing (WES) was performed on DNA of the proband and the data were analyzed for probable pathogenic variants. Segregation of the identified variant was validated by Sanger sequencing. Results: Analysis of the WES data identified a novel nonsense mutation, c.762C>G, in the PNPLA1 (patatin-like phospholipase domain containing 1) gene. The protein product of of this gene is involved in lipid organization during cornified cell envelope formation. The variant is predicted to result in the generation of a premature truncation site at amino acid position 254 (p.Tyr254*). This would result in the loss of a large C-terminal portion of the protein suggesting it to be rendered nonfunctional. In silico protein structure modeling confirmed a detrimental effect of the variation on protein structure. Conclusions: The study supports the evidence for the prevalence of PNPLA1 mutations in distant ethnic groups. Despite the significant number of reported ARCI cases with PNPLA1 variants, a straightforward genotype-phenotype correlation cannot be established.


Assuntos
Ictiose Lamelar/genética , Lipase/genética , Adulto , Idoso , Códon sem Sentido/genética , Grupos Étnicos/genética , Família , Feminino , Genes Recessivos/genética , Humanos , Ictiose Lamelar/metabolismo , Lipase/fisiologia , Masculino , Pessoa de Meia-Idade , Mutação/genética , Paquistão , Linhagem , Fenótipo , Sequenciamento Completo do Exoma/métodos
9.
PLoS Negl Trop Dis ; 13(5): e0007354, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31067234

RESUMO

BACKGROUND: Toll-like receptors (TLRs) are sentinel receptors of the innate immune system. TLR4 detects bacterial lipopolysaccharide (LPS) and TLR5 detects bacterial flagellin. A common human nonsense polymorphism, TLR5:c.1174C>T, results in a non-functional TLR5 protein. Individuals carrying this variant have decreased mortality from melioidosis, infection caused by the flagellated Gram-negative bacterium Burkholderia pseudomallei. Although impaired flagellin-dependent signaling in carriers of TLR5:c.1174C>T is well established, this study tested the hypothesis that a functional effect of TLR5:c.1174C>T is flagellin-independent and involves LPS-TLR4 pathways. METHODOLOGY/PRINCIPAL FINDINGS: Whole blood from two independent cohorts of individuals genotyped at TLR5:c.1174C>T was stimulated with wild type or aflagellated B. pseudomallei or purified bacterial motifs followed by plasma cytokine measurements. Blood from individuals carrying the TLR5:c.1174C>T variant produced less IL-6 and IL-10 in response to an aflagellated B. pseudomallei mutant and less IL-8 in response to purified B. pseudomallei LPS than blood from individuals without the variant. TLR5 expression in THP1 cells was silenced using siRNA; these cells were stimulated with LPS before cytokine levels in cell supernatants were quantified by ELISA. In these cells following LPS stimulation, silencing of TLR5 with siRNA reduced both TNF-α and IL-8 levels. These effects were not explained by differences in TLR4 mRNA expression or NF-κB or IRF activation. CONCLUSIONS/SIGNIFICANCE: The effects of the common nonsense TLR5:c.1174C>T polymorphism on the host inflammatory response to B. pseudomallei may not be restricted to flagellin-driven pathways. Moreover, TLR5 may modulate TLR4-dependent cytokine production. While these results may have broader implications for the role of TLR5 in the innate immune response in melioidosis and other conditions, further studies of the mechanisms underlying these observations are required.


Assuntos
Burkholderia pseudomallei/imunologia , Flagelina/imunologia , Melioidose/genética , Melioidose/imunologia , Polimorfismo Genético , Receptor 5 Toll-Like/genética , Adolescente , Adulto , Idoso , Burkholderia pseudomallei/genética , Códon sem Sentido , Estudos de Coortes , Feminino , Flagelina/genética , Humanos , Imunidade Inata , Interleucina-10/genética , Interleucina-10/imunologia , Masculino , Melioidose/microbiologia , Pessoa de Meia-Idade , NF-kappa B/genética , NF-kappa B/imunologia , Mutação Puntual , Receptor 5 Toll-Like/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Adulto Jovem
10.
Orphanet J Rare Dis ; 14(1): 92, 2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-31046801

RESUMO

Inherited ichthyoses belong to a large and heterogeneous group of mendelian disorders of cornification, and can be distinguished by the quality and distribution of scaling and hyperkeratosis, by other dermatologic and extracutaneous involvement, and by inheritance. We present the genetic analysis results of probands with X-linked ichthyosis, autosomal recessive congenital ichthyosis, keratinopathic ichthyosis, and a patient with Netherton syndrome. Genetic diagnostics was complemented by in silico missense variant analysis based on 3D protein structures and commonly used prediction programs to compare the yields of these two approaches to each other. This analysis revealed various structural defects in proteins coded by mutated genes while no defects were associated with known polymorphisms. Two patients with pathogenic variants in the ABCA12 gene have a premature termination codon mutation on one allele and a silent variant on the second. The silent variants c.69G > A and c.4977G > A are localised in the last nucleotide of exon 1 and exon 32, respectively, and probably affect mRNA splicing. The phenotype of both patients is very severe, including a picture harlequin foetus after birth; later (at 3 and 6 years of age, respectively) ectropin, eclabion, generalised large polygonal scaling and erythema.


Assuntos
Ictiose/etiologia , Transportadores de Cassetes de Ligação de ATP/genética , Códon sem Sentido/genética , República Tcheca , Predisposição Genética para Doença/genética , Humanos , Ictiose/genética , Fenótipo
11.
BMC Med Genet ; 20(1): 91, 2019 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-31132985

RESUMO

BACKGROUND: Hereditary sensory and autonomic neuropathy (HSAN) type II is a group of extremely rare autosomal recessive neurological disorders with heterogeneous clinical and genetic characteristics. METHODS: We performed high-depth next-generation targeted sequencing using a custom-ordered "HSAN" panel, covering WNK1, NTRK1, NGF, SPTLC1 and IKBKAP genes, to identify pathogenic variants of the proband as well as the family members. We also performed whole exome sequencing to further investigate the potential occurrence of additional pathogenic variants in genes that were not covered by the "HSAN" panel. Quantitative real-time PCR was used to identify pathogenic copy number variations (CNVs) and to analyze the mRNA level of WNK1 gene of the family. Western blot analysis was performed to evaluate the WNK1 protein expression level. RESULTS: After sequencing, a novel nonsense variant (c.2747 T > G, p.Leu916Ter) in exon 9 of WNK1 gene was identified in two patients (hemizygous) and their mother (heterozygous). This variant is absent in all public databases as well as in 600 Han Chinese healthy controls. The region of this variant is evolutionary highly conserved. Furthermore, by quantitative real-time PCR using DNA of the pedigree, we revealed a large deletion containing the whole WNK1 gene in two patients. The WNK1 expression levels of the patients were significantly reduced. CONCLUSIONS: Our study firstly revealed that the coexistence of a novel WNK1 nonsense variant and a CNV resulted in HSAN type IIA in a Han Chinese family.


Assuntos
Códon sem Sentido , Variações do Número de Cópias de DNA , Neuropatias Hereditárias Sensoriais e Autônomas/genética , Proteína Quinase 1 Deficiente de Lisina WNK/genética , Sequência de Aminoácidos , Sequência de Bases , Análise Mutacional de DNA , Saúde da Família , Feminino , Neuropatias Hereditárias Sensoriais e Autônomas/metabolismo , Neuropatias Hereditárias Sensoriais e Autônomas/patologia , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Masculino , Linhagem , Homologia de Sequência de Aminoácidos , Proteína Quinase 1 Deficiente de Lisina WNK/metabolismo
12.
Yi Chuan ; 41(5): 359-364, 2019 May 20.
Artigo em Chinês | MEDLINE | ID: mdl-31106771

RESUMO

The genetic compensation response (GCR) was firstly described in zebrafish to explain the phenotypic discrepancies between gene-knockout and gene-knockdown, whereby a deleterious mutation, but not gene-knockdown, can lead to the transcriptional upregulation of related genes, which can assume the function of the mutated gene. This phenomenon was also found in other model systems including mice and Arabidopsis. However, the underlying molecular mechanism of the GCR remains elusive until two papers were published in Nature on April 3, 2019: one from our lab and the other from Stainier's lab. Using different genetic mutants of various genes in zebrafish or culture cells of mice, both of us reveal that the upregulation of compensatory genes is only triggered by mutations that generate a premature termination codon (PTC); the compensatory genes share nucleotide sequence homology to the mutated genes; nonsense mRNA mediated decay pathway (NMD) is essential for the induction of GCR, and the increased transcription of the compensatory genes is accompanied by an enhancement of H3K4 trimethylation (H3K4me3) at their transcription start site (TSS) regions. In this review, we summarize the mechanisms of the GCR proposed in the two studies.


Assuntos
Códon sem Sentido , Degradação do RNAm Mediada por Códon sem Sentido , Ativação Transcricional , Animais , Histonas , Metilação , Camundongos , Mutação , RNA Mensageiro/genética , Sítio de Iniciação de Transcrição , Peixe-Zebra
13.
Eur J Med Genet ; 62(7): 103664, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31067494

RESUMO

Ophthalmo-acromelic syndrome is a rare autosomal recessive disorder characterized by ocular and skeletal abnormalities. Ocular findings present as a wide spectrum, ranging from mild microphthalmia to true anophthalmia. Short 5th finger, synostosis of 4th and 5th metacarpals, and oligodactyly in feet are frequent limb malformations. Homozygous variants in the SMOC1 gene (SPARC-related modular calcium-binding protein 1 gene) were identified as causative for the syndrome. A 9-month-old female patient is presented herein, who was diagnosed with ophthalmo-acromelic syndrome and had a homozygous nonsense mutation (p.Arg75Ter) in SMOC1, along with a review of the literature.


Assuntos
Síndrome de Waardenburg/genética , Códon sem Sentido , Feminino , Homozigoto , Humanos , Lactente , Osteonectina/genética , Síndrome de Waardenburg/patologia
14.
Orthod Craniofac Res ; 22 Suppl 1: 163-167, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31074142

RESUMO

OBJECTIVE: Craniofacial microsmia is the second most common congenital disorder with mostly unilateral defects of ear, temporomandibular joint, mandible, and muscles of facial expression and mastication. The objective of this study was to identify, if there were any, de novo germline or somatic variants in a patient with Occulo-Auriculo-Vertebral Spectrum (OAVS) using whole-exome sequencing. SETTINGS AND SAMPLE POPULATION: Trio/Family-based study of an OAVS proband. MATERIALS AND METHODS: Children's Mercy Hospital Institutional Review Board approved this study and a request-to-rely was procured from the University of Missouri Kansas City IRB. Informed assent/consent was obtained for all family members prior to any research activities. The peripheral blood/affected side tissues from corrective surgery of the proband and peripheral blood samples from unaffected parents were collected. The isolated genomic DNA were enriched for exomes and sequenced on an Illlumina HiSeq 2500 instrument yielding paired-end 125 nucleotide reads (84X coverage). Gapped alignment to reference sequences (GRCh37.p5) was performed with BWA and the GATK and analysis completed using custom-developed software. RESULTS: Analyses revealed that the proband carried a de novo germ line nonsense substitution (c.901C>T) in AMIGO2 gene, and missense substitutions in ZCCHC14 (c.1198C>T), and in SZT2 genes (c.2951C>T). CONCLUSIONS: The nonsense substitution in AMIGO2 gene introduces a premature stop codon possibly rendering the gene non-functional via nonsense-mediated pathway decay-therefore considered a stronger candidate. Further functional studies are required to confirm whether loss-of-function variants in AMIGO2 can cause OAVS.


Assuntos
Códon sem Sentido , Síndrome de Goldenhar , Criança , DNA , Exoma , Humanos , Proteínas do Tecido Nervoso
15.
PLoS Genet ; 15(5): e1008146, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31136578

RESUMO

Several horse breeds have been specifically selected for the ability to exhibit alternative patterns of locomotion, or gaits. A premature stop codon in the gene DMRT3 is permissive for "gaitedness" across breeds. However, this mutation is nearly fixed in both American Standardbred trotters and pacers, which perform a diagonal and lateral gait, respectively, during harness racing. This suggests that modifying alleles must influence the preferred gait at racing speeds in these populations. A genome-wide association analysis for the ability to pace was performed in 542 Standardbred horses (n = 176 pacers, n = 366 trotters) with genotype data imputed to ~74,000 single nucleotide polymorphisms (SNPs). Nineteen SNPs on nine chromosomes (ECA1, 2, 6, 9, 17, 19, 23, 25, 31) reached genome-wide significance (p < 1.44 x 10-6). Variant discovery in regions of interest was carried out via whole-genome sequencing. A set of 303 variants from 22 chromosomes with putative modifying effects on gait was genotyped in 659 Standardbreds (n = 231 pacers, n = 428 trotters) using a high-throughput assay. Random forest classification analysis resulted in an out-of-box error rate of 0.61%. A conditional inference tree algorithm containing seven SNPs predicted status as a pacer or trotter with 99.1% accuracy and subsequently performed with 99.4% accuracy in an independently sampled population of 166 Standardbreds (n = 83 pacers, n = 83 trotters). This highly accurate algorithm could be used by owners/trainers to identify Standardbred horses with the potential to race as pacers or as trotters, according to the genotype identified, prior to initiating training and would enable fine-tuning of breeding programs with designed matings. Additional work is needed to determine both the algorithm's utility in other gaited breeds and whether any of the predictive SNPs play a physiologically functional role in the tendency to pace or tag true functional alleles.


Assuntos
Marcha/genética , Cavalos/genética , Algoritmos , Alelos , Animais , Biomarcadores , Códon sem Sentido/genética , Frequência do Gene/genética , Variação Genética/genética , Estudo de Associação Genômica Ampla , Genótipo , Locomoção/genética , Mutação/genética , Polimorfismo de Nucleotídeo Único/genética , Seleção Artificial , Fatores de Transcrição/genética
16.
Mol Genet Metab ; 127(1): 107-115, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31101435

RESUMO

The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative disorders characterized by progressive declines in neurological functions following normal development. The NCLs are distinguished from similar disorders by the accumulation of autofluorescent lysosomal storage bodies in neurons and many other cell types, and are classified as lysosomal storage diseases. At least 13 genes contain pathogenic sequence variants that underlie different forms of NCL. Naturally occurring canine NCLs can serve as models to develop better understanding of the disease pathologies and for preclinical evaluation of therapeutic interventions for these disorders. To date 14 sequence variants in 8 canine orthologs of human NCL genes have been found to cause progressive neurological disorders similar to human NCLs in 12 different dog breeds. A mixed breed dog with parents of uncertain breed background developed progressive neurological signs consistent with NCL starting at approximately 11 to 12 months of age, and when evaluated with magnetic resonance imaging at 21 months of age exhibited diffuse brain atrophy. Due to the severity of neurological decline the dog was euthanized at 23 months of age. Cerebellar and cerebral cortical neurons contained massive accumulations of autofluorescent storage bodies the contents of which had the appearance of tightly packed membranes. A whole genome sequence, generated with DNA from the affected dog contained a homozygous C-to-T transition at position 30,574,637 on chromosome 22 which is reflected in the mature CLN5 transcript (CLN5: c.619C > T) and converts a glutamine codon to a termination codon (p.Gln207Ter). The identical nonsense mutation has been previously associated with NCL in Border Collies, Australian Cattle Dogs, and a German Shepherd-Australian Cattle Dog mix. The current whole genome sequence and a previously generated whole genome sequence for an Australian Cattle Dog with NCL share a rare homozygous haplotype that extends for 87 kb surrounding 22: 30, 574, 637 and includes 21 polymorphic sites. When genotyped at 7 of these polymorphic sites, DNA samples from the German Shepherd-Australian Cattle Dog mix and from 5 Border Collies with NCL that were homozygous for the CLN5: c.619 T allele also shared this homozygous haplotype, suggesting that the NCL in all of these dogs stems from the same founding mutation event that may have predated the establishment of the modern dog breeds. If so, the CLN5 nonsence allele is probably segregating in other, as yet unidentified, breeds. Thus, dogs exhibiting similar NCL-like signs should be screened for this CLN5 nonsense allele regardless of breed.


Assuntos
Códon sem Sentido , Doenças do Cão/genética , Proteínas de Membrana/genética , Lipofuscinoses Ceroides Neuronais/veterinária , Animais , Austrália , Cruzamento , Cerebelo/patologia , Cães/genética , Homozigoto , Imagem por Ressonância Magnética , Lipofuscinoses Ceroides Neuronais/diagnóstico por imagem , Lipofuscinoses Ceroides Neuronais/genética , Linhagem , Sequenciamento Completo do Genoma
18.
Mol Genet Genomic Med ; 7(5): e622, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30938079

RESUMO

BACKGROUND: Duchenne muscular dystrophy (DMD) is the most common form of inherited muscular dystrophy. Germline mutations in dystrophin (DMD) gene cause DMD, with a X-linked recessive mode of inheritance. Patients with DMD are usually characterized by weakness of muscle, usually started since childhood and gradually the patient will unable to stand and walk. METHODS: In our present study, we identified four unrelated Chinese patients with DMD from four Chinese families. Whole exome sequencing was performed for genetic molecular analysis for these probands. RESULTS: Whole exome sequencing and confirmatory Sanger sequencing identified four novel nonsense mutations in these four unrelated Chinese patients, respectively. All these four mutations lead to the formation of a truncated DMD protein by formation of a premature stop codon. According to the variant interpretation guidelines of American College of Medical Genetics and Genomics (ACMG), these four novel nonsense mutations are categorized as "likely pathogenic" variants. CONCLUSION: Our present finding not only identified four novel loss-of-function mutations in dystrophin (DMD) gene but also strongly emphasized the significance of whole exome sequencing as the most efficient way of identifying the candidate genes and mutations which enables us for easy and rapid clinical diagnosis, follow-up, and management of DMD patients.


Assuntos
Distrofina/genética , Mutação com Perda de Função , Distrofia Muscular de Duchenne/genética , Adulto , Criança , Códon sem Sentido , Feminino , Testes Genéticos , Humanos , Masculino , Distrofia Muscular de Duchenne/patologia , Linhagem , Sequenciamento Completo do Exoma
19.
Gene ; 704: 113-120, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30974196

RESUMO

Usher syndrome (USH) is a clinically common autosomal recessive disorder characterized by retinitis pigmentosa (RP) and sensorineural hearing loss with or without vestibular dysfunction. In this study, we identified a Hunan family of Chinese descent with two affected members clinically diagnosed with Usher syndrome type 3 (USH3) displaying hearing, visual acuity, and olfactory decline. Whole-exome sequencing (WES) identified a nonsense variant in ABHD12 gene that was confirmed to be segregated in this family by Sanger sequencing and exhibited a recessive inheritance pattern. In this family, two patients carried homozygous variant in the ABHD12 (NM_015600: c.249C>G). Mutation of ABHD12, an enzyme that hydrolyzes an endocannabinoid lipid transmitter, caused incomplete PHARC syndrome, as demonstrated in previous reports. Therefore, we also conducted a summary based on variants in ABHD12 in PHARC patients, and in PHARC patients showing that there was no obvious correlation between the genotype and phenotype. We believe that this should be considered during the differential diagnosis of USH. Our findings predicted the potential function of this gene in the development of hearing and vision loss, particularly with regard to impaired signal transmission, and identified a novel nonsense variant to expand the variant spectrum in ABHD12.


Assuntos
Códon sem Sentido , Monoacilglicerol Lipases/genética , Síndromes de Usher/genética , Adulto , Idoso , Ataxia/genética , Ataxia/patologia , Catarata/genética , Catarata/patologia , Criança , Família , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Homozigoto , Humanos , Masculino , Linhagem , Fenótipo , Polineuropatias/genética , Polineuropatias/patologia , Retinite Pigmentosa/genética , Retinite Pigmentosa/patologia , Síndromes de Usher/patologia , Sequenciamento Completo do Exoma
20.
Gene ; 704: 86-90, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30978479

RESUMO

The purpose of this study is to profile the clinical and genetic features of Japanese Waardenburg syndrome (WS) patients and validate the W index. Sixteen Japanese WS families with congenital sensorineural hearing loss were included in the study. The inner canthal, interpupillary, and outer canthal distances (ICD, IPD, and OCD) were measured for all patients, and patients were screened for presence of PAX3, MITF, SOX10, and EDNRB mutations. The WS patients were clinically classified under the current W index as follows: 13 families with WS1, 2 families with WS2, and 1 family with WS4. In the 13 WS1 families, genetic tests found PAX3 mutations in 5 families, MITF mutations in 4 families, SOX10 mutations in 3 families, and EDNRB mutations in 1 family. 61% of clinically classified WS1 patients under the current W index conflicted with the genetic classification, which implies W index is not appropriate for Japanese population. Resetting the threshold of W index or novel index formulated with ethnicity matched samples is necessary for clinical classification which is consistent with genetic classification for WS patients with distinct ethnicity.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Síndrome de Waardenburg/diagnóstico , Síndrome de Waardenburg/genética , Adulto , Criança , Códon sem Sentido , Análise Mutacional de DNA , Família , Feminino , Mutação da Fase de Leitura , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Testes Genéticos , Humanos , Japão , Masculino , Fator de Transcrição Associado à Microftalmia/genética , Fator de Transcrição PAX3/genética , Linhagem , Receptor de Endotelina B/genética , Fatores de Transcrição SOXE/genética , Síndrome de Waardenburg/etnologia
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