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1.
Genet Med ; 2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33144681

RESUMO

PURPOSE: Pathogenic variants in the X-linked gene NEXMIF (previously KIAA2022) are associated with intellectual disability (ID), autism spectrum disorder, and epilepsy. We aimed to delineate the female and male phenotypic spectrum of NEXMIF encephalopathy. METHODS: Through an international collaboration, we analyzed the phenotypes and genotypes of 87 patients with NEXMIF encephalopathy. RESULTS: Sixty-three females and 24 males (46 new patients) with NEXMIF encephalopathy were studied, with 30 novel variants. Phenotypic features included developmental delay/ID in 86/87 (99%), seizures in 71/86 (83%) and multiple comorbidities. Generalized seizures predominated including myoclonic seizures and absence seizures (both 46/70, 66%), absence with eyelid myoclonia (17/70, 24%), and atonic seizures (30/70, 43%). Males had more severe developmental impairment; females had epilepsy more frequently, and varied from unaffected to severely affected. All NEXMIF pathogenic variants led to a premature stop codon or were deleterious structural variants. Most arose de novo, although X-linked segregation occurred for both sexes. Somatic mosaicism occurred in two males and a family with suspected parental mosaicism. CONCLUSION: NEXMIF encephalopathy is an X-linked, generalized developmental and epileptic encephalopathy characterized by myoclonic-atonic epilepsy overlapping with eyelid myoclonia with absence. Some patients have developmental encephalopathy without epilepsy. Males have more severe developmental impairment. NEXMIF encephalopathy arises due to loss-of-function variants.

2.
Fam Cancer ; 2020 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-32504210

RESUMO

Peutz-Jeghers syndrome (PJS) is a hereditary polyposis syndrome characterized by hamartomatous Peutz-Jeghers polyps in the gastrointestinal tract, mucocutaneous pigmentations, and increased risk for intestinal and extraintestinal cancer. In more than two-third of patients it is possible to detect pathogenic variants in the serine/threonine kinase 11 (STK11) gene, but so far is knowledge about genetic causes in the remaining part of patients limited. Reports of STK11 mosaicism are rare but may be an explanation in some patients without initial findings of pathogenic variants in STK11. We report two Danish patients with STK11 mosaicism detected in blood when using Next-Generation Sequencing. This is only the sixth and seventh patient reported in the literature, and we compare phenotypes of the reported cases. The results indicate that STK11 mosaicism is more frequent than anticipated and highlight that mosaicism should be considered in patients with clinical suspicion of PJS or patients fulfilling the diagnostic criteria.

3.
J Clin Invest ; 130(8): 4069-4080, 2020 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-32379725

RESUMO

Haploinsufficiency of factors governing genome stability underlies hereditary breast and ovarian cancer. One significant pathway that is disabled as a result is homologous recombination repair (HRR). With the aim of identifying new candidate genes, we examined early-onset breast cancer patients negative for BRCA1 and BRCA2 pathogenic variants. Here, we focused on CtIP (RBBP8 gene), which mediates HRR through the end resection of DNA double-strand breaks (DSBs). Notably, these patients exhibited a number of rare germline RBBP8 variants. Functional analysis revealed that these variants did not affect DNA DSB end resection efficiency. However, expression of a subset of variants led to deleterious nucleolytic degradation of stalled DNA replication forks in a manner similar to that of cells lacking BRCA1 or BRCA2. In contrast to BRCA1 and BRCA2, CtIP deficiency promoted the helicase-driven destabilization of RAD51 nucleofilaments at damaged DNA replication forks. Taken together, our work identifies CtIP as a critical regulator of DNA replication fork integrity, which, when compromised, may predispose to the development of early-onset breast cancer.

4.
Cancers (Basel) ; 12(2)2020 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-31991861

RESUMO

Germline protein truncating variants (PTVs) in the FANCM gene have been associated with a 2-4-fold increased breast cancer risk in case-control studies conducted in different European populations. However, the distribution and the frequency of FANCM PTVs in Europe have never been investigated. In the present study, we collected the data of 114 European female breast cancer cases with FANCM PTVs ascertained in 20 centers from 13 European countries. We identified 27 different FANCM PTVs. The p.Gln1701* PTV is the most common PTV in Northern Europe with a maximum frequency in Finland and a lower relative frequency in Southern Europe. On the contrary, p.Arg1931* seems to be the most common PTV in Southern Europe. We also showed that p.Arg658*, the third most common PTV, is more frequent in Central Europe, and p.Gln498Thrfs*7 is probably a founder variant from Lithuania. Of the 23 rare or unique FANCM PTVs, 15 have not been previously reported. We provide here the initial spectrum of FANCM PTVs in European breast cancer cases.

5.
Cancer Res ; 80(3): 624-638, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31723001

RESUMO

Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3' region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25-2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63-5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71-4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12-11.54; P = 0.0002). No genotype-phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. SIGNIFICANCE: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Predisposição Genética para Doença , Genômica/métodos , Mutação , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Associação Genética , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Adulto Jovem
6.
Case Rep Genet ; 2019: 9650184, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31485359

RESUMO

Gorlin syndrome is mainly caused by pathogenic germline variants in the tumour suppressor genes PTCH1 and SUFU, both regulatory genes in the hedgehog pathway. However, the phenotypes of patients with PTCH1 and SUFU pathogenic variants seem to differ. We present a family with a frameshift variant in the SUFU gene c.954del, p.Asn319Thrfs∗42 leading to meningiomas and multiple basal cell-carcinomas.

7.
NPJ Genom Med ; 4: 13, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31263571

RESUMO

Genomic screening of cancer patients for predisposing variants is traditionally based on age at onset, family history and type of cancer. Whereas the clinical guidelines have proven efficient in identifying families exhibiting classical attributes of hereditary cancer, the frequency of patients with alternative presentations is unclear. We identified and characterized germline variants in 636 patients with advanced solid cancer using whole exome sequencing. Pathogenic and likely pathogenic germline variants among 168 genes associated with hereditary cancer were considered. These variants were identified in 17.8% of the patients and within a wide range of cancer types. In particular, patients with mesothelioma, ovarian cancer, cervical cancer, urothelial cancer, and cancer of unknown primary origin displayed high frequencies of pathogenic variants. Variants were predominantly found in DNA-repair pathways and about half were within genes involved in homologous recombination repair. Twenty-two BRCA1 and BRCA2 germline variants were identified in 12 different cancer types, of which 10 (45%) were not previously identified in these patients based on the current clinical guidelines. Loss of heterozygosity and somatic second hits were identified in several of the affected genes, supporting possible causality for cancer development. A potential treatment target based on the pathogenic germline variant could be suggested in 25 patients (4%). The study demonstrates a high frequency of pathogenic germline variants in the homologous recombination pathway in patients with advanced solid cancers. We infer that genetic screening in this group of patients may reveal high-risk families and identify patients with potential PARP inhibitor sensitive tumors.

8.
Clin Nutr ESPEN ; 27: 120-126, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30144884

RESUMO

BACKGROUND & AIMS: An unhealthy diet is a risk factor for ischemic heart disease (IHD) and therefore cardiac rehabilitation (CR) should include dietary interventions. In 2007, CR became a shared responsibility between Danish hospitals and municipalities. Later, a national clinical guideline including recommendations on dietary interventions was developed to facilitate implementation of CR. The aim of the present study is: 1) To describe provision of dietary interventions in CR for IHD patients in Denmark in 2013 and 2015 emphasizing differences between hospitals and municipalities, and 2) To evaluate the implementation of the national clinical guideline in clinical practice. METHODS: A repeated nationwide cross-sectional electronic survey was carried out in 2013 and 2015. Participation was mandatory for all Danish hospital departments offering CR (n = 36), but voluntary for municipalities (n = 98) reaching response rates of 82% and 89% in 2013 and 2015, respectively. The electronic survey covered the core components of dietary interventions in CR as described in the national clinical guideline. RESULTS: In 2015, 72% of municipalities provided dietary interventions. This proportion was significantly higher in hospitals (94%, p = 0.007). 26% and 38% of hospitals screened systematically for dietary intervention needs in 2013 and 2015, respectively. Corresponding results from municipalities were 26% and 29%. No significant differences were seen in clinical practice over time. CONCLUSIONS: The results of this study identified a major gap between recommendations in the national clinical guideline and actual clinical practice on dietary interventions in CR in Danish hospitals and municipalities. The study confirmed that implementation of guidelines in clinical practice takes time and requires an intensive effort.


Assuntos
Reabilitação Cardíaca/métodos , Dieta Saudável , Isquemia Miocárdica/dietoterapia , Isquemia Miocárdica/reabilitação , Avaliação Nutricional , Guias de Prática Clínica como Assunto , Estudos Cross-Over , Assistência à Saúde , Dinamarca/epidemiologia , Humanos , Isquemia Miocárdica/epidemiologia , Isquemia Miocárdica/fisiopatologia , Padrões de Prática Médica
10.
Front Neurosci ; 10: 531, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27920664

RESUMO

Gilles de la Tourette syndrome (GTS) is a neuropsychiatric disorder characterized by multiple motor and vocal tics. GTS is a complex disorder, with environmental factors and several genes involved. Although variations within a few genes such as AADAC, NRXN1, SLITRK1, HDC, and IMMP2L have been tentatively associated with GTS (in a small number of patients), the causative genes underlying GTS pathophysiology remain unknown. In a previous genome-wide association study (GWAS) a single nucleotide polymorphism (SNP, rs2060546) near the Netrin-4 (NTN4 - MIM 610401) gene was shown to be associated with GTS [odds ratio (OR) = 1.7; p-value = 5.8 × 10-7] thus warranting further investigations. As NTN4 is one of the axon guidance molecules expressed in the central nervous system and it interacts with the encoded proteins of SLIT and WNT genes guiding the growth cone toward its target, it is an attractive candidate susceptibility gene for GTS. In this study we attempted to replicate the association of rs2060546 with GTS by genotyping a Danish cohort of 240 GTS patients and 1006 healthy controls. Our results did not reveal an association (OR = 1.363; p-value = 0.3329) in the Danish cohort alone, which may be due to the small sample size. However, a meta-analysis including the present cohort and a total of 1316 GTS patients and 5023 controls from the GTS GWAS Replication Initiative (GGRI) and the first GTS-GWAS yielded a significant signal (OR = 3.74; p-value = 0.00018) and same direction of effect in the three cohorts. Thus, our study strengthens the evidence of the possible involvement of NTN4 in GTS etiology, suggesting that further studies in even larger samples and functional studies are warranted to investigate the role of this region in GTS pathogenesis.

11.
Hum Mutat ; 37(4): 385-95, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26929209

RESUMO

Chromothripsis (CTH) is a phenomenon where multiple localized double-stranded DNA breaks result in complex genomic rearrangements. Although the DNA-repair mechanisms involved in CTH have been described, the mechanisms driving the localized "shattering" process remain unclear. High-throughput sequence analysis of a familial germline CTH revealed an inserted SVAE retrotransposon associated with a 110-kb deletion displaying hallmarks of L1-mediated retrotransposition. Our analysis suggests that the SVAE insertion did not occur prior to or after, but concurrent with the CTH event. We also observed L1-endonuclease potential target sites in other breakpoints. In addition, we found four Alu elements flanking the 110-kb deletion and associated with an inversion. We suggest that chromatin looping mediated by homologous Alu elements may have brought distal DNA regions into close proximity facilitating DNA cleavage by catalytically active L1-endonuclease. Our data provide the first evidence that active and inactive human retrotransposons can serve as endogenous mutagens driving CTH in the germline.


Assuntos
Elementos Alu , Cromotripsia , Mutação em Linhagem Germinativa , Recombinação Homóloga , Elementos Nucleotídeos Longos e Dispersos , Sequência de Bases , Pontos de Quebra do Cromossomo , Cromossomos Humanos Par 3 , Cromossomos Humanos Par 5 , Humanos , Repetições Minissatélites , Mutagênese Insercional , Retroelementos , Deleção de Sequência
12.
Biol Psychiatry ; 79(5): 383-391, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-26444075

RESUMO

BACKGROUND: Gilles de la Tourette syndrome (GTS) is a complex neuropsychiatric disorder with a strong genetic influence where copy number variations are suggested to play a role in disease pathogenesis. In a previous small-scale copy number variation study of a GTS cohort (n = 111), recurrent exon-affecting microdeletions of four genes, including the gene encoding arylacetamide deacetylase (AADAC), were observed and merited further investigations. METHODS: We screened a Danish cohort of 243 GTS patients and 1571 control subjects for submicroscopic deletions and duplications of these four genes. The most promising candidate gene, AADAC, identified in this Danish discovery sample was further investigated in cohorts from Iceland, the Netherlands, Hungary, Germany, and Italy, and a final meta-analysis, including a total of 1181 GTS patients and 118,730 control subjects from these six European countries, was performed. Subsequently, expression of the candidate gene in the central nervous system was investigated using human and mouse brain tissues. RESULTS: In the Danish cohort, we identified eight patients with overlapping deletions of AADAC. Investigation of the additional five countries showed a significant association between the AADAC deletion and GTS, and a final meta-analysis confirmed the significant association (p = 4.4 × 10(-4); odds ratio = 1.9; 95% confidence interval = 1.33-2.71). Furthermore, RNA in situ hybridization and reverse transcription-polymerase chain reaction studies revealed that AADAC is expressed in several brain regions previously implicated in GTS pathology. CONCLUSIONS: AADAC is a candidate susceptibility factor for GTS and the present findings warrant further genomic and functional studies to investigate the role of this gene in the pathogenesis of GTS.


Assuntos
Variações do Número de Cópias de DNA/genética , Deleção de Sequência/genética , Síndrome de Tourette/genética , Adulto , Animais , Transtorno do Deficit de Atenção com Hiperatividade/genética , Estudos de Coortes , Comorbidade , Dinamarca , Éxons , Feminino , Técnicas de Genotipagem , Alemanha , Humanos , Hungria , Islândia , Itália , Masculino , Camundongos , Países Baixos
13.
Genet Med ; 18(5): 494-500, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26312826

RESUMO

PURPOSE: Parentally transmitted germ-line chromothripsis (G-CTH) has been identified in only a few cases. Most of these rearrangements were stably transmitted, in an unbalanced form, from a healthy mother to her child with congenital abnormalities probably caused by de novo copy-number changes of dosage sensitive genes. We describe a G-CTH transmitted through three generations in 11 healthy carriers. METHODS: Conventional cytogenetic analysis, mate-pair sequencing, and polymerase chain reaction (PCR) were used to identify the chromosome rearrangement and characterize the breakpoints in all three generations. RESULTS: We identified an apparently balanced translocation t(3;5), later shown to be a G-CTH, in all individuals of a three-generation family. The G-CTH stably segregated without occurrence of additional rearrangements; however, several spontaneous abortions were reported, possibly due to unbalanced transmission. Although seven protein-coding genes are interrupted, no clinical features can be definitively attributed to the affected genes. However, it can be speculated that truncation of one of these genes, encoding ataxia-telangiectasia and Rad3-related protein kinase (ATR), a key component of the DNA damage response, may be related to G-CTH formation. CONCLUSION: G-CTH rearrangements are not always associated with abnormal phenotypes and may be misinterpreted as balanced two-way translocations, suggesting that G-CTH is an underdiagnosed phenomenon.Genet Med 18 5, 494-500.


Assuntos
Cromotripsia , Anormalidades Congênitas/genética , Células Germinativas/citologia , Translocação Genética/genética , Aborto Espontâneo/fisiopatologia , Adolescente , Adulto , Criança , Anormalidades Congênitas/fisiopatologia , Feminino , Rearranjo Gênico , Heterozigoto , Humanos , Hibridização in Situ Fluorescente , Masculino , Análise de Sequência de DNA
14.
Neuromolecular Med ; 17(4): 423-30, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26376812

RESUMO

Schizophrenia is a severe psychiatric disorder with a core component of impaired cognitive function still remaining as one of the greatest challenges in the pharmacological treatment of the disorder. The CHRNA7 gene, encoding the subunit of the human α7 nicotinic acetylcholine receptor (α7nAChR), is suggested as a susceptibility factor for schizophrenia. CHRNA7 has also been genetically linked to the P50 auditory evoked potential deficit, a candidate endophenotype of schizophrenia, but not to prepulse inhibition of the startle reflex (PPI). In this study, 95 antipsychotic-naïve schizophrenic patients and 450 unaffected controls were screened for CHRNA7 promoter variants to investigate the association with schizophrenia, P50 suppression and PPI. We found that the promoter variant -194C (rs28531779) was significantly associated with schizophrenia, but did not find any association of this variant with P50 suppression or PPI. In addition, individuals with CHRNA7 promoter variants had elevated startle magnitude in pulse-alone trials compared to individuals without a variant. The present findings provide further support for a role of the α7nAChR in schizophrenia and show a genetic link between CHRNA7 and startle magnitude, indicating that cholinergic neurotransmission involving the α7nAChR could be involved in sensory registration processes.


Assuntos
Potenciais Evocados/genética , Inibição Pré-Pulso/genética , Regiões Promotoras Genéticas/genética , Esquizofrenia/genética , Receptor Nicotínico de Acetilcolina alfa7/genética , Adulto , Estudos de Casos e Controles , Dinamarca , Potenciais Evocados/fisiologia , Feminino , Variação Genética , Humanos , Masculino , Inibição Pré-Pulso/fisiologia , Desempenho Psicomotor , Reflexo Anormal/genética , Reflexo Anormal/fisiologia , Reflexo de Sobressalto/genética , Reflexo de Sobressalto/fisiologia , Esquizofrenia/fisiopatologia , Adulto Jovem , Receptor Nicotínico de Acetilcolina alfa7/fisiologia
15.
BMC Med Genet ; 16: 40, 2015 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-26099342

RESUMO

BACKGROUND: Cornea plana (CNA) is a hereditary congenital abnormality of the cornea characterized by reduced corneal curvature, extreme hypermetropia, corneal clouding and hazy corneal limbus. The recessive form, CNA2, is associated with homozygous or compound heterozygous mutations of the keratocan gene (KERA) on chromosome 12q22. To date, only nine different disease-associated KERA mutations, including four missense mutations, have been described. CASE PRESENTATION: In this report, we present clinical data from a Turkish family with autosomal recessive cornea plana. In some of the affected individuals, hypotrichosis was found. KERA was screened for mutations using Sanger sequencing. We detected a novel KERA variant, p.(Ile225Thr), that segregates with the disease in the homozygous form. The three-dimensional structure of keratocan protein was modelled, and we showed that this missense variation is predicted to destabilize the structure of keratocan, leading to the classical ocular phenotype in the affected individuals. All the four known missense mutations, including the variation found in this family, affect the conserved residues of the leucine rich repeat domain of keratocan. These mutations are predicted to result in destabilization of the protein. CONCLUSION: We present the 10th pathogenic KERA mutation identified so far. Protein modelling is a useful tool in predicting the effect of missense mutations. This case underline the importance of the leucin rich repeat domain for the protein function, and this knowledge will ease the interpretation of future findings of mutations in these areas in other families with cornea plana.


Assuntos
Córnea/anormalidades , Doenças da Córnea/genética , Oftalmopatias Hereditárias/genética , Hiperopia/genética , Hipotricose/genética , Proteoglicanas/química , Proteoglicanas/genética , Adulto , Sequência de Bases , Criança , Feminino , Humanos , Masculino , Modelos Químicos , Mutação de Sentido Incorreto/genética , Linhagem , Conformação Proteica , Análise de Sequência de DNA , Turquia , Adulto Jovem
18.
Psychiatry Res ; 225(3): 268-75, 2015 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-25595337

RESUMO

Gilles de la Tourette syndrome (GTS) is a neuropsychiatric disorder with a strong genetic etiology; however, finding of candidate genes is hampered by its genetic heterogeneity and the influence of non-genetic factors on disease pathogenesis. We report a case of a male patient with GTS, obsessive compulsive disorder, attention-deficit/hyperactivity-disorder, as well as other comorbidities, and a translocation t(3;9)(q25.1;q34.3) inherited from a mother with tics. Mate-pair sequencing revealed that the translocation breakpoints truncated the olfactomedin 1 (OLFM1) gene and two uncharacterized transcripts. Reverse-transcription PCR identified several fusion transcripts in the carriers, and OLFM1 expression was found to be high in GTS-related human brain regions. As OLFM1 plays a role in neuronal development it is a likely candidate gene for neuropsychiatric disorders and haploinsufficiency of OLFM1 could be a contributing risk factor to the phenotype of the carriers. In addition, one of the fusion transcripts may exert a dominant-negative or gain-of-function effect. OLFM1 is unlikely to be a major GTS susceptibility gene as no point mutations or copy number variants affecting OLFM1 were identified in 175 additional patients. The translocation described is thus a unique event, but further studies in larger cohorts are required to elucidate involvement of OLFM1 in GTS pathogenesis.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Cromossomos Humanos Par 3/genética , Cromossomos Humanos Par 9/genética , Proteínas da Matriz Extracelular/genética , Glicoproteínas/genética , Transtorno Obsessivo-Compulsivo/genética , Síndrome de Tourette/genética , Translocação Genética/genética , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Estudos de Coortes , Comorbidade , Dinamarca , Humanos , Masculino , Transtorno Obsessivo-Compulsivo/epidemiologia , Mutação Puntual , Síndrome de Tourette/epidemiologia , Adulto Jovem
20.
Eur J Hum Genet ; 22(11): 1283-9, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24549057

RESUMO

Tourette syndrome is a neurodevelopmental disorder characterized by multiple motor and vocal tics, and the disorder is often accompanied by comorbidities such as attention-deficit hyperactivity-disorder and obsessive compulsive disorder. Tourette syndrome has a complex etiology, but the underlying environmental and genetic factors are largely unknown. IMMP2L (inner mitochondrial membrane peptidase, subunit 2) located on chromosome 7q31 is one of the genes suggested as a susceptibility factor in disease pathogenesis. Through screening of a Danish cohort comprising 188 unrelated Tourette syndrome patients for copy number variations, we identified seven patients with intragenic IMMP2L deletions (3.7%), and this frequency was significantly higher (P=0.0447) compared with a Danish control cohort (0.9%). Four of the seven deletions identified did not include any known exons of IMMP2L, but were within intron 3. These deletions were found to affect a shorter IMMP2L mRNA species with two alternative 5'-exons (one including the ATG start codon). We showed that both transcripts (long and short) were expressed in several brain regions, with a particularly high expression in cerebellum and hippocampus. The current findings give further evidence for the role of IMMP2L as a susceptibility factor in Tourette syndrome and suggest that intronic changes in disease susceptibility genes should be investigated further for presence of alternatively spliced exons.


Assuntos
Endopeptidases/genética , Deleção de Genes , Síndrome de Tourette/genética , Animais , Transtorno do Deficit de Atenção com Hiperatividade/genética , Estudos de Casos e Controles , Cromossomos Humanos Par 7/genética , Variações do Número de Cópias de DNA , Dinamarca , Grupo com Ancestrais do Continente Europeu/genética , Éxons , Feminino , Rearranjo Gênico , Predisposição Genética para Doença , Humanos , Hibridização in Situ Fluorescente , Masculino , Camundongos , Análise em Microsséries , Transtorno Obsessivo-Compulsivo/genética , Análise de Sequência de DNA , Tiques/genética
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