Publications by authors named "Míriam Guitart"

38 Publications

The Novel KIF1A Missense Variant (R169T) Strongly Reduces Microtubule Stimulated ATPase Activity and Is Associated With NESCAV Syndrome.

Front Neurosci 2021 26;15:618098. Epub 2021 May 26.

Genetics Laboratory, UDIAT-Centre Diagnòstic, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Sabadell, Spain.

KIF1A is a microtubule-dependent motor protein responsible for fast anterograde transport of synaptic vesicle precursors in neurons. Pathogenic variants in have been associated with a wide spectrum of neurological disorders. Here, we report a patient presenting a severe neurodevelopmental disorder carrying a novel missense variant p.Arg169Thr (R169T) in the KIF1A motor domain. The clinical features present in our patient match with those reported for NESCAV syndrome including severe developmental delay, spastic paraparesis, motor sensory neuropathy, bilateral optic nerve atrophy, progressive cerebellar atrophy, epilepsy, ataxia, and hypotonia. Here, we demonstrate that the microtubule-stimulated ATPase activity of the KIF1A is strongly reduced in the motor domain of the R169T variant. Supporting this, structural modeling suggests that this variant impairs the interaction of the KIF1A motor domain with microtubules. The characterization of the molecular effect of the R169T variant on the KIF1A protein together with the presence of the typical clinical features indicates its causal pathogenic effect.
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http://dx.doi.org/10.3389/fnins.2021.618098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187576PMC
May 2021

Targeted Next-Generation Sequencing in Patients with Suggestive X-Linked Intellectual Disability.

Genes (Basel) 2020 01 2;11(1). Epub 2020 Jan 2.

Biocruces Bizkaia Health Research Institute, 48903 Barakaldo, Spain.

X-linked intellectual disability (XLID) is known to contribute up to 10% of intellectual disability (ID) in males and could explain the increased ratio of affected males observed in patients with ID. Over the past decade, next-generation sequencing has clearly stimulated the gene discovery process and has become part of the diagnostic procedure. We have performed targeted next-generation sequencing of 82 XLID genes on 61 non-related male patients with suggestive non-syndromic XLID. These patients were initially referred to the molecular genetics laboratory to exclude Fragile X Syndrome. The cohort includes 47 male patients with suggestive X-linked family history of ID meaning that they had half-brothers or maternal cousins or uncles affected; and 14 male patients with ID and affected brothers whose mothers show skewed X-inactivation. Sequencing data analysis identified 17 candidate variants in 16 patients. Seven families could be re-contacted and variant segregation analysis of the respective eight candidate variants was performed: , , , , , , and . Our results show the utility of targeted next-generation sequencing in unravelling the genetic origin of XLID, especially in retrospective cases. Variant segregation and additional studies like RNA sequencing and biochemical assays also helped in re-evaluating and further classifying the genetic variants found.
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http://dx.doi.org/10.3390/genes11010051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017351PMC
January 2020

Discoidin domain receptor 1 gene variants are associated with decreased white matter fractional anisotropy and decreased processing speed in schizophrenia.

J Psychiatr Res 2019 03 24;110:74-82. Epub 2018 Dec 24.

Hospital Universitari Institut Pere Mata, IISPV, Universitat Rovira i Virgili, Reus, Spain; Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain. Electronic address:

DDR1 has been linked to schizophrenia (SZ) and myelination. Here, we tested whether DDR1 variants in people at risk for SZ influence white matter (WM) structural variations and cognitive processing speed (PS). First, following a case-control design (Study 1), SZ patients (N = 1193) and controls (N = 1839) were genotyped for rs1264323 and rs2267641 at DDR1, and the frequencies were compared. We replicated the association between DDR1 and SZ (rs1264323, adjusted P = 0.015). Carriers of the rs1264323AA combined with the rs2267641AC or CC genotype are at risk to develop SZ compared to the other genotype combinations. Second, SZ patients (Study 2, N = 194) underwent an evaluation of PS using the Trail Making Test (TMT) and DDR1 genotyping. To compare PS between DDR1 genotype groups, we conducted an analysis of covariance (including rs1264323 as a covariate) and found that SZ patients with the rs2267641CC genotype had decreased PS compared to patients with the AA and AC genotypes. Third, 54 patients (Study 3) from Study 2 were selected based on rs1264323 genotype to undergo reevaluation, including a DTI-MRI brain scan. To test for associations between PS, WM microstructure and DDR1 genotype, we first localized those WM regions where fractional anisotropy (FA) was correlated with PS and tested whether FA showed differences between the rs1264323 genotypes. SZ patients with the rs1264323AA genotype showed decreased FA in WM regions associated with decreased PS. We conclude that DDR1 variants may confer a risk of SZ through WM microstructural alterations leading to cognitive dysfunction.
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http://dx.doi.org/10.1016/j.jpsychires.2018.12.021DOI Listing
March 2019

Identification of a de novo splicing variant in the Coffin-Siris gene, SMARCE1, in a patient with Angelman-like syndrome.

Mol Genet Genomic Med 2019 01 11;7(1):e00511. Epub 2018 Dec 11.

Genetics Laboratory, UDIAT-Centre Diagnòstic, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Sabadell, Spain.

Background: Patients affected by Angelman syndrome (AS) present severe intellectual disability, lack of speech, ataxia, seizures, abnormal electroencephalography (EEG), and a characteristic behavioral phenotype. Around 10% of patients with a clinical diagnosis of AS (AS-like) do not have an identifiable molecular defect. Some of these patients harbor alternative genetic defects that present overlapping features with AS.

Methods: Trio whole-exome sequence was performed on patient and parent's DNA extracted from peripheral blood. Exome data were filtered according to a de novo autosomal dominant inheritance. cDNA analysis was carried out to assess the effect of the splice site variant.

Results: We identified a novel heterozygous SMARCE1 splicing variant that leads to an exon skipping in a patient with an Angelman-like phenotype. Missense variants in the SMARCE1 gene are known to cause Coffin-Siris syndrome (CSS), which is a rare congenital syndrome. Clinical reevaluation of the patient confirmed the presence of characteristic clinical features of CSS, many of them overlapping with AS.

Conclusions: Taking into account the novel finding reported in this study, we consider that CSS should be added to the expanding list of differential diagnoses for AS.
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http://dx.doi.org/10.1002/mgg3.511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6382443PMC
January 2019

Factor Structure of the Spanish Version of the Edinburgh Postnatal Depression Scale.

Actas Esp Psiquiatr 2018 Sep 1;46(5):174-82. Epub 2018 Sep 1.

Hospital Clinic, Universidad de Valencia, CIBERSAM, Valencia, España.

Introduction: The Edinburgh Postnatal Depression Scale (EPDS) is considered the gold standard in screening for postpartum depression. Although the Spanish version has been widely used, its factorial structure has not yet been studied .

Methods: A total of 1,204 women completed the EPDS 32 weeks after delivery. To avoid multiple testing, we split the sample into two halves, randomly drawing two subsamples of 602 participants each. We conducted exploratory factor analysis (EFA), followed by an oblimin rotation with the first sub-sample. Confirmatory factor analysis (CFA) was conducted using a Weighted Least Squares Means and Variance (WLSMV) estimation of the data. We explored different solutions between two and four factors. We compared the factors between two groups with depression and non-depression (evaluated with the Diagnostic Interview for Genetic Studies (DIGS) for the DSM-IV).

Results: The EFA indicated a three-factor model consisting of anxiety, depression and anhedonia. The results of the CFA confirmed the three-factor model (χ2=99.203, p<0.001; RMSEA=0.06, 90% CI=0.04/0.07, CFI=0.87 and TLI=0.82). Women with depression in the first 32 weeks obtained higher scores for anxiety, depression and anhedonia dimensions (p<0.001).

Conclusions: This is the first study of confirmatory analysis with the Spanish version of EPDS in a large sample of women without psychiatric care during pregnancy. A three-factor model consisting of anxiety, depression and anhedonia was used. Women with depression had a higher score in the three dimensions of the EPDS.
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September 2018

High Incidence of Copy Number Variants in Adults with Intellectual Disability and Co-morbid Psychiatric Disorders.

Behav Genet 2018 07 7;48(4):323-336. Epub 2018 Jun 7.

Genetics lab, UDIAT-centre diagnostic. Parc Taulí Hospital Universitari. Institut d'Investigació i Innovació Parc Taulí I3PT. Universitat Autònoma de Barcelona, C/Parc Tauli,1, 08208, Sabadell, Barcelona, Spain.

A genetic analysis of unexplained mild-moderate intellectual disability and co-morbid psychiatric or behavioural disorders is not systematically conducted in adults. A cohort of 100 adult patients affected by both phenotypes were analysed in order to identify the presence of copy number variants (CNVs) responsible for their condition identifying a yield of 12.8% of pathogenic CNVs (19% when including clinically recognizable microdeletion syndromes). Moreover, there is a detailed clinical description of an additional 11% of the patients harbouring possible pathogenic CNVs-including a 7q31 deletion (IMMP2L) in two unrelated patients and duplications in 3q29, 9p24.2p24.1 and 15q14q15.1-providing new evidence of its contribution to the phenotype. This study adds further proof of including chromosomal microarray analysis (CMA) as a mandatory test to improve the diagnosis in the adult patients in psychiatric services.
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http://dx.doi.org/10.1007/s10519-018-9902-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6028865PMC
July 2018

Neurodevelopmental risk copy number variants in adults with intellectual disabilities and comorbid psychiatric disorders.

Br J Psychiatry 2018 05;212(5):287-294

Department of Human Genetics,Centre for Human Genetics,University Hospitals Leuven,Leuven,Belgium.

Background: Copy number variants (CNVs) are established risk factors for neurodevelopmental disorders. To date the study of CNVs in psychiatric illness has focused on single disorder populations. The role of CNVs in individuals with intellectual disabilities and psychiatric comorbidities are less well characterised.AimsTo determine the type and frequency of CNVs in adults with intellectual disabilities and comorbid psychiatric disorders.

Method: A chromosomal microarray analysis of 599 adults recruited from intellectual disabilities psychiatry services at three European sites.

Results: The yield of pathogenic CNVs was high - 13%. Focusing on established neurodevelopmental disorder risk loci we find a significantly higher frequency in individuals with intellectual disabilities and comorbid psychiatric disorder (10%) compared with healthy controls (1.2%, P<0.0001), schizophrenia (3.1%, P<0.0001) and intellectual disability/autism spectrum disorder (6.5%, P < 0.00084) populations.

Conclusions: In the largest sample of adults with intellectual disabilities and comorbid psychiatric disorders to date, we find a high rate of pathogenic CNVs. This has clinical implications for the use of genetic investigations in intellectual disability psychiatry.Declaration of interestNone.
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http://dx.doi.org/10.1192/bjp.2017.65DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083594PMC
May 2018

Novel intragenic deletions within the UBE3A gene in two unrelated patients with Angelman syndrome: case report and review of the literature.

BMC Med Genet 2017 11 21;18(1):137. Epub 2017 Nov 21.

Genetics Laboratory, UDIAT-Centre Diagnòstic, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Parc del Taulí 1, 08208, Barcelona, Sabadell, Spain.

Background: Patients with Angelman syndrome (AS) are affected by severe intellectual disability with absence of speech, distinctive dysmorphic craniofacial features, ataxia and a characteristic behavioral phenotype. AS is caused by the lack of expression in neurons of the UBE3A gene, which is located in the 15q11.2-q13 imprinted region. Functional loss of UBE3A is due to 15q11.2-q13 deletion, mutations in the UBE3A gene, paternal uniparental disomy and genomic imprinting defects.

Case Presentation: We report here two patients with clinical features of AS referred to our hospital for clinical follow-up and genetic diagnosis. Methylation Specific-Multiplex Ligation-Dependent Probe Amplification (MS-MLPA) of the 15q11.2-q13 region was carried out in our laboratory as the first diagnostic tool detecting two novel UBE3A intragenic deletions. Subsequently, the MLPA P336-A2 kit was used to confirm and determine the size of the UBE3A deletion in the two patients. A review of the clinical features of previously reported patients with whole UBE3A gene or partial intragenic deletions is presented here together with these two new patients.

Conclusion: Although rare, UBE3A intragenic deletions may represent a small fraction of AS patients without a genetic diagnosis. Testing for UBE3A intragenic exonic deletions should be performed in those AS patients with a normal methylation pattern and no mutations in the UBE3A gene.
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http://dx.doi.org/10.1186/s12881-017-0500-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5696761PMC
November 2017

[Phenotype variability in thirteen 16p11.2 deletion patients].

An Pediatr (Engl Ed) 2018 Jul 14;89(1):62-63. Epub 2017 Oct 14.

Laboratorio de Genética, UDIAT-Centre Diagnòstic Hospital de Sabadell, Corporació Sanitària Parc Taulí, Fundació Parc Taulí Institut Universitari UAB, Sabadell, España.

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http://dx.doi.org/10.1016/j.anpedi.2017.08.003DOI Listing
July 2018

Copy number rather than epigenetic alterations are the major dictator of imprinted methylation in tumors.

Nat Commun 2017 09 7;8(1):467. Epub 2017 Sep 7.

Imprinting and Cancer group, Cancer Epigenetic and Biology Program (PEBC), Institut d'Investigació Biomedica de Bellvitge (IDIBELL), Avinguda Granvia, L'Hospitalet de Llobregat, 08907, Barcelona, Spain.

It has been postulated that imprinting aberrations are common in tumors. To understand the role of imprinting in cancer, we have characterized copy-number and methylation in over 280 cancer cell lines and confirm our observations in primary tumors. Imprinted differentially methylated regions (DMRs) regulate parent-of-origin monoallelic expression of neighboring transcripts in cis. Unlike single-copy CpG islands that may be prone to hypermethylation, imprinted DMRs can either loose or gain methylation during tumorigenesis. Here, we show that methylation profiles at imprinted DMRs often not represent genuine epigenetic changes but simply the accumulation of underlying copy-number aberrations (CNAs), which is independent of the genome methylation state inferred from cancer susceptible loci. Our results reveal that CNAs also influence allelic expression as loci with copy-number neutral loss-of-heterozygosity or amplifications may be expressed from the appropriate parental chromosomes, which is indicative of maintained imprinting, although not observed as a single expression foci by RNA FISH.Altered genomic imprinting is frequently reported in cancer. Here, the authors analyze copy number and methylation in cancer cell lines and primary tumors to show that imprinted methylation profiles represent the accumulation of copy number alteration, rather than epigenetic alterations.
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http://dx.doi.org/10.1038/s41467-017-00639-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5589900PMC
September 2017

Paternal transmission of a FMR1 full mutation allele.

Am J Med Genet A 2017 Oct 16;173(10):2795-2797. Epub 2017 Aug 16.

Biochemistry and Molecular Genetics Department, Hospital Clinic, Barcelona, Spain.

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability (ID) and autism. In most of cases, the molecular basis of this syndrome is a CGG repeat expansion in the 5' untranslated region of the FMR1 gene. It is inherited as an X linked dominant trait, with a reduced penetrance (80% for males and 30% for females). Full mutation (FM) expansion from premutated alleles (PM) is only acquired via maternal meiosis, while paternal transmission always remains in the PM range. We present a 16-year-old girl with a mild fragile X syndrome phenotype. FMR1 gene study showed that the patient inherited a mosaic premutation-full mutation with an unmethylated uninterrupted allele (175, >200 CGG) from her father. The father showed an 88 CGG uninterrupted unmethylated allele in blood and sperm cells. To our knowledge, this is the first case of a FMR1 mosaic premutation-full mutation allele inherited from a PM father. In our opinion, the most likely explanation could be a postzygotic somatic expansion. We can conclude that in rare cases of a child with a full mutation whose mother does not carry a premutation, the possibility of paternal transmission should be considered.
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http://dx.doi.org/10.1002/ajmg.a.38384DOI Listing
October 2017

RNA editing independently occurs at three mir-376a-1 sites and may compromise the stability of the microRNA hairpin.

Gene 2017 Sep 12;628:109-116. Epub 2017 Jul 12.

Institute of Evolutionary Biology (IBE) (Universitat Pompeu Fabra-CSIC), Barcelona 08003, Spain; School of Medicine, University of Magallanes, Punta Arenas, Chile. Electronic address:

RNA editing is being recognized as an important post-transcriptional mechanism that may have crucial roles in introducing genetic variation and phenotypic diversity. Despite microRNA editing recurrence, defining its biological relevance is still under extended debate. To better understand microRNA editing function and regulation we performed an exhaustive characterization of the A-to-I site-specific patterns in mir-376a-1, a mammalian microRNA which RNA editing is involved in the regulation of development and in disease. Thorough an integrative approach based on high-throughput small RNA sequencing, Sanger sequencing and computer simulations we explored mir-376a-1 editing in samples from various individuals and primate species including human placenta and macaque, gorilla, chimpanzee and human brain cortex. We observed that mir-376a-1 editing is a common phenomenon in the mature and primary microRNA molecules and it is more frequently detected in brain than in placenta. Primary mir-376a-1 is edited at three positions, -1, +4 and +44. Editing frequency estimations and in silico simulations indicated that editing was not equally recurrent along the three mir-376a-1 sites, nevertheless no epistatic interactions among them were observed. Particularly, the +4 site, located in the seed region of the mature miR-376a-5p, reached the highest editing frequency in all samples. Secondary structure predictions revealed that the +4 position was the one that conferred the highest stability to the mir-376a-1 hairpin. We suggest that molecular stability might partially explain the editing recurrence observed in certain microRNAs and that editing events conferring new functional regulatory roles in particular tissues and species could have been conserved along evolution, as it might be the case of mir-376a-1 in primate brain cortex.
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http://dx.doi.org/10.1016/j.gene.2017.07.032DOI Listing
September 2017

Lack of Postprandial Peak in Brain-Derived Neurotrophic Factor in Adults with Prader-Willi Syndrome.

PLoS One 2016;11(9):e0163468. Epub 2016 Sep 29.

Department of Endocrinology and Nutrition, Sabadell University Hospital, Corporació Sanitària Parc Taulí, Sabadell, Spain, Autonomous University of Barcelona, Bellaterra, Spain.

Context: Prader-Willi syndrome (PWS) is characterized by severe hyperphagia. Brain-derived neurotrophic factor (BDNF) and leptin are reciprocally involved in energy homeostasis.

Objectives: To analyze the role of BDNF and leptin in satiety in genetic subtypes of PWS.

Design: Experimental study.

Setting: University hospital.

Subjects: 90 adults: 30 PWS patients; 30 age-sex-BMI-matched obese controls; and 30 age-sex-matched lean controls.

Interventions: Subjects ingested a liquid meal after fasting ≥10 hours.

Main Outcome Measures: Leptin and BDNF levels in plasma extracted before ingestion and 30', 60', and 120' after ingestion. Hunger, measured on a 100-point visual analogue scale before ingestion and 60' and 120' after ingestion.

Results: Fasting BDNF levels were lower in PWS than in controls (p = 0.05). Postprandially, PWS patients showed only a truncated early peak in BDNF, and their BDNF levels at 60' and 120' were lower compared with lean controls (p<0.05). Leptin was higher in PWS patients than in controls at all time points (p<0.001). PWS patients were hungrier than controls before and after eating. The probability of being hungry was associated with baseline BDNF levels: every 50-unit increment in BDNF decreased the odds of being hungry by 22% (OR: 0.78, 95%CI: 0.65-0.94). In uniparental disomy, the odds of being hungry decreased by 66% (OR: 0.34, 90%CI: 0.13-0.9). Postprandial leptin patterns did no differ among genetic subtypes.

Conclusions: Low baseline BDNF levels and lack of postprandial peak may contribute to persistent hunger after meals. Uniparental disomy is the genetic subtype of PWS least affected by these factors.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0163468PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5042477PMC
September 2016

Complete APTX deletion in a patient with ataxia with oculomotor apraxia type 1.

BMC Med Genet 2015 Aug 19;16:61. Epub 2015 Aug 19.

Department of Clinical Genetics, Erasmus Medical Center, P.O. Box 2040, Rotterdam, 3000 CA, The Netherlands.

Background: Ataxia with oculomotor apraxia type 1 is an autosomal-recessive neurodegenerative disorder characterized by a childhood onset of slowly progressive cerebellar ataxia, followed by oculomotor apraxia and a severe primary motor peripheral axonal motor neuropathy. Ataxia with oculomotor apraxia type 1 is caused by bi-allelic mutations in APTX (chromosome 9p21.1).

Case Presentation: Our patient has a clinical presentation that is typical for ataxia with oculomotor apraxia type 1 with no particularly severe phenotype. Multiplex Ligation-dependent Probe Amplification analysis resulted in the identification of a homozygous deletion of all coding APTX exons (3 to 9). SNP array analysis using the Illumina Infinium CytoSNP-850 K microarray indicated that the deletion was about 62 kb. Based on the SNP array results, the breakpoints were found using direct sequence analysis: c.-5 + 1225_*44991del67512, p.0?. Both parents were heterozygous for the deletion. Homozygous complete APTX deletions have been described in literature for two other patients. We obtained a sample from one of these two patients and characterized the deletion (156 kb) as c.-23729_*115366del155489, p.0?, including the non-coding exons 1A and 2 of APTX. The more severe phenotype reported for this patient is not observed in our patient. It remains unclear whether the larger size of the deletion (156 kb vs 62 kb) plays a role in the phenotype (no extra genes are deleted).

Conclusion: Here we described an ataxia with oculomotor apraxia type 1 patient who has a homozygous deletion of the complete coding region of APTX. In contrast to the patient with the large deletion, our patient does not have a severe phenotype. More patients with deletions of APTX are required to investigate a genotype-phenotype effect.
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http://dx.doi.org/10.1186/s12881-015-0213-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4593195PMC
August 2015

A 11.7-Mb Paracentric Inversion in Chromosome 1q Detected in Prenatal Diagnosis Associated with Familial Intellectual Disability.

Cytogenet Genome Res 2015 31;146(2):109-14. Epub 2015 Jul 31.

Unitat de Biologia Celx2219;lular i Genx00E8;tica Mx00E8;dica, Departament de Biologia Celx2219;lular, Fisiologia i Immunologia, Facultat de Medicina, Universitat Autx00F2;noma de Barcelona, Bellaterra, Spain.

Most apparent balanced chromosomal inversions are usually clinically asymptomatic; however, infertility, miscarriages, and mental retardation have been reported in inversion carriers. We present a small family with a paracentric inversion 1q42.13q43 detected in routine prenatal diagnosis. Molecular cytogenetic methods defined the size of the inversion as 11.7 Mb and excluded other unbalanced chromosomal alterations in the patients. Our findings suggest that intellectual disability is caused by dysfunction, disruption, or position effects of genes located at or near the breakpoints involved in this inversion.
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http://dx.doi.org/10.1159/000437127DOI Listing
January 2016

A common cognitive, psychiatric, and dysmorphic phenotype in carriers of NRXN1 deletion.

Mol Genet Genomic Med 2014 Nov 18;2(6):512-21. Epub 2014 Aug 18.

Laboratori de Genètica, UDIAT-Centre Diagnòstic, Corporació Sanitària Parc Taulí, Institut Universitari Parc Tauli-UAB Sabadell, Spain.

Deletions in the 2p16.3 region that includes the neurexin (NRXN1) gene are associated with intellectual disability and various psychiatric disorders, in particular, autism and schizophrenia. We present three unrelated patients, two adults and one child, in whom we identified an intragenic 2p16.3 deletion within the NRXN1 gene using an oligonucleotide comparative genomic hybridization array. The three patients presented dual diagnosis that consisted of mild intellectual disability and autism and bipolar disorder. Also, they all shared a dysmorphic phenotype characterized by a long face, deep set eyes, and prominent premaxilla. Genetic analysis of family members showed two inherited deletions. A comprehensive neuropsychological examination of the 2p16.3 deletion carriers revealed the same phenotype, characterized by anxiety disorder, borderline intelligence, and dysexecutive syndrome. The cognitive pattern of dysexecutive syndrome with poor working memory and reduced attention switching, mental flexibility, and verbal fluency was the same than those of the adult probands. We suggest that in addition to intellectual disability and psychiatric disease, NRXN1 deletion is a risk factor for a characteristic cognitive and dysmorphic profile. The new cognitive phenotype found in the 2p16.3 deletion carriers suggests that 2p16.3 deletions might have a wide variable expressivity instead of incomplete penetrance.
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http://dx.doi.org/10.1002/mgg3.105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4303221PMC
November 2014

Genetic testing in hereditary breast and ovarian cancer using massive parallel sequencing.

Biomed Res Int 2014 26;2014:542541. Epub 2014 Jun 26.

Laboratorio de Genética, UDIAT-Centre Diagnòstic, Corporació Sanitària Parc Taulí Institut Universitari (UAB), Parc Taulí s/n, Sabadell, 08208 Barcelona, Spain.

High throughput methods such as next generation sequencing are increasingly used in molecular diagnosis. The aim of this study was to develop a workflow for the detection of BRCA1 and BRCA2 mutations using massive parallel sequencing in a 454 GS Junior bench top sequencer. Our approach was first validated in a panel of 23 patients containing 62 unique variants that had been previously Sanger sequenced. Subsequently, 101 patients with familial breast and ovarian cancer were studied. BRCA1 and BRCA2 exon enrichment has been performed by PCR amplification using the BRCA MASTR kit (Multiplicom). Bioinformatic analysis of reads is performed with the AVA software v2.7 (Roche). In total, all 62 variants were detected resulting in a sensitivity of 100%. 71 false positives were called resulting in a specificity of 97.35%. All of them correspond to deletions located in homopolymeric stretches. The analysis of the homopolymers stretches of 6 bp or longer using the BRCA HP kit (Multiplicom) increased the specificity of the detection of BRCA1 and BRCA2 mutations to 99.99%. We show here that massive parallel pyrosequencing can be used as a diagnostic strategy to test for BRCA1 and BRCA2 mutations meeting very stringent sensitivity and specificity parameters replacing traditional Sanger sequencing with a lower cost.
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http://dx.doi.org/10.1155/2014/542541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4098986PMC
May 2015

Molecular testing for fragile X: analysis of 5062 tests from 1105 fragile X families--performed in 12 clinical laboratories in Spain.

Biomed Res Int 2014 28;2014:195793. Epub 2014 May 28.

Servicio de Bioquímica y Genética Molecular, Hospital Clinic, IDIBAPS, CIBER de Enfermedades Raras (CIBERER-ISCIII), 08036 Barcelona, Spain.

Fragile X syndrome is the most common inherited form of intellectual disability. Here we report on a study based on a collaborative registry, involving 12 Spanish centres, of molecular diagnostic tests in 1105 fragile X families comprising 5062 individuals, of whom, 1655 carried a full mutation or were mosaic, three cases had deletions, 1840 had a premutation, and 102 had intermediate alleles. Two patients with the full mutation also had Klinefelter syndrome. We have used this registry to assess the risk of expansion from parents to children. From mothers with premutation, the overall rate of allele expansion to full mutation is 52.5%, and we found that this rate is higher for male than female offspring (63.6% versus 45.6%; P < 0.001). Furthermore, in mothers with intermediate alleles (45-54 repeats), there were 10 cases of expansion to a premutation allele, and for the smallest premutation alleles (55-59 repeats), there was a 6.4% risk of expansion to a full mutation, with 56 repeats being the smallest allele that expanded to a full mutation allele in a single meiosis. Hence, in our series the risk for alleles of <59 repeats is somewhat higher than in other published series. These findings are important for genetic counselling.
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http://dx.doi.org/10.1155/2014/195793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4058505PMC
February 2015

MECP2 gene study in a large cohort: testing of 240 female patients and 861 healthy controls (519 females and 342 males).

J Mol Diagn 2013 Sep 26;15(5):723-9. Epub 2013 Jun 26.

Molecular Genetics Laboratory, Genetics Service, BioCruces Health Research Institute, Cruces University Hospital, Barakaldo-Bizkaia, Spain.

The MECP2 gene located on Xq28 is one of the most important genes contributing to the spectrum of neurodevelopmental disorders. Therefore, we present our experience in the molecular study of this gene. MECP2 was thoroughly tested for the presence of mutations (sequencing of four exons and rearrangements) in 120 female patients: 28 with classic Rett syndrome, five with atypical Rett syndrome, and 87 with heterogeneous phenotypes with some Rett-like features. Another 120 female patients with intellectual disability of unknown origin were also studied, but in these cases we only tested exons 3 and 4. Finally, 861 healthy controls (519 females and 342 males) were also studied for exon 3 and 4. Eighteen different pathological mutations were found, five of them previously undescribed, and four large deletions detected by multiplex ligation-dependent probe amplification. All were de novo mutations not present in the parents. In conclusion, i) MECP2 is one of the most important genes in the diagnosis of genetic intellectual disability in females; ii) MECP2 must be studied not only in patients with classical/atypical Rett syndrome but also in patients with other phenotypes related to Rett syndrome; and iii) for the new variants, it is important to perform complementary studies, including the analysis of large populations of healthy individuals and the use of in silico programs.
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http://dx.doi.org/10.1016/j.jmoldx.2013.05.002DOI Listing
September 2013

[The genetic bases of neurodevelopmental disorders].

Rev Neurol 2013 Feb;56 Suppl 1:S23-34

Centre Medic Psyncron, Sabadell, Barcelona, Spain.

In the last decade, progress made in genetics is questioning the current implicit nosological model in the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision (DSM-IV-TR) and the International Classification of Diseases, tenth revision. Both the categorical nature and the comorbidity detected on applying diagnostic criteria become unsustainable in the light of the genetic architecture that is emerging from studies being conducted on the genetics of mental disorders. The classical paradigms -one gene for one disease- or even a specific distinctive genetic pattern for each condition, are concepts restricted to specific cases. In this review the objective is to describe the current scenario that has arisen following the latest advances in genetics. The lines of work being traced by research both in the present and in the near future include: the identification of variations in the number of copies (both frequent and rare), indiscriminately linked to different disorders; the concurrence of multiple variants for a single disorder; the double hit phenomenon; and epigenetic modulation. The new version of the DSM, fully aware of the deficiencies in the current model, will mark a turning point that, while somewhat timid, is decidedly oriented towards incorporating a dimensional conception of mental disorders.
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February 2013

Genome-wide allelic methylation analysis reveals disease-specific susceptibility to multiple methylation defects in imprinting syndromes.

Hum Mutat 2013 Apr 19;34(4):595-602. Epub 2013 Feb 19.

Imprinting and Cancer Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.

Genomic imprinting is the parent-of-origin-specific allelic transcriptional silencing observed in mammals, which is governed by DNA methylation established in the gametes and maintained throughout the development. The frequency and extent of epimutations associated with the nine reported imprinting syndromes varies because it is evident that aberrant preimplantation maintenance of imprinted differentially methylated regions (DMRs) may affect multiple loci. Using a custom Illumina GoldenGate array targeting 27 imprinted DMRs, we profiled allelic methylation in 65 imprinting defect patients. We identify multilocus hypomethylation in numerous Beckwith-Wiedemann syndrome, transient neonatal diabetes mellitus (TNDM), and pseudohypoparathyroidism 1B patients, and an individual with Silver-Russell syndrome. Our data reveal a broad range of epimutations exist in certain imprinting syndromes, with the exception of Prader-Willi syndrome and Angelman syndrome patients that are associated with solitary SNRPN-DMR defects. A mutation analysis identified a 1 bp deletion in the ZFP57 gene in a TNDM patient with methylation defects at multiple maternal DMRs. In addition, we observe missense variants in ZFP57, NLRP2, and NLRP7 that are not consistent with maternal effect and aberrant establishment or methylation maintenance, and are likely benign. This work illustrates that further extensive molecular characterization of these rare patients is required to fully understand the mechanism underlying the etiology of imprint establishment and maintenance.
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http://dx.doi.org/10.1002/humu.22276DOI Listing
April 2013

Analysis of the C9orf72 gene in patients with amyotrophic lateral sclerosis in Spain and different populations worldwide.

Hum Mutat 2013 Jan 11;34(1):79-82. Epub 2012 Oct 11.

Department of Neurology, ALS Unit, Instituto de Investigación Biomédica Hospital 12 de Octubre, Madrid, Spain.

A hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9orf72) can cause amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD). We assessed its frequency in 781 sporadic ALS (sALS) and 155 familial ALS (fALS) cases, and in 248 Spanish controls. We tested the presence of the reported founder haplotype among mutation carriers and in 171 Ceph Europeans from Utah (CEU), 170 Yoruba Africans, 81 Han Chinese, and 85 Japanese subjects. The C9orf72 expansion was present in 27.1% of fALS and 3.2% of sALS. Mutation carriers showed lower age at onset (P = 0.04), shorter survival (P = 0.02), greater co-occurrence of FTD (P = 8.2 × 10(-5)), and more family history of ALS (P = 1.4 × 10(-20)), than noncarriers. No association between alleles within the normal range and the risk of ALS was found (P = 0.12). All 61 of the mutation carriers were tested and a patient carrying 28 hexanucleotide repeats presented with the founder haplotype. This haplotype was found in 5.6% Yoruba Africans, 8.9% CEU, 3.9% Japanese, and 1.6% Han Chinese chromosomes.
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http://dx.doi.org/10.1002/humu.22211DOI Listing
January 2013

Establishment of the first WHO international genetic reference panel for Prader Willi and Angelman syndromes.

Eur J Hum Genet 2011 Aug 18;19(8):857-64. Epub 2011 May 18.

National Institute for Biological Standards and Control, Blanche Lane, South Mimms, Herts, UK.

Prader Willi and Angelman syndromes are clinically distinct genetic disorders both mapping to chromosome region 15q11-q13, which are caused by a loss of function of paternally or maternally inherited genes in the region, respectively. With clinical diagnosis often being difficult, particularly in infancy, confirmatory genetic diagnosis is essential to enable clinical intervention. However, the latter is challenged by the complex genetics behind both disorders and the unmet need for characterised reference materials to aid accurate molecular diagnosis. With this in mind, a panel of six genotyping reference materials for Prader Willi and Angelman syndromes was developed, which should be stable for many years and available to all diagnostic laboratories. The panel comprises three Prader Willi syndrome materials (two with different paternal deletions, and one with maternal uniparental disomy (UPD)) and three Angelman syndrome materials (one with a maternal deletion, one with paternal UPD or an epigenetic imprinting centre defect, and one with a UBE3A point mutation). Genomic DNA was bulk-extracted from Epstein-Barr virus-transformed lymphoblastoid cell lines established from consenting patients, and freeze-dried as aliquots in glass ampoules. In total, 37 laboratories from 26 countries participated in a collaborative study to assess the suitability of the panel. Participants evaluated the blinded, triplicate materials using their routine diagnostic methods against in-house controls or externally sourced uncertified reference materials. The panel was established by the Expert Committee on Biological Standardization of the World Health Organization as the first International Genetic Reference Panel for Prader Willi and Angelman syndromes.
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http://dx.doi.org/10.1038/ejhg.2011.59DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3172937PMC
August 2011

Comprehensive copy number variant (CNV) analysis of neuronal pathways genes in psychiatric disorders identifies rare variants within patients.

J Psychiatr Res 2010 Oct 15;44(14):971-8. Epub 2010 Apr 15.

CIBER en Epidemiología y Salud Pública (CIBERESP), Genes and Disease Program, Center for Genomic Regulation (CRG-UPF), Barcelona 08003, Catalonia, Spain.

Background: Copy number variations (CNV) have become an important source of human genome variability noteworthy to consider when studying genetic susceptibility to complex diseases. As recent studies have found evidences for the potential involvement of CNVs in psychiatric disorders, we have studied the dosage effect of structural genome variants as a possible susceptibility factor for different psychiatric disorders in a candidate gene approach.

Methods: After selection of 68 psychiatric disorders' candidate genes overlapping with CNVs, MLPA assays were designed to determine changes in copy number of these genes. The studied sample consisted of 724 patients with psychiatric disorders (accounting for anxiety disorders, mood disorders, eating disorders and schizophrenia) and 341 control individuals.

Results: CNVs were detected in 30 out of the 68 genes screened, indicating that a considerable proportion of neuronal pathways genes contain CNVs. When testing the overall burden of rare structural genomic variants in the different psychiatric disorders compared to control individuals, there was no statistically significant difference in the total amount of gains and losses. However, 14 out of the 30 changes were only found in psychiatric disorder patients but not in control individuals. These genes include GRM7, previously associated to major depression disorder and bipolar disorder, SLC6A13, in anxiety disorders, and S100B, SSTR5 and COMT in schizophrenia.

Conclusions: Although we have not been able to found a clear association between the studied CNVs and psychiatric disorders, the rare variants found only within the patients could account for a step further towards understanding the pathophysiology of psychiatric disorders.
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http://dx.doi.org/10.1016/j.jpsychires.2010.03.007DOI Listing
October 2010

Association study of 44 candidate genes with depressive and anxiety symptoms in post-partum women.

J Psychiatr Res 2010 Aug 22;44(11):717-24. Epub 2010 Jan 22.

Fundación Pública Galega de Medicina Xenómica-SERGAS, Hospital Clínico Universitario, Santiago de Compostela, Spain.

The post-partum period is a time of extreme vulnerability for a whole spectrum of psychiatric disorders. Delivery may be considered an important risk factor in genetically susceptible women. Five hundred and eight SNPs in 44 genes at candidate pathways putatively related to mood changes after delivery were genotyped in a multicenter cohort of 1804 women from Spain. Participants completed two scales at 2-3 days, 8 weeks, and 32 weeks post-partum, the Edinburgh Post-partum Depression Scale (EPDS) and the Spielberger State-Trait Anxiety Inventory (STAI). Those women who scored 9 or more on EPDS were evaluated for major depression using the Diagnostic Interview for Genetics Studies (DIGS) adapted for post-partum depression. Association with major depression was assessed using likelihood ratio tests under a codominant genotype model. Association with scale scores was tested using linear mixed models to take into account repeated measures over time. Two intronic SNPs, one at the serotonin transporter gene (SLC6A4) and another at dopa decarboxylase (DDC), were significantly associated to STAI anxiety scores after multiple testing correction (nominal P=0.0000513 and 0.000097, respectively). In addition, post hoc analysis at the unphased haplotype level using nominal significant SNPs revealed an association with a combination of three SNPs at protein kinase C, beta (PRKCB) with major depression, significant after multiple testing correction (nominal global P=0.0001596). In conclusion, we detected a role of SLC6A4 in mood changes after stressful events, and revealed new putative associations involving DDC and PRKCB. Therefore, these genes deserve further investigation to confirm these results.
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http://dx.doi.org/10.1016/j.jpsychires.2009.12.012DOI Listing
August 2010

BAC array CGH in patients with Velocardiofacial syndrome-like features reveals genomic aberrations on chromosome region 1q21.1.

BMC Med Genet 2009 Dec 23;10:144. Epub 2009 Dec 23.

Genes and Disease Program, CIBER en Epidemiología y Salud Pública (CIBERESP), Center for Genomic Regulation (CRG), Barcelona, Catalonia, Spain.

Background: Microdeletion of the chromosome 22q11.2 region is the most common genetic aberration among patients with velocardiofacial syndrome (VCFS) but a subset of subjects do not show alterations of this chromosome region.

Methods: We analyzed 18 patients with VCFS-like features by comparative genomic hybridisation (aCGH) array and performed a face-to-face slide hybridization with two different arrays: a whole genome and a chromosome 22-specific BAC array. Putative rearrangements were confirmed by FISH and MLPA assays.

Results: One patient carried a combination of rearrangements on 1q21.1, consisting in a microduplication of 212 kb and a close microdeletion of 1.15 Mb, previously reported in patients with variable phenotypes, including mental retardation, congenital heart defects (CHD) and schizophrenia. While 326 control samples were negative for both 1q21.1 rearrangements, one of 73 patients carried the same 212-kb microduplication, reciprocal to TAR microdeletion syndrome. Also, we detected four copy number variants (CNVs) inherited from one parent (a 744-kb duplication on 10q11.22; a 160 kb duplication and deletion on 22q11.21 in two cases; and a gain of 140 kb on 22q13.2), not present in control subjects, raising the potential role of these CNVs in the VCFS-like phenotype.

Conclusions: Our results confirmed aCGH as a successful strategy in order to characterize additional submicroscopic aberrations in patients with VCF-like features that fail to show alterations in 22q11.2 region. We report a 212-kb microduplication on 1q21.1, detected in two patients, which may contribute to CHD.
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http://dx.doi.org/10.1186/1471-2350-10-144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2805625PMC
December 2009

[Prader Willi syndrome patients: study of 77 patients].

Med Clin (Barc) 2009 Nov 13;133(17):649-56. Epub 2009 Sep 13.

Unitat de Biologia Cellular, Facultat de Biociències, Universitat Autònoma de Barcelona, Barcelona, España.

Background: The Prader-Willi syndrome (PWS) is a disease of genetic origin. It is characterized by neonatal hypotonia, hypogonadism, hiperfagia leading to obesity, low stature, developmental delay, moderate mental retardation, abnormal behavior and characteristic facial appearance. It is caused by the loss or the inactivation of paternal genes of the imprinted region 15q11-13. There are different genetic causes: paternal 15q11-q13 deletion in 70% of patients, maternal uniparental disomy in the 20-25% and less than 5% have an imprinting defect. We present the results obtained in the transverse clinical - genetic study of 77 PWS patients.

Patients And Methods: There has been realized the study of 374 suspected PWS patients. Cytogenetics studies of bands G and hybridization in situ fluorescent (FISH) and molecular genetics analysis of microsatellites, Southern blot, MS-PCR and sequenciation were carried out. Holm's criteria use for the correlation phenotype - genotype in 48 patients.

Results: PWS was confirmed in 77 patients, 46 deletion, 16 uniparental disomy, two imprinting defect and 13 only PWS methylation pattern. Significant differences do not observe in the correlation phenotype - genotype.

Conclusions: The frequencies of the molecular alterations, 71.87 % deletion, 25 % UPD and 3.12 % DI, they are similar to described in the literature. It presents the algorithm of diagnosis used with the MS-PCR as rapid technology to confirm PWS.
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http://dx.doi.org/10.1016/j.medcli.2009.04.051DOI Listing
November 2009

Novel UBE3A mutations causing Angelman syndrome: different parental origin for single nucleotide changes and multiple nucleotide deletions or insertions.

Am J Med Genet A 2009 Mar;149A(3):343-8

Unitat de Biologia Cel.lular, Facultat de Biociències, Universitat Autònoma de Barcelona, Bellaterra, Spain.

Angelman syndrome (AS) is a genetic disorder caused by a deficiency of UBE3A imprinted gene expression from the maternal chromosome 15. In 10% of AS cases the genetic cause is a mutation affecting the maternal copy of the UBE3A gene. In two large Spanish series of clinically stringently selected and nonstringently selected patients, we have identified 11 pathological mutations--eight of them novel mutations--and 14 sequence changes considered polymorphic variants. Remarkably, single nucleotide substitutions are more likely to be inherited, while multiple nucleotide deletions or insertions are less frequently inherited, thus indicating that single nucleotide substitutions are more likely to originate from the paternal germline. Additionally, there seems to be a different distribution of nucleotide changes and multiple nucleotide deletions or insertions along the UBE3A gene sequence.
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http://dx.doi.org/10.1002/ajmg.a.32659DOI Listing
March 2009

Identification of new putative susceptibility genes for several psychiatric disorders by association analysis of regulatory and non-synonymous SNPs of 306 genes involved in neurotransmission and neurodevelopment.

Am J Med Genet B Neuropsychiatr Genet 2009 Sep;150B(6):808-16

CIBER en Epidemiología y Salud Pública (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain.

A fundamental difficulty in human genetics research is the identification of the spectrum of genetic variants that contribute to the susceptibility to common/complex disorders. We tested here the hypothesis that functional genetic variants may confer susceptibility to several related common disorders. We analyzed five main psychiatric diagnostic categories (substance-abuse, anxiety, eating, psychotic, and mood disorders) and two different control groups, representing a total of 3,214 samples, for 748 promoter and non-synonymous single nucleotide polymorphisms (SNPs) at 306 genes involved in neurotransmission and/or neurodevelopment. We identified strong associations to individual disorders, such as growth hormone releasing hormone (GHRH) with anxiety disorders, prolactin regulatory element (PREB) with eating disorders, ionotropic kainate glutamate receptor 5 (GRIK5) with bipolar disorder and several SNPs associated to several disorders, that may represent individual and related disease susceptibility factors. Remarkably, a functional SNP, rs945032, located in the promoter region of the bradykinin receptor B2 gene (BDKRB2) was associated to three disorders (panic disorder, substance abuse, and bipolar disorder), and two additional BDKRB2 SNPs to obsessive-compulsive disorder and major depression, providing evidence for common variants of susceptibility to several related psychiatric disorders. The association of BDKRB2 (odd ratios between 1.65 and 3.06) to several psychiatric disorders supports the view that a common genetic variant could confer susceptibility to clinically related phenotypes, and defines a new functional hint in the pathophysiology of psychiatric diseases.
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http://dx.doi.org/10.1002/ajmg.b.30902DOI Listing
September 2009