Publications by authors named "Birgitte Bertelsen"

26 Publications

  • Page 1 of 1

NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns.

Genet Med 2021 02 4;23(2):363-373. Epub 2020 Nov 4.

Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-020-00988-9DOI Listing
February 2021

Two cases of somatic STK11 mosaicism in Danish patients with Peutz-Jeghers syndrome.

Fam Cancer 2021 01 6;20(1):55-59. Epub 2020 Jun 6.

Danish Polyposis Registry, Hvidovre Hospital, Gastrounit, Hvidovre, Denmark.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10689-020-00191-4DOI Listing
January 2021

Germline RBBP8 variants associated with early-onset breast cancer compromise replication fork stability.

J Clin Invest 2020 08;130(8):4069-4080

Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI127521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7410048PMC
August 2020

The Spectrum of Protein Truncating Variants in European Breast Cancer Cases.

Cancers (Basel) 2020 01 26;12(2). Epub 2020 Jan 26.

Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, Prague 12853, Czech Republic.

Germline protein truncating variants (PTVs) in the 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 PTVs in Europe have never been investigated. In the present study, we collected the data of 114 European female breast cancer cases with PTVs ascertained in 20 centers from 13 European countries. We identified 27 different 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 PTVs, 15 have not been previously reported. We provide here the initial spectrum of PTVs in European breast cancer cases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12020292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073216PMC
January 2020

Association of Genomic Domains in and with Prostate Cancer Risk and Aggressiveness.

Cancer Res 2020 02 13;80(3):624-638. Epub 2019 Nov 13.

Unité de Prévention et d'Epidémiologie Génétique, Centre Léon Bérard, Lyon, France.

Pathogenic sequence variants (PSV) in or () are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 and 171 male PSV carriers with prostate cancer, and 3,388 and 2,880 male PSV carriers without prostate cancer. PSVs in the 3' region of (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; = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63-5.95; = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71-4.68; = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12-11.54; = 0.0002). No genotype-phenotype associations were detected for PSVs in . These results demonstrate that specific 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-19-1840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7553241PMC
February 2020

Novel Frameshift Variant Leading to Meningioma in Three Generations in a Family with Gorlin Syndrome.

Case Rep Genet 2019 28;2019:9650184. Epub 2019 Jul 28.

Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Gorlin syndrome is mainly caused by pathogenic germline variants in the tumour suppressor genes and , both regulatory genes in the hedgehog pathway. However, the phenotypes of patients with and pathogenic variants seem to differ. We present a family with a frameshift variant in the gene c.954del, p.Asn319Thrfs42 leading to meningiomas and multiple basal cell-carcinomas.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2019/9650184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6702821PMC
July 2019

High frequency of pathogenic germline variants within homologous recombination repair in patients with advanced cancer.

NPJ Genom Med 2019 21;4:13. Epub 2019 Jun 21.

1Center for Genomic Medicine, Rigshospitalet, Copenhagen, Denmark.

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 and 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41525-019-0087-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6588611PMC
June 2019

Dietary interventions in cardiac rehabilitation - The gap between guidelines and clinical practice.

Clin Nutr ESPEN 2018 10 14;27:120-126. Epub 2018 Jun 14.

REHPA - The Danish Knowledge Centre for Rehabilitation and Palliative Care, Department of Oncology, Odense University Hospital, and Department of Clinical Research, University of Southern Denmark, Vestergade 17, DK-5700, Nyborg, Denmark. Electronic address:

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clnesp.2018.05.007DOI Listing
October 2018

A Danish national effort of BRCA1/2 variant classification.

Acta Oncol 2018 01 23;57(1):159-162. Epub 2017 Nov 23.

g Department of Clinical Genetics , Odense University Hospital , Odense , Denmark.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/0284186X.2017.1400693DOI Listing
January 2018

Investigation of SNP rs2060546 Immediately Upstream to in a Danish Gilles de la Tourette Syndrome Cohort.

Front Neurosci 2016 22;10:531. Epub 2016 Nov 22.

Applied Human Molecular Genetics, Kennedy Center, Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Glostrup, Denmark.

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 , and 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 ( - MIM 610401) gene was shown to be associated with GTS [odds ratio (OR) = 1.7; -value = 5.8 × 10-7] thus warranting further investigations. As is one of the axon guidance molecules expressed in the central nervous system and it interacts with the encoded proteins of and 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; -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; -value = 0.00018) and same direction of effect in the three cohorts. Thus, our study strengthens the evidence of the possible involvement of 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnins.2016.00531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5118467PMC
November 2016

Germline Chromothripsis Driven by L1-Mediated Retrotransposition and Alu/Alu Homologous Recombination.

Hum Mutat 2016 Apr 4;37(4):385-95. Epub 2016 Feb 4.

Applied Human Molecular Genetics, Kennedy Center, Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Glostrup, 2600, Denmark.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/humu.22953DOI Listing
April 2016

Association of AADAC Deletion and Gilles de la Tourette Syndrome in a Large European Cohort.

Biol Psychiatry 2016 Mar 3;79(5):383-391. Epub 2015 Sep 3.

Clinic of Psychiatry, Social Psychiatry and Psychotherapy, and Institute of Human Genetics, Hannover Medical School, Hannover, Germany.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biopsych.2015.08.027DOI Listing
March 2016

Association Study of CHRNA7 Promoter Variants with Sensory and Sensorimotor Gating in Schizophrenia Patients and Healthy Controls: A Danish Case-Control Study.

Neuromolecular Med 2015 Dec 16;17(4):423-30. Epub 2015 Sep 16.

Center for Clinical Intervention and Neuropsychiatric Schizophrenia Research, Faculty of Health Sciences, Psychiatric Center Glostrup, University of Copenhagen, Ndr. Ringvej 29-67, 2600, Glostrup, Denmark.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12017-015-8371-9DOI Listing
December 2015

A germline chromothripsis event stably segregating in 11 individuals through three generations.

Genet Med 2016 05 27;18(5):494-500. Epub 2015 Aug 27.

Department of Clinical Genetics, Applied Human Molecular Genetics, Kennedy Center, Copenhagen University Hospital, Glostrup, Denmark.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/gim.2015.112DOI Listing
May 2016

Case report: a novel KERA mutation associated with cornea plana and its predicted effect on protein function.

BMC Med Genet 2015 Jun 23;16:40. Epub 2015 Jun 23.

Applied Human Molecular Genetics, Kennedy Center, Copenhagen University Hospital, Rigshospitalet, Gl. Landevej 7, Glostrup, 2600, Denmark.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12881-015-0179-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4630934PMC
June 2015

Association study between CDH2 and Gilles de la Tourette syndrome in a Danish cohort.

Psychiatry Res 2015 Aug 19;228(3):974-5. Epub 2015 May 19.

Applied Human Molecular Genetics, Kennedy Center, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.psychres.2015.05.010DOI Listing
August 2015

A mosaic small supernumerary marker chromosome 17 in a patient with Tourette syndrome, ADHD and intellectual disability: A case story and review of the literature.

Psychiatry Res 2015 Jul 31;228(1):179-81. Epub 2015 Mar 31.

Applied Human Molecular Genetics, Kennedy Center, Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.psychres.2015.03.022DOI Listing
July 2015

A t(3;9)(q25.1;q34.3) translocation leading to OLFM1 fusion transcripts in Gilles de la Tourette syndrome, OCD and ADHD.

Psychiatry Res 2015 Feb 30;225(3):268-75. Epub 2014 Dec 30.

Department of Clinical Genetics, Applied Human Molecular Genetics, Kennedy Center, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark. Electronic address:

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.psychres.2014.12.028DOI Listing
February 2015

Intragenic deletions affecting two alternative transcripts of the IMMP2L gene in patients with Tourette syndrome.

Eur J Hum Genet 2014 Nov 19;22(11):1283-9. Epub 2014 Feb 19.

Applied Human Molecular Genetics, Kennedy Center, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ejhg.2014.24DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4200436PMC
November 2014

Chromosomal rearrangements in Tourette syndrome: implications for identification of candidate susceptibility genes and review of the literature.

Neurogenetics 2013 Nov 29;14(3-4):197-203. Epub 2013 Aug 29.

Applied Human Molecular Genetics, Kennedy Center, Rigshospitalet, Copenhagen University Hospital, Glostrup, 2600, Denmark.

Tourette syndrome (TS) is a childhood-onset complex neurobiological disorder characterized by a combination of persistent motor and vocal tics and frequent presence of other neuropsychiatric comorbidities. TS shares the fate of other complex disorders, where the genetic etiology is largely unknown, and identification of susceptibility genes through linkage and association studies has been complicated due to inherent difficulties such as no clear mode of inheritance, genetic heterogeneity, and apparently incomplete penetrance. Positional cloning through mapping of disease-related chromosome rearrangements has been an efficient tool for the cloning of disease genes in several Mendelian disorders and in a number of complex disorders. Through cytogenetic investigation of 205 TS patients, we identified three possibly disease-associated chromosome rearrangements rendering this approach relevant in chasing TS susceptibility genes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10048-013-0372-yDOI Listing
November 2013

Microduplication of 15q13.3 and Xq21.31 in a family with Tourette syndrome and comorbidities.

Am J Med Genet B Neuropsychiatr Genet 2013 Dec 27;162B(8):825-31. Epub 2013 Jul 27.

Applied Human Molecular Genetics, Kennedy Center, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark.

Tourette syndrome (TS) is a childhood onset neurodevelopmental disorder. Although it is widely accepted that genetic factors play a significant role in TS pathogenesis the etiology of this disorder is largely unknown. Identification of rare copy number variations (CNVs) as susceptibility factors in several neuropsychiatric disorders such as attention deficit-hyperactivity disorder (ADHD), autism and schizophrenia, suggests involvement of these rare structural changes also in TS etiology. In a male patient with TS, ADHD, and OCD (obsessive compulsive disorder) we identified two microduplications (at 15q13.3 and Xq21.31) inherited from a mother with subclinical ADHD. The 15q duplication included the CHRNA7 gene; while two genes, PABPC5 and PCDH11X, were within the Xq duplication. The Xq21.31 duplication was present in three brothers with TS including the proband, but not in an unaffected brother, whereas the 15q duplication was present only in the proband and his mother. The structural variations observed in this family may contribute to the observed symptoms, but further studies are necessary to investigate the possible involvement of the described variations in the TS etiology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.b.32186DOI Listing
December 2013

Sequence analysis of SLITRK1 for var321 in Danish patients with Tourette syndrome and review of the literature.

Psychiatr Genet 2013 Jun;23(3):130-3

Applied Human Molecular Genetics, Kennedy Center, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark.

Tourette syndrome (TS) is a complex neuropsychiatric disorder characterized by multiple motor and vocal tics and is often accompanied by comorbidities such as attention deficit hyperactivity disorder and obsessive-compulsive disorder. The complex etiology of TS and its co-occurrence with other disorders impedes linking genetic changes with disease segregation. One of the few genes that has been linked to TS is the SLITRK1 (Slit and Trk-like 1) gene, where four variations have been suggested as possible disease-associated changes. One of these variations, which has been reported in six unrelated TS patients, was a noncoding variant (var321) at the 3'-untranslated region of SLITRK1 within a conserved binding site for microRNA has-mir-189. To elucidate the potential role of var321 in disease pathogenesis, a cohort of 112 deeply phenotyped Danish TS patients was investigated for this variation. We could not detect var321 in the present cohort, suggesting that this is not a common variant among Danish TS patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/YPG.0b013e328360c880DOI Listing
June 2013

[The genetics of Gilles de la Tourette syndrome].

Ugeskr Laeger 2012 Feb;174(8):484-7

Center for Anvendt Human Molekylærgenetik, Kennedy Centret, Gl. Landevej 7, 2600 Glostrup, Denmark.

Knowledge about the aetiology of Gilles de la Tourette syndrome (GTS) is very limited. GTS has a complex mode of inheritance in which both genetic and environmental factors are believed to be involved in disease development. Different approaches to identify GTS associated genes have led to the discovery of several candidate genes. However, none of these has been shown to be major causative genes associated with the development of GTS. Future use of large clinical cohorts and new technologies will hopefully result in the identification of genes associated with GTS.
View Article and Find Full Text PDF

Download full-text PDF

Source
February 2012

Novel heterozygous nonsense mutation of the OPTN gene segregating in a Danish family with ALS.

Neurobiol Aging 2012 Jan 26;33(1):208.e1-5. Epub 2011 Aug 26.

Center for Applied Human Molecular Genetics, The Kennedy Center, Glostrup, Denmark.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder. About 10% of ALS cases are familial (FALS) and the genetic defect is known only in approximately 20%-30% of these cases. The most common genetic cause of ALS is SOD1 (superoxide dismutase 1) mutation. Very recently, mutations of the optineurin gene (OPTN), which is involved in open-angle glaucoma, were identified in 3 Japanese patients/families with ALS, and subsequently in a few FALS patients of European descent. We found a heterozygous nonsense mutation (c.493C>T, p.Gln165X, exon 6) in the OPTN gene in a Danish patient with ALS, and the mutation segregated from his affected father. The p.Gln165X mutation could not be detected in 1070 healthy Danish controls, in 1000 Danish individuals with metabolic phenotypes or in 64 sporadic ALS (SALS) cases. The p.Gln165X mutation described in this study is the first mutation reported in a Danish family and is likely involved in disease pathogenesis. Until now, only few OPTN mutations have been associated with ALS. As the underlying genetic defect is known only in approximately 20%-30% of FALS families, further screening of these cases is necessary for establishing the contribution of OPTN mutations in disease pathogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neurobiolaging.2011.07.001DOI Listing
January 2012

Three new loci for determining x chromosome inactivation patterns.

J Mol Diagn 2011 Sep 2;13(5):537-40. Epub 2011 Jul 2.

Center for Applied Human Molecular Genetics, The Kennedy Center, Glostrup, Denmark.

The analysis of X chromosome inactivation (XCI) patterns is a widely used diagnostic tool in clinical practice when investigating X-linked diseases. The most commonly used assay to determine XCI patterns takes advantage of a locus within the androgen receptor (AR) gene. This PCR-based assay relies on two differentially methylated restriction enzyme sites (HpaII) and a polymorphic repeat located within this locus. Although highly informative, this locus is not always sufficient to evaluate the X-inactivation status in X-linked disorders. We have identified three new loci that can be used to determine XCI patterns in a methylation-sensitive PCR-based assay. All three loci contain polymorphic repeats and a methylation-sensitive restriction enzyme (HpaII) site, methylation of which was shown to correlate with XCI. DNA from 60 females was used to estimate the heterozygosity of these new loci. The reliability of the loci was validated by showing a high correlation between the results obtained by employing the new loci and the AR locus using DNA from 15 females who were informative for all four loci. Altogether, we show that these loci can be applied easily in molecular diagnostic laboratories, either as a supplement or as an alternative to the existing AR assay.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jmoldx.2011.05.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3157618PMC
September 2011
-->