Publications by authors named "Gabriela M Repetto"

41 Publications

Pharmacogenetics in Psychiatry: Perceived Value and Opinions in a Chilean Sample of Practitioners.

Front Pharmacol 2021 15;12:657985. Epub 2021 Apr 15.

Center for Genetics and Genomics, Instituto de Ciencias e Innovación en Medicina, Facultad de Medicina, Clínica Alemana Universidad Del Desarrollo, Santiago, Chile.

Use of pharmacogenetics (PGx) testing to guide clinical decisions is growing in developed countries. Published guidelines for gene-drug pair analysis are available for prescriptions in psychiatry, but information on their utilization, barriers, and health outcomes in Latin America is limited. As a result, this work aimed at exploring current use, opinions, and perceived obstacles on PGx testing among psychiatrists in Chile, via an online, anonymous survey. Among 123 respondents (5.9% of registered psychiatrists in the country), 16.3% reported ever requesting a PGx test. The vast majority (95%) of tests were ordered by clinicians practicing in the Metropolitan Region of Santiago. Having more than 20 years in practice was positively associated with prior use of PGx (p 0.02, OR 3.74 (1.19-11.80)), while working in the public health system was negatively associated (OR 0.30 (0.10-0.83)). Perceived barriers to local implementation included insufficient evidence of clinical utility, limited clinicians' knowledge on PGx and on test availability, and health systems' issues, such as costs and reimbursement. Despite the recognition of these barriers, 80% of respondents asserted that it is likely that they will incorporate PGx tests in their practice in the next five years. Given these results, we propose next steps to facilitate implementation such as further research in health outcomes and clinical utility of known and novel clinically actionable variants, growth in local sequencing capabilities, education of clinicians, incorporation of clinical decision support tools, and economic evaluations, all in local context.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2021.657985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082421PMC
April 2021

Clinical, neuroimaging, and molecular spectrum of TECPR2-associated hereditary sensory and autonomic neuropathy with intellectual disability.

Hum Mutat 2021 Jun 11;42(6):762-776. Epub 2021 May 11.

Oxford Centre for Genomic Medicine, Oxford, UK.

Bi-allelic TECPR2 variants have been associated with a complex syndrome with features of both a neurodevelopmental and neurodegenerative disorder. Here, we provide a comprehensive clinical description and variant interpretation framework for this genetic locus. Through international collaboration, we identified 17 individuals from 15 families with bi-allelic TECPR2-variants. We systemically reviewed clinical and molecular data from this cohort and 11 cases previously reported. Phenotypes were standardized using Human Phenotype Ontology terms. A cross-sectional analysis revealed global developmental delay/intellectual disability, muscular hypotonia, ataxia, hyporeflexia, respiratory infections, and central/nocturnal hypopnea as core manifestations. A review of brain magnetic resonance imaging scans demonstrated a thin corpus callosum in 52%. We evaluated 17 distinct variants. Missense variants in TECPR2 are predominantly located in the N- and C-terminal regions containing β-propeller repeats. Despite constituting nearly half of disease-associated TECPR2 variants, classifying missense variants as (likely) pathogenic according to ACMG criteria remains challenging. We estimate a pathogenic variant carrier frequency of 1/1221 in the general and 1/155 in the Jewish Ashkenazi populations. Based on clinical, neuroimaging, and genetic data, we provide recommendations for variant reporting, clinical assessment, and surveillance/treatment of individuals with TECPR2-associated disorder. This sets the stage for future prospective natural history studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/humu.24206DOI Listing
June 2021

Effects of copy number variations on brain structure and risk for psychiatric illness: Large-scale studies from the ENIGMA working groups on CNVs.

Hum Brain Mapp 2021 Feb 21. Epub 2021 Feb 21.

Center for Neuroimaging, Genetics and Genomics, School of Psychology, NUI Galway, Galway, Ireland.

The Enhancing NeuroImaging Genetics through Meta-Analysis copy number variant (ENIGMA-CNV) and 22q11.2 Deletion Syndrome Working Groups (22q-ENIGMA WGs) were created to gain insight into the involvement of genetic factors in human brain development and related cognitive, psychiatric and behavioral manifestations. To that end, the ENIGMA-CNV WG has collated CNV and magnetic resonance imaging (MRI) data from ~49,000 individuals across 38 global research sites, yielding one of the largest studies to date on the effects of CNVs on brain structures in the general population. The 22q-ENIGMA WG includes 12 international research centers that assessed over 533 individuals with a confirmed 22q11.2 deletion syndrome, 40 with 22q11.2 duplications, and 333 typically developing controls, creating the largest-ever 22q11.2 CNV neuroimaging data set. In this review, we outline the ENIGMA infrastructure and procedures for multi-site analysis of CNVs and MRI data. So far, ENIGMA has identified effects of the 22q11.2, 16p11.2 distal, 15q11.2, and 1q21.1 distal CNVs on subcortical and cortical brain structures. Each CNV is associated with differences in cognitive, neurodevelopmental and neuropsychiatric traits, with characteristic patterns of brain structural abnormalities. Evidence of gene-dosage effects on distinct brain regions also emerged, providing further insight into genotype-phenotype relationships. Taken together, these results offer a more comprehensive picture of molecular mechanisms involved in typical and atypical brain development. This "genotype-first" approach also contributes to our understanding of the etiopathogenesis of brain disorders. Finally, we outline future directions to better understand effects of CNVs on brain structure and behavior.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hbm.25354DOI Listing
February 2021

Contribution of Mitochondrial DNA Heteroplasmy to the Congenital Cardiac and Palatal Phenotypic Variability in Maternally Transmitted 22q11.2 Deletion Syndrome.

Genes (Basel) 2021 Jan 13;12(1). Epub 2021 Jan 13.

Center for Genetics and Genomics, Facultad de Medicina Clínica Alemana, Universidad del Desarrollo, Santiago 7710162, Chile.

Congenital heart disease (CHD) and palatal anomalies (PA), are among the most common characteristics of 22q11.2 deletion syndrome (22q11.2DS), but they show incomplete penetrance, suggesting the presence of additional factors. The 22q11.2 deleted region contains nuclear encoded mitochondrial genes, and since mitochondrial function is critical during development, we hypothesized that changes in the mitochondrial DNA (mtDNA) could be involved in the intrafamilial variability of CHD and PA in cases of maternally inherited 22q11.2DS. To investigate this, we studied the transmission of heteroplasmic mtDNA alleles in seventeen phenotypically concordant and discordant mother-offspring 22q11.2DS pairs. We sequenced their mtDNA and identified 26 heteroplasmic variants at >1% frequency, representing 18 transmissions. The median allele frequency change between a mother and her child was twice as much, with a wider distribution range, in PA discordant pairs, -value = 0.039 (permutation test, 11 concordant vs. 7 discordant variants), but not in CHD discordant pairs, -value = 0.441 (9 vs. 9). Only the variant m.9507T>C was considered to be pathogenic, but it was unrelated to the structural phenotypes. Our study is novel, yet our results are not consistent with mtDNA variation contributing to PA or CHD in 22q11.2DS. Larger cohorts and additional factors should be considered moving forward.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/genes12010092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828421PMC
January 2021

Barriers and Considerations for Diagnosing Rare Diseases in Indigenous Populations.

Front Pediatr 2020 14;8:579924. Epub 2020 Dec 14.

Western Australian Register of Developmental Anomalies, Perth, WA, Australia.

Advances in omics and specifically genomic technologies are increasingly transforming rare disease diagnosis. However, the benefits of these advances are disproportionately experienced within and between populations, with Indigenous populations frequently experiencing diagnostic and therapeutic inequities. The International Rare Disease Research Consortium (IRDiRC) multi-stakeholder partnership has been advancing toward the vision of all people living with a rare disease receiving an accurate diagnosis, care, and available therapy within 1 year of coming to medical attention. In order to further progress toward this vision, IRDiRC has created a taskforce to explore the access barriers to diagnosis of rare genetic diseases faced by Indigenous peoples, with a view of developing recommendations to overcome them. Herein, we provide an overview of the state of play of current barriers and considerations identified by the taskforce, to further stimulate awareness of these issues and the passage toward solutions. We focus on analyzing barriers to accessing genetic services, participating in genomic research, and other aspects such as concerns about data sharing, the handling of biospecimens, and the importance of capacity building.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fped.2020.579924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767925PMC
December 2020

No association between genetic variants in MAOA, OXTR, and AVPR1a and cooperative strategies.

PLoS One 2020 23;15(12):e0244189. Epub 2020 Dec 23.

Centro de Genética y Genómica, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Santiago, Chile.

The effort to understand the genetic basis of human sociality has been encouraged by the diversity and heritability of social traits like cooperation. This task has remained elusive largely because most studies of sociality and genetics use sample sizes that are often unable to detect the small effects that single genes may have on complex social behaviors. The lack of robust findings could also be a consequence of a poor characterization of social phenotypes. Here, we explore the latter possibility by testing whether refining measures of cooperative phenotypes can increase the replication of previously reported associations between genetic variants and cooperation in small samples. Unlike most previous studies of sociality and genetics, we characterize cooperative phenotypes based on strategies rather than actions. Measuring strategies help differentiate between similar actions with different underlaying social motivations while controlling for expectations and learning. In an admixed Latino sample (n = 188), we tested whether cooperative strategies were associated with three genetic variants thought to influence sociality in humans-MAOA-uVNTR, OXTR rs53576, and AVPR1 RS3. We found no association between cooperative strategies and any of the candidate genetic variants. Since we were unable to replicate previous observations our results suggest that refining measurements of cooperative phenotypes as strategies is not enough to overcome the inherent statistical power problem of candidate gene studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244189PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757875PMC
March 2021

Using common genetic variation to examine phenotypic expression and risk prediction in 22q11.2 deletion syndrome.

Nat Med 2020 12 9;26(12):1912-1918. Epub 2020 Nov 9.

Centro de Genética y Genómica, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Santiago, Chile.

The 22q11.2 deletion syndrome (22q11DS) is associated with a 20-25% risk of schizophrenia. In a cohort of 962 individuals with 22q11DS, we examined the shared genetic basis between schizophrenia and schizophrenia-related early trajectory phenotypes: sub-threshold symptoms of psychosis, low baseline intellectual functioning and cognitive decline. We studied the association of these phenotypes with two polygenic scores, derived for schizophrenia and intelligence, and evaluated their use for individual risk prediction in 22q11DS. Polygenic scores were not only associated with schizophrenia and baseline intelligence quotient (IQ), respectively, but schizophrenia polygenic score was also significantly associated with cognitive (verbal IQ) decline and nominally associated with sub-threshold psychosis. Furthermore, in comparing the tail-end deciles of the schizophrenia and IQ polygenic score distributions, 33% versus 9% of individuals with 22q11DS had schizophrenia, and 63% versus 24% of individuals had intellectual disability. Collectively, these data show a shared genetic basis for schizophrenia and schizophrenia-related phenotypes and also highlight the future potential of polygenic scores for risk stratification among individuals with highly, but incompletely, penetrant genetic variants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41591-020-1103-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7975627PMC
December 2020

Human genetics and genomics meetings going virtual: practical lessons learned from two international meetings in early 2020.

Hum Genomics 2020 07 8;14(1):27. Epub 2020 Jul 8.

Australian Institute of Tropical Health and Medicine, James Cook University, Smithfield, QLD 4878, Australia.

The recent coronavirus disease 2019 (COVID-19) pandemic has caused worldwide disruption which also extends to the arena of scientific meetings around the world. Here, we explore the lessons learned from moving two human genetics and genomics meetings quickly to an online format in early 2020. The tips presented herein may be useful not only for future virtual meetings but may also enrich future physical if not hybrid meetings once they resume.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40246-020-00275-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341463PMC
July 2020

Mapping Subcortical Brain Alterations in 22q11.2 Deletion Syndrome: Effects of Deletion Size and Convergence With Idiopathic Neuropsychiatric Illness.

Am J Psychiatry 2020 07 12;177(7):589-600. Epub 2020 Feb 12.

Imaging Genetics Center, Mark and Mary Stevens Institute for Neuroimaging and Informatics, Keck School of Medicine, Los Angeles (Ching, Villalon Reina, Zavaliangos-Petropulu, Thompson); Department of Biomedical Engineering, Armour College of Engineering, Illinois Institute of Technology, Chicago (Gutman); Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, Los Angeles (Ching, Sun, Lin, Jonas, Pacheco-Hansen, Vajdi, Forsyth, Bearden); Department of Psychology, UCLA, Los Angeles (Ching, Forsyth, Bearden); Department of Biomedical Engineering, Oregon Health and Science University, Portland (Ragothaman); Department of Biomedical Engineering, Duke University, Durham, N.C. (Isaev); Graduate Interdepartmental Program in Neuroscience, UCLA School of Medicine, Los Angeles (Lin, Jonas); Department of Psychiatry, University of Pittsburgh, Pittsburgh (Jalbrzikowski); Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, the Netherlands (Bakker, van Amelsvoort); Department of Radiology and Nuclear Medicine, Amsterdam University Medical Centers, Amsterdam (Bakker); Department of Psychology, Syracuse University, Syracuse, N.Y. (Antshel); Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse (Fremont, Kates); School of Psychology, University of Newcastle, Newcastle, Australia (Campbell, McCabe); MIND Institute and Department of Psychiatry and Behavioral Sciences, University of California Davis, Davis (McCabe, Durdle, Goodrich-Hunsaker, Simon); Institute of Psychiatry, Psychology, and Neuroscience, Sackler Institute for Translational Neurodevelopment, and Department of Forensic and Neurodevelopmental Sciences, King's College London (Craig, Daly, Gudbrandsen, C.M. Murphy, D.G. Murphy); Bethlem Royal Hospital, National Institute for Health Research Maudsley Biomedical Research Centre, and SLaM NHS Foundation Trust, National Autism Unit, London (Craig); Behavioural Genetics Clinic, Adult Autism Service, Behavioural and Developmental Psychiatry Clinical Academic Group, South London and Maudsley NHS Foundation Trust, London (C.M. Murphy, D.G. Murphy); Department of Psychiatry, Royal College of Surgeons in Ireland, and Education and Research Centre, Beaumont Hospital, Dublin (K.C. Murphy); Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands (Fiksinski, Koops, Vorstman); Clinical Genetics Research Program (Bassett, Fiksinski, Chow), Clinical Genetics Service (Chow), Campbell Family Mental Health Research Institute (Bassett), Centre for Addiction and Mental Health, Toronto; Dalglish Family 22q Clinic (Bassett, Fiksinski), Department of Mental Health, and Toronto General Hospital Research Institute (Bassett); University Health Network, Toronto (Fiksinski, Bassett); Department of Psychiatry, University of Toronto, Toronto (Bassett, Vorstman, Chow); Program in Genetics and Genome Biology, Research Institute, and Department of Psychiatry, Hospital for Sick Children, Toronto (Vorstman); Division of Human Genetics and 22q and You Center, Children's Hospital of Philadelphia, Philadelphia (Crowley, Emanuel, McDonald-McGinn, Zackai); Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia (Emanuel, McDonald-McGinn, Zackai); Department of Psychiatry, University of Pennsylvania Perelman School of Medicine and Children's Hospital of Philadelphia, Philadelphia (Gur); Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia (Roalf, Ruparel); Departments of Radiology and Psychiatry, Hospital of the University of Pennsylvania, Philadelphia (Schmitt); Department of Psychological and Brain Sciences, University of California, Santa Barbara (Durdle); Department of Neurology, University of Utah, Salt Lake City (Goodrich-Hunsaker); Child Health Evaluative Sciences, Hospital for Sick Children Research Institute, Toronto (Butcher); Department Psychiatry, University of British Columbia, Vancouver (Vila-Rodriguez); MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, U.K. (Cunningham, Doherty, Linden, Moss, Owen, van den Bree); Cardiff University Brain Research Imaging Centre, Cardiff, U.K. (Doherty, Linden); Department of Psychiatry, Pontificia Universidad Católica de Chile, Santiago (Crossley); Clinica Alemana, Universidad del Desarrollo, Centro de Genética y Genomica, Facultad de Medicina, Santiago (Repetto); Departments of Neurology, Psychiatry, Radiology, Engineering, Pediatrics, and Ophthalmology, University of Southern California, Los Angeles (Thompson).

Objective: 22q11.2 deletion syndrome (22q11DS) is among the strongest known genetic risk factors for schizophrenia. Previous studies have reported variable alterations in subcortical brain structures in 22q11DS. To better characterize subcortical alterations in 22q11DS, including modulating effects of clinical and genetic heterogeneity, the authors studied a large multicenter neuroimaging cohort from the ENIGMA 22q11.2 Deletion Syndrome Working Group.

Methods: Subcortical structures were measured using harmonized protocols for gross volume and subcortical shape morphometry in 533 individuals with 22q11DS and 330 matched healthy control subjects (age range, 6-56 years; 49% female).

Results: Compared with the control group, the 22q11DS group showed lower intracranial volume (ICV) and thalamus, putamen, hippocampus, and amygdala volumes and greater lateral ventricle, caudate, and accumbens volumes (Cohen's d values, -0.90 to 0.93). Shape analysis revealed complex differences in the 22q11DS group across all structures. The larger A-D deletion was associated with more extensive shape alterations compared with the smaller A-B deletion. Participants with 22q11DS with psychosis showed lower ICV and hippocampus, amygdala, and thalamus volumes (Cohen's d values, -0.91 to 0.53) compared with participants with 22q11DS without psychosis. Shape analysis revealed lower thickness and surface area across subregions of these structures. Compared with subcortical findings from other neuropsychiatric disorders studied by the ENIGMA consortium, significant convergence was observed between participants with 22q11DS with psychosis and participants with schizophrenia, bipolar disorder, major depressive disorder, and obsessive-compulsive disorder.

Conclusions: In the largest neuroimaging study of 22q11DS to date, the authors found widespread alterations to subcortical brain structures, which were affected by deletion size and psychotic illness. Findings indicate significant overlap between 22q11DS-associated psychosis, idiopathic schizophrenia, and other severe neuropsychiatric illnesses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1176/appi.ajp.2019.19060583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419015PMC
July 2020

Genetic contributors to risk of schizophrenia in the presence of a 22q11.2 deletion.

Mol Psychiatry 2020 Feb 3. Epub 2020 Feb 3.

Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA.

Schizophrenia occurs in about one in four individuals with 22q11.2 deletion syndrome (22q11.2DS). The aim of this International Brain and Behavior 22q11.2DS Consortium (IBBC) study was to identify genetic factors that contribute to schizophrenia, in addition to the ~20-fold increased risk conveyed by the 22q11.2 deletion. Using whole-genome sequencing data from 519 unrelated individuals with 22q11.2DS, we conducted genome-wide comparisons of common and rare variants between those with schizophrenia and those with no psychotic disorder at age ≥25 years. Available microarray data enabled direct comparison of polygenic risk for schizophrenia between 22q11.2DS and independent population samples with no 22q11.2 deletion, with and without schizophrenia (total n = 35,182). Polygenic risk for schizophrenia within 22q11.2DS was significantly greater for those with schizophrenia (p = 6.73 × 10). Novel reciprocal case-control comparisons between the 22q11.2DS and population-based cohorts showed that polygenic risk score was significantly greater in individuals with psychotic illness, regardless of the presence of the 22q11.2 deletion. Within the 22q11.2DS cohort, results of gene-set analyses showed some support for rare variants affecting synaptic genes. No common or rare variants within the 22q11.2 deletion region were significantly associated with schizophrenia. These findings suggest that in addition to the deletion conferring a greatly increased risk to schizophrenia, the risk is higher when the 22q11.2 deletion and common polygenic risk factors that contribute to schizophrenia in the general population are both present.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41380-020-0654-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396297PMC
February 2020

Rare diseases in Chile: challenges and recommendations in universal health coverage context.

Orphanet J Rare Dis 2019 12 11;14(1):289. Epub 2019 Dec 11.

Centro de Genética y Genómica, Instituto de Ciencias e Innovación en Medicina, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Santiago, Chile.

Rare diseases (RDs) are a large number of diverse conditions with low individual prevalence, but collectively may affect up to 3.5-5.9% of the population. They have psychosocial and economic impact on patients and societies, and are a significant problem for healthcare systems, especially for countries with limited resources. In Chile, financial protection exists for 20 known RDs through different programs that cover diagnosis and treatments. Although beneficial for a number of conditions, most RD patients are left without a proper legal structure that guarantees a financial coverage, and in a vulnerable situation. In this review, we present and analyze the main challenges of the Chilean healthcare system and legislation on RDs, and other ambits of the RD ecosystem, including patient advocacy groups and research. Finally, we propose a set of policy recommendations that includes creating a patient registry, eliciting social preferences on health and financial coverage, improving access to clinical genetic services and therapies, promoting research on RDs and establishing a Latin-American cooperation network, all aimed at promoting equitable quality healthcare access for people living with RDs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13023-019-1261-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6958742PMC
December 2019

Complete Sequence of the 22q11.2 Allele in 1,053 Subjects with 22q11.2 Deletion Syndrome Reveals Modifiers of Conotruncal Heart Defects.

Am J Hum Genet 2020 01 20;106(1):26-40. Epub 2019 Dec 20.

The Virtual Center for Velo-Cardio-Facial Syndrome, Syracuse, NY 13206, USA.

The 22q11.2 deletion syndrome (22q11.2DS) results from non-allelic homologous recombination between low-copy repeats termed LCR22. About 60%-70% of individuals with the typical 3 megabase (Mb) deletion from LCR22A-D have congenital heart disease, mostly of the conotruncal type (CTD), whereas others have normal cardiac anatomy. In this study, we tested whether variants in the hemizygous LCR22A-D region are associated with risk for CTDs on the basis of the sequence of the 22q11.2 region from 1,053 22q11.2DS individuals. We found a significant association (FDR p < 0.05) of the CTD subset with 62 common variants in a single linkage disequilibrium (LD) block in a 350 kb interval harboring CRKL. A total of 45 of the 62 variants were associated with increased risk for CTDs (odds ratio [OR) ranges: 1.64-4.75). Associations of four variants were replicated in a meta-analysis of three genome-wide association studies of CTDs in affected individuals without 22q11.2DS. One of the replicated variants, rs178252, is located in an open chromatin region and resides in the double-elite enhancer, GH22J020947, that is predicted to regulate CRKL (CRK-like proto-oncogene, cytoplasmic adaptor) expression. Approximately 23% of patients with nested LCR22C-D deletions have CTDs, and inactivation of Crkl in mice causes CTDs, thus implicating this gene as a modifier. Rs178252 and rs6004160 are expression quantitative trait loci (eQTLs) of CRKL. Furthermore, set-based tests identified an enhancer that is predicted to target CRKL and is significantly associated with CTD risk (GH22J020946, sequence kernal association test (SKAT) p = 7.21 × 10) in the 22q11.2DS cohort. These findings suggest that variance in CTD penetrance in the 22q11.2DS population can be explained in part by variants affecting CRKL expression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2019.11.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7077921PMC
January 2020

Somatic Mosaicism for Paternal Uniparental Disomy of 11p15.5 Region in Adrenal and Liver Tissues in a Newborn with Atypical Beckwith-Wiedemann Syndrome.

J Pediatr Genet 2019 Dec 11;8(4):226-230. Epub 2019 Jun 11.

Center for Genetics and Genomics, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Santiago, Chile.

Beckwith-Wiedemann syndrome (BWS) is characterized by overgrowth and increased risk of embryonic tumors. It results from alterations in genes controlled by imprinting centers H19DMR (Imprinting Center [IC] 1) and KvDMR (IC2). Strategies for diagnostic confirmation include methylation analysis and sequencing. We present a newborn with placentomegaly, hyperinsulinism and adrenal cytomegaly, but no typical external features of BWS. The patient had normal genetic studies in blood. However, adrenal and liver tissues showed hypermethylation of IC1 and hypomethylation of IC2. Microsatellite analysis confirmed mosaic paternal uniparental disomy. This study demonstrates the importance of analyzing additional tissues to reduce underdiagnosis of somatic mosaicism in BWS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0039-1692197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824882PMC
December 2019

Association between phenotype and deletion size in 22q11.2 microdeletion syndrome: systematic review and meta-analysis.

Orphanet J Rare Dis 2019 08 9;14(1):195. Epub 2019 Aug 9.

Centro de Genética y Genómica, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Avda Las Condes, 12438, Santiago, Chile.

Background: Chromosome 22q11.2 microdeletion syndrome, a disorder caused by heterozygous loss of genetic material in chromosome region 22q11.2, has a broad range of clinical symptoms. The most common congenital anomalies involve the palate in 80% of patients, and the heart in 50-60% of them. The cause of the phenotypic variability is unknown. Patients usually harbor one of three common deletions sizes: 3, 2 and 1.5 Mb, between low copy repeats (LCR) designated A-D, A-C and A-B, respectively. This study aimed to analyze the association between these 3 deletion sizes and the presence of congenital cardiac and/or palatal malformations in individuals with this condition. A systematic review and meta-analysis were conducted, merging relevant published studies with data from Chilean patients to increase statistical power.

Results: Eight articles out of 432 were included; the data from these studies was merged with our own, achieving a total of 1514 and 487 patients to evaluate cardiac and palate malformations, respectively. None of the compared deleted chromosomal segments were statistically associated with cardiac defects (OR: 0.654 [0.408-1.046]; OR : 1.291 [0.860-1.939]) or palate anomalies (OR: 1.731 [0.708-4.234]; OR : 0.628 [0.286-1.382]).

Conclusions: The lack of association between deletion size and CHD or PA found in this meta-analysis suggests that deletion size does not explain the incomplete penetrance of these 2 major manifestations, and that the critical region for the development of heart and palatal abnormalities is within LCR A-B, the smallest region of overlap among the three deletion sizes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13023-019-1170-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6688301PMC
August 2019

Systems Analysis of the 22q11.2 Microdeletion Syndrome Converges on a Mitochondrial Interactome Necessary for Synapse Function and Behavior.

J Neurosci 2019 05 4;39(18):3561-3581. Epub 2019 Mar 4.

Departments of Cell Biology,

Neurodevelopmental disorders offer insight into synaptic mechanisms. To unbiasedly uncover these mechanisms, we studied the 22q11.2 syndrome, a recurrent copy number variant, which is the highest schizophrenia genetic risk factor. We quantified the proteomes of 22q11.2 mutant human fibroblasts from both sexes and mouse brains carrying a 22q11.2-like defect, Molecular ontologies defined mitochondrial compartments and pathways as some of top ranked categories. In particular, we identified perturbations in the SLC25A1-SLC25A4 mitochondrial transporter interactome as associated with the 22q11.2 genetic defect. Expression of SLC25A1-SLC25A4 interactome components was affected in neuronal cells from schizophrenia patients. Furthermore, hemideficiency of the SLC25A1 or SLC25A4 orthologues, dSLC25A1-sea and dSLC25A4-sesB, affected synapse morphology, neurotransmission, plasticity, and sleep patterns. Our findings indicate that synapses are sensitive to partial loss of function of mitochondrial solute transporters. We propose that mitoproteomes regulate synapse development and function in normal and pathological conditions in a cell-specific manner. We address the central question of how to comprehensively define molecular mechanisms of the most prevalent and penetrant microdeletion associated with neurodevelopmental disorders, the 22q11.2 microdeletion syndrome. This complex mutation reduces gene dosage of ∼63 genes in humans. We describe a disruption of the mitoproteome in 22q11.2 patients and brains of a 22q11.2 mouse model. In particular, we identify a network of inner mitochondrial membrane transporters as a hub required for synapse function. Our findings suggest that mitochondrial composition and function modulate the risk of neurodevelopmental disorders, such as schizophrenia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1523/JNEUROSCI.1983-18.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6495129PMC
May 2019

Efficacy of gamification-based smartphone application for weight loss in overweight and obese adolescents: study protocol for a phase II randomized controlled trial.

Ther Adv Endocrinol Metab 2018 Jun 27;9(6):167-176. Epub 2018 Apr 27.

Disciplina de Emergencias Clínicas, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil.

Background: Overweight and obesity are significant public health concerns that are prevalent in younger age cohorts. Preventive or therapeutic interventions are difficult to implement and maintain over time. On the other hand, the majority of adolescents in the United States have a smartphone, representing a huge potential for innovative digitized interventions, such as weight loss programs delivered smartphone applications. Although the number of available smartphone applications is increasing, evidence for their effectiveness in weight loss is insufficient. Therefore, the proposed study aims to assess the efficacy of a gamification-based smartphone application for weight loss in overweight and obese adolescents. The trial is designed to be a phase II, single-centre, two-arm, triple-blinded, randomized controlled trial (RCT) with a duration of 6 months.

Method: The intervention consists of a smartphone application that provides both tracking and gamification elements, while the control arm consists of an identically designed application solely with tracking features of health information. The proposed trial will be conducted in an urban primary care clinic of an academic centre in the United States of America, with expertise in the management of overweight and obese adolescents. Eligible adolescents will be followed for 6 months. Changes in body mass index score from baseline to 6 months will be the primary outcome. Secondary objectives will explore the effects of the gamification-based application on adherence, as well as anthropometric, metabolic and behavioural changes. A required sample size of 108 participants (54 participants per group) was calculated.

Discussion: The benefits of the proposed study include mid-term effects in weight reduction for overweight and obese adolescents. The current proposal will contribute to fill a gap in the literature on the mid-term effects of gamification-based interventions to control weight in adolescents. This trial is a well-designed RCT that is in line with the Consolidated Standards of Reporting Trials statement.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/2042018818770938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5956638PMC
June 2018

Deletion size analysis of 1680 22q11.2DS subjects identifies a new recombination hotspot on chromosome 22q11.2.

Hum Mol Genet 2018 04;27(7):1150-1163

Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA.

Recurrent, de novo, meiotic non-allelic homologous recombination events between low copy repeats, termed LCR22s, leads to the 22q11.2 deletion syndrome (22q11.2DS; velo-cardio-facial syndrome/DiGeorge syndrome). Although most 22q11.2DS patients have a similar sized 3 million base pair (Mb), LCR22A-D deletion, some have nested LCR22A-B or LCR22A-C deletions. Our goal is to identify additional recurrent 22q11.2 deletions associated with 22q11.2DS, serving as recombination hotspots for meiotic chromosomal rearrangements. Here, using data from Affymetrix 6.0 microarrays on 1680 22q11.2DS subjects, we identified what appeared to be a nested proximal 22q11.2 deletion in 38 (2.3%) of them. Using molecular and haplotype analyses from 14 subjects and their parent(s) with available DNA, we found essentially three types of scenarios to explain this observation. In eight subjects, the proximal breakpoints occurred in a small sized 12 kb LCR distal to LCR22A, referred to LCR22A+, resulting in LCR22A+-B or LCR22A+-D deletions. Six of these eight subjects had a nested 22q11.2 deletion that occurred during meiosis in a parent carrying a benign 0.2 Mb duplication of the LCR22A-LCR22A+ region with a breakpoint in LCR22A+. Another six had a typical de novo LCR22A-D deletion on one allele and inherited the LCR22A-A+ duplication from the other parent thus appearing on microarrays to have a nested deletion. LCR22A+ maps to an evolutionary breakpoint between mice and humans and appears to serve as a local hotspot for chromosome rearrangements on 22q11.2.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/hmg/ddy028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6059186PMC
April 2018

Genome-Wide Association Study to Find Modifiers for Tetralogy of Fallot in the 22q11.2 Deletion Syndrome Identifies Variants in the Locus on 5q14.3.

Circ Cardiovasc Genet 2017 Oct;10(5)

From the Department of Genetics (T.G., J.H.C., H.N., C.L.C., T.W., B.E.M.) and Department of Epidemiology and Population Health (T.W.), Albert Einstein College of Medicine, Bronx, NY; Center for Human Genetics, Facultad de Medicina Clinica Alemana Universidad del Desarrollo, Santiago, Chile (G.M.R.); Division of Human Genetics (D.M.M.M., E.E.M., E.Z., B.S.E.), Division of Cardiology (E.G.), and Department of Pediatrics (E.G.), Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia; Department of Genetics, Wroclaw Medical University, Poland (A.B.); Clinical Genetics Research Program, Center for Addiction and Mental Health and Department of Psychiatry, University of Toronto (A.S.B., E.W.C.C.); Dalglish Family 22q Clinic, Department of Psychiatry and Toronto General Research Institute, University Health Network, Canada (A.S.B.); Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Canada (A.S.B.); Center for Human Genetics, University of Leuven (KU Leuven), Belgium (A.S., J.V., K.D.); The Child Psychiatry Division, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel (D.G.); Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Israel (D.G., M.C., E.M.); Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University, Petah Tikva, Israel (M.C., E.M.); Developmental Imaging and Psychopathology Lab, University of Geneva School of Medicine, Switzerland (M.S., S.E.); Department of Genetic Medicine, UNIGE and iGE3 Institute of Genetics and Genomics of Geneva, University of Geneva Medical Center, Switzerland (S.E.A.); Marcus Autism Center, Children's Healthcare of Atlanta, GA (K.C.); Division of Pediatric Cardiovascular Surgery, Children's Hospital of Wisconsin, Milwaukee (A.T.-M., M.E.M.); Department of Surgery, Medical College of Wisconsin, Milwaukee (A.T.-M., M.E.M.); Department of Medical Genetics, Bambino Gesù Hospital, Rome, Italy (M.C.D., B.D.); Department of Pediatrics, La Sapienza University of Rome, Italy (B.M.); Department of Medical Genetics, Aix Marseille University, APHM, GMGF, Timone Hospital, France (N.P., T.B.); Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California at Los Angeles (L.K.-W., C.E.B.); Department of Genetics, Polish Mother's Memorial Hospital, Research Institute, Łódź, Poland (M.P., W.H.); Department of Cardiology and Division of Genetics, Boston Children's Hospital, MA (A.E.R.); M.I.N.D. Institute and Department of Psychiatry and Behavioral Sciences (F.T.) and M.I.N.D. Institute and Department of Biochemistry and Molecular Medicine (T.J.S.), University of California, Davis; Department of Psychiatry and Psychology, University of Maastricht, The Netherlands (E.D.A.V.D., T.A.v.A.); Department of Psychiatry and Behavioral Sciences, and Program in Neuroscience, SUNY Upstate Medical University, Syracuse, NY (T.A.v.A., W.R.K.); Department of Human Genetics, Emory University School of Medicine, Atlanta, GA (H.R.J., D.J.C.); Department of Biostatistics and Bioinformatics, Emory University Rollins School of Public Health, Atlanta, GA (H.R.J.); and Human Genetics Center and Department of Epidemiology, Human Genetics and Environmental Sciences, UTHealth School of Public Health, Houston, TX (A.J.A., L.E.M.).

Background: The 22q11.2 deletion syndrome (22q11.2DS; DiGeorge syndrome/velocardiofacial syndrome) occurs in 1 of 4000 live births, and 60% to 70% of affected individuals have congenital heart disease, ranging from mild to severe. In our cohort of 1472 subjects with 22q11.2DS, a total of 62% (n=906) have congenital heart disease and 36% (n=326) of these have tetralogy of Fallot (TOF), comprising the largest subset of severe congenital heart disease in the cohort.

Methods And Results: To identify common genetic variants associated with TOF in individuals with 22q11.2DS, we performed a genome-wide association study using Affymetrix 6.0 array and imputed genotype data. In our cohort, TOF was significantly associated with a genotyped single-nucleotide polymorphism (rs12519770, =2.98×10) in an intron of the adhesion (G-protein-coupled receptor V1) gene on chromosome 5q14.3. There was also suggestive evidence of association between TOF and several additional single-nucleotide polymorphisms in this region. Some genome-wide significant loci in introns or noncoding regions could affect regulation of genes nearby or at a distance. On the basis of this possibility, we examined existing Hi-C chromatin conformation data to identify genes that might be under shared transcriptional regulation within the region on 5q14.3. There are 6 genes in a topologically associated domain of chromatin with , including (Myocyte-specific enhancer factor 2C). is the only gene that is known to affect heart development in mammals and might be of interest with respect to 22q11.2DS.

Conclusions: In conclusion, common variants may contribute to TOF in 22q11.2DS and may function in cardiac outflow tract development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCGENETICS.116.001690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5647121PMC
October 2017

Rare Genome-Wide Copy Number Variation and Expression of Schizophrenia in 22q11.2 Deletion Syndrome.

Am J Psychiatry 2017 11 28;174(11):1054-1063. Epub 2017 Jul 28.

From the Dalglish Family 22q Clinic, Department of Psychiatry, University Health Network, Toronto; the Department of Psychiatry and Toronto General Research Institute, University Health Network, Toronto; the Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto; the Department of Psychiatry, University of Toronto, Toronto; the Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto; the Centre for Applied Genomics and Program in Genetics and Genome Biology, the Hospital for Sick Children, Toronto; the Medical Genetics Residency Training Program, University of Toronto, Toronto; the Department of Psychiatry and Psychology, Maastricht University, Maastricht, the Netherlands; the Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia; the Departments of Pediatrics and of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia; the Centre for Human Genetics, University of Leuven (KU Leuven), Leuven, Belgium; the Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, Wales; the Department of Psychiatry, Royal College of Surgeons in Ireland, Dublin; the Department of Child and Adolescent Psychiatry, King's College London; the Department of Psychiatry, Tel Aviv University, Tel Aviv, Israel; the Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, UCLA, Los Angeles; Office Médico-Pédagogique Research Unit, Department of Psychiatry, University of Geneva School of Medicine, Geneva; the Department of Psychiatry and Behavioral Sciences, Upstate Medical University, State University of New York, Syracuse; Département de Génétique Médicale, Centre Hospitalier Universitaire de Marseille - Hôpital de la Timone, Marseilles, France; the Department of Pediatrics, Duke University, Durham, N.C.; the Department of Psychology, University of Newcastle, Newcastle, Australia; the Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands; the Department of Human Genetics, Emory University, Atlanta; Centro de Genética y Genómica, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Santiago, Chile; the Department of Psychiatry and Behavioral Sciences, UC Davis, Sacramento, Calif.; Molecular Genetics and McLaughlin Centre, and Laboratory Medicine and Pathobiology, University of Toronto, Toronto; the Department of Genetics, Albert Einstein College of Medicine, Bronx, N.Y.; and Genome Diagnostics, Department of Paediatric Laboratory Medicine, the Hospital for Sick Children, Toronto.

Objective: Chromosome 22q11.2 deletion syndrome (22q11.2DS) is associated with a more than 20-fold increased risk for developing schizophrenia. The aim of this study was to identify additional genetic factors (i.e., "second hits") that may contribute to schizophrenia expression.

Method: Through an international consortium, the authors obtained DNA samples from 329 psychiatrically phenotyped subjects with 22q11.2DS. Using a high-resolution microarray platform and established methods to assess copy number variation (CNV), the authors compared the genome-wide burden of rare autosomal CNV, outside of the 22q11.2 deletion region, between two groups: a schizophrenia group and those with no psychotic disorder at age ≥25 years. The authors assessed whether genes overlapped by rare CNVs were overrepresented in functional pathways relevant to schizophrenia.

Results: Rare CNVs overlapping one or more protein-coding genes revealed significant between-group differences. For rare exonic duplications, six of 19 gene sets tested were enriched in the schizophrenia group; genes associated with abnormal nervous system phenotypes remained significant in a stepwise logistic regression model and showed significant interactions with 22q11.2 deletion region genes in a connectivity analysis. For rare exonic deletions, the schizophrenia group had, on average, more genes overlapped. The additional rare CNVs implicated known (e.g., GRM7, 15q13.3, 16p12.2) and novel schizophrenia risk genes and loci.

Conclusions: The results suggest that additional rare CNVs overlapping genes outside of the 22q11.2 deletion region contribute to schizophrenia risk in 22q11.2DS, supporting a multigenic hypothesis for schizophrenia. The findings have implications for understanding expression of psychotic illness and herald the importance of whole-genome sequencing to appreciate the overall genomic architecture of schizophrenia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1176/appi.ajp.2017.16121417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5665703PMC
November 2017

Partial microduplication in the histone acetyltransferase complex member KANSL1 is associated with congenital heart defects in 22q11.2 microdeletion syndrome patients.

Sci Rep 2017 05 11;7(1):1795. Epub 2017 May 11.

Centro de Genética y Genómica, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Santiago, Chile.

22q11.2 microdeletion syndrome (22q11.2DS) is the most common microdeletion disorder in humans, with an incidence of 1/4000 live births. It is caused by a heterozygous deletion of 1.5-3 Mb on chromosome region 22q11.2. Patients with the deletion present features that include neuropsychiatric problems, craniofacial abnormalities and cardiovascular malformations. However, the phenotype is highly variable and the factors related to the clinical heterogeneity are not fully understood. About 65% of patients with 22q11.2DS have congenital heart defects (CHD). The main goal of this study was to identify common CNVs in 22q11.2DS patients that could be associated with the incomplete penetrance of CHD. Analysis of genomic DNA from 253 patients with 22q11.2DS using array technology showed an association between a microduplication located in region 17q21.31 and CHD (p-value = 0.023, OR = 2.75, 95% CI = 1.17-7.03). This region includes the first three exons of KANSL1 gene. Bioinformatic analysis showed that KANSL1 and CRKL, a gene in the commonly deleted region of 22q11.2DS, are part of the same regulatory module in a miRNA-mRNA network. These results show that a KANSL1 microduplication, in combination with the 22q11.2 deletion, is associated with increased risk of CHD in these patients, suggesting that KANSL1 plays a role as a modifier gene in 22q11.2DS patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-017-01896-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5431949PMC
May 2017

Neuroimaging and clinical features in adults with a 22q11.2 deletion at risk of Parkinson's disease.

Brain 2017 May;140(5):1371-1383

Clinical Genetics Research Program and Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.

The recurrent 22q11.2 deletion is a genetic risk factor for early-onset Parkinson's disease. Adults with the associated 22q11.2 deletion syndrome (22q11.2DS) may exhibit phenotypes that could help identify those at highest risk and reveal disease trajectories. We investigated clinical and neuroimaging features relevant to Parkinson's disease in 26 adults: 13 with 22q11.2DS at genetic risk of Parkinson's disease (mean age = 41.5 years, standard deviation = 9.7), 12 healthy age and sex-matched controls, and a 22q11.2DS patient with l-DOPA-responsive early-onset Parkinson's disease. Neuroimaging included transcranial sonography and positron emission tomography using 11C-dihydrotetrabenazine (11C-DTBZ), a radioligand that binds to the presynaptic vesicular monoamine transporter. The 22q11.2DS group without Parkinson's disease demonstrated significant motor and olfactory deficits relative to controls. Eight (61.5%) were clinically classified with parkinsonism. Transcranial sonography showed a significantly larger mean area of substantia nigra echogenicity in the 22q11.2DS risk group compared with controls (P = 0.03). The 22q11.2DS patient with Parkinson's disease showed the expected pattern of severely reduced striatal 11C-DTBZ binding. The 22q11.2DS group without Parkinson's disease however showed significantly elevated striatal 11C-DTBZ binding relative to controls (∼33%; P < 0.01). Results were similar within the 22q11.2DS group for those with (n = 7) and without (n = 6) psychotic illness. These findings suggest that manifestations of parkinsonism and/or evolution to Parkinson's disease in this genetic at-risk population may include a hyperdopaminergic mechanism. Adequately powered longitudinal studies and animal models are needed to evaluate the relevance of the observed clinical and imaging phenotypes to Parkinson's disease and other disorders that are more prevalent in 22q11.2DS, such as schizophrenia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/brain/awx053DOI Listing
May 2017

TBC1D24 genotype-phenotype correlation: Epilepsies and other neurologic features.

Neurology 2016 07 8;87(1):77-85. Epub 2016 Jun 8.

Objective: To evaluate the phenotypic spectrum associated with mutations in TBC1D24.

Methods: We acquired new clinical, EEG, and neuroimaging data of 11 previously unreported and 37 published patients. TBC1D24 mutations, identified through various sequencing methods, can be found online (http://lovd.nl/TBC1D24).

Results: Forty-eight patients were included (28 men, 20 women, average age 21 years) from 30 independent families. Eighteen patients (38%) had myoclonic epilepsies. The other patients carried diagnoses of focal (25%), multifocal (2%), generalized (4%), and unclassified epilepsy (6%), and early-onset epileptic encephalopathy (25%). Most patients had drug-resistant epilepsy. We detail EEG, neuroimaging, developmental, and cognitive features, treatment responsiveness, and physical examination. In silico evaluation revealed 7 different highly conserved motifs, with the most common pathogenic mutation located in the first. Neuronal outgrowth assays showed that some TBC1D24 mutations, associated with the most severe TBC1D24-associated disorders, are not necessarily the most disruptive to this gene function.

Conclusions: TBC1D24-related epilepsy syndromes show marked phenotypic pleiotropy, with multisystem involvement and severity spectrum ranging from isolated deafness (not studied here), benign myoclonic epilepsy restricted to childhood with complete seizure control and normal intellect, to early-onset epileptic encephalopathy with severe developmental delay and early death. There is no distinct correlation with mutation type or location yet, but patterns are emerging. Given the phenotypic breadth observed, TBC1D24 mutation screening is indicated in a wide variety of epilepsies. A TBC1D24 consortium was formed to develop further research on this gene and its associated phenotypes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000002807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4932231PMC
July 2016

Accuracy of a Genetic Test for the Diagnosis of Hypolactasia in Chilean Children: Comparison With the Breath Test.

J Pediatr Gastroenterol Nutr 2016 07;63(1):e10-3

*Pediatric Gastroenterology Unit, Department of Pediatrics†Center for Genetics and Genomics, Facultad de Medicina, Clínica Alemana, Universidad del Desarrollo, Santiago, Chile.

Background: Lactase nonpersistence (LNP) in humans is a genetically determined trait. This age-dependent decrease of lactase expression is most frequently caused by single nucleotide polymorphisms in the regulatory region of the lactase (LCT) gene. The homozygous LCT-13,910C/C genotype (rs 4988235) predominates in Caucasian adults with LNP, and is useful for its diagnosis in this population. The accuracy of this genetic test (GT) has not been completely established in children or in a Latin-American population.

Objectives: The aim of the study was to determine diagnostic accuracy of GT for LNP in Chilean children using the lactose breath test (BT) as a reference, and to compare diagnostic yield in preschool- (<6 years) and in school-age (≥6 years) children.

Methods: Children referred for BT for diagnosis of lactose malabsorption to the Gastroenterology Laboratory at Clínica Alemana, Santiago, from October 2011 to March 2012 were invited to participate. After informed consent, symptom questionnaires, both historic and post lactose ingestion were completed. H2 and CH4 in expired air and -13,910 C>T single nucleotide polymorphism by polymerase chain reaction, restriction enzyme analysis, and/or Sanger sequencing were determined. GT accuracy was calculated compared to BT as reference method. Diagnostic yield of GT in preschool- and school-age children was compared.

Results: Lactose malabsorption was detected by BT in 42 of 60 children (70%). Genotype -13,910C/C was identified in 41 of 60 patients (68%). GT showed 80% sensitivity, 63% specificity, and 74% accuracy for LNP in the preschool population. In school-age children values were higher, 85%, 80%, and 84%, respectively.

Conclusions: GT results were significantly concordant with BT results for hypolactasia detection in Chilean children, particularly in those of age 6 years and older.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MPG.0000000000001208DOI Listing
July 2016

Current Controversies in Diagnosis and Management of Cleft Palate and Velopharyngeal Insufficiency.

Biomed Res Int 2015 26;2015:196240. Epub 2015 Jul 26.

Ian Jackson Craniofacial and Cleft Palate Clinic, Neuroscience Progra, m Beaumont Health System, 3535 West 13 Mile Road, Royal Oak, MI 48073, USA.

Background: One of the most controversial topics concerning cleft palate is the diagnosis and treatment of velopharyngeal insufficiency (VPI).

Objective: This paper reviews current genetic aspects of cleft palate, imaging diagnosis of VPI, the planning of operations for restoring velopharyngeal function during speech, and strategies for speech pathology treatment of articulation disorders in patients with cleft palate.

Materials And Methods: An updated review of the scientific literature concerning genetic aspects of cleft palate was carried out. Current strategies for assessing and treating articulation disorders associated with cleft palate were analyzed. Imaging procedures for assessing velopharyngeal closure during speech were reviewed, including a recent method for performing intraoperative videonasopharyngoscopy.

Results: Conclusions from the analysis of genetic aspects of syndromic and nonsyndromic cleft palate and their use in its diagnosis and management are presented. Strategies for classifying and treating articulation disorders in patients with cleft palate are presented. Preliminary results of the use of multiplanar videofluoroscopy as an outpatient procedure and intraoperative endoscopy for the planning of operations which aimed to correct VPI are presented.

Conclusion: This paper presents current aspects of the diagnosis and management of patients with cleft palate and VPI including 3 main aspects: genetics and genomics, speech pathology and imaging diagnosis, and surgical management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2015/196240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4529889PMC
May 2016

Genetic structure characterization of Chileans reflects historical immigration patterns.

Nat Commun 2015 Mar 17;6:6472. Epub 2015 Mar 17.

Center for Genetics and Genomics, Facultad de Medicina, Clinica Alemana, Universidad del Desarrollo, Av. Las Condes 12438, Lo Barnechea, Santiago 7710162, Chile.

Identifying the ancestral components of genomes of admixed individuals helps uncovering the genetic basis of diseases and understanding the demographic history of populations. We estimate local ancestry on 313 Chileans and assess the contribution from three continental populations. The distribution of ancestry block-length suggests an average admixing time around 10 generations ago. Sex-chromosome analyses confirm imbalanced contribution of European men and Native-American women. Previously known genes under selection contain SNPs showing large difference in allele frequencies. Furthermore, we show that assessing ancestry is harder at SNPs with higher recombination rates and easier at SNPs with large difference in allele frequencies at the ancestral populations. Two observations, that African ancestry proportions systematically decrease from North to South, and that European ancestry proportions are highest in central regions, show that the genetic structure of Chileans is under the influence of a diffusion process leading to an ancestry gradient related to geography.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ncomms7472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4382693PMC
March 2015

Chromosomal microarrays testing in children with developmental disabilities and congenital anomalies.

J Pediatr (Rio J) 2015 Mar-Apr;91(2):189-95. Epub 2014 Oct 30.

Center for Human Genetics, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Santiago, Chile; Hospital Padre Hurtado, Santiago, Chile.

Objectives: Clinical use of microarray-based techniques for the analysis of many developmental disorders has emerged during the last decade. Thus, chromosomal microarray has been positioned as a first-tier test. This study reports the first experience in a Chilean cohort.

Methods: Chilean patients with developmental disabilities and congenital anomalies were studied with a high-density microarray (CytoScan™ HD Array, Affymetrix, Inc., Santa Clara, CA, USA). Patients had previous cytogenetic studies with either a normal result or a poorly characterized anomaly.

Results: This study tested 40 patients selected by two or more criteria, including: major congenital anomalies, facial dysmorphism, developmental delay, and intellectual disability. Copy number variants (CNVs) were found in 72.5% of patients, while a pathogenic CNV was found in 25% of patients and a CNV of uncertain clinical significance was found in 2.5% of patients.

Conclusion: Chromosomal microarray analysis is a useful and powerful tool for diagnosis of developmental diseases, by allowing accurate diagnosis, improving the diagnosis rate, and discovering new etiologies. The higher cost is a limitation for widespread use in this setting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jped.2014.07.003DOI Listing
August 2015

Case fatality rate and associated factors in patients with 22q11 microdeletion syndrome: a retrospective cohort study.

BMJ Open 2014 Nov 6;4(11):e005041. Epub 2014 Nov 6.

Hospital Dr. Roberto del Rio, Santiago, Chile.

Objective: Chromosome 22q11.2 deletion is the most commonly occurring known microdeletion syndrome. Deaths related to the syndrome have been reported, but the magnitude of death has not been quantified. This study evaluated the deletion's impact on survival and its clinical manifestations in a large cohort of Chilean patients.

Design: Demographic and clinical data of individuals with 22q11 deletions diagnosed between 1998 and 2013 were collected from medical records and death certificates. Case fatality rate was calculated and compared with national vital statistics. OR with 95% CI analysis was used to assess the association between clinical manifestations and death.

Setting: Genetic services in tertiary care centres in Chile, following patients with 22q11.2 deletion.

Outcomes: Fatality rate and associated factors.

Results: 59 of 419 patients (14.1%) died during the study period at a median of 3.4 months (range 0 to 32 years of age). Factors associated with death included congenital heart disease (OR 5.27; 95% CI 2.06 to 13.99; p<0.0001), hypocalcaemia (OR 4.27; 95% CI 1.67 to 11.15; p<0.002) and airway malacia (OR 13.37; 95% CI 1.19 to 110.51; p<0.002). Patients with deletions and defects such as tetralogy of Fallot with or without pulmonary atraesia, truncus arteriosus or ventricular septal defect, had a 2.6-fold to 4.6-fold higher death rate compared with nationwide reports for the same types of defects.

Conclusions: In this cohort, we observed a death rate of 14.1%, implying that one in seven patients with 22q11 deletion died during the study period. Significant associations with cardiac defects, hypocalcaemia and airway malacia were observed. Furthermore, the death risk in patients with 22q11 deletion and cardiac defects exceeded the global figures observed in Chile for infants with structurally similar but apparently isolated anomalies. These observations indicate a need to identify patients who may require specific perioperative management to improve survival.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmjopen-2014-005041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4225234PMC
November 2014

The genetic basis of DOORS syndrome: an exome-sequencing study.

Lancet Neurol 2014 Jan 29;13(1):44-58. Epub 2013 Nov 29.

Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK; Manchester Centre for Genomic Centre for Genetic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK; St Mary's Hospital, Manchester Academic Health Science Centre, Manchester, UK.

Background: Deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS) syndrome is a rare autosomal recessive disorder of unknown cause. We aimed to identify the genetic basis of this syndrome by sequencing most coding exons in affected individuals.

Methods: Through a search of available case studies and communication with collaborators, we identified families that included at least one individual with at least three of the five main features of the DOORS syndrome: deafness, onychodystrophy, osteodystrophy, intellectual disability, and seizures. Participants were recruited from 26 centres in 17 countries. Families described in this study were enrolled between Dec 1, 2010, and March 1, 2013. Collaborating physicians enrolling participants obtained clinical information and DNA samples from the affected child and both parents if possible. We did whole-exome sequencing in affected individuals as they were enrolled, until we identified a candidate gene, and Sanger sequencing to confirm mutations. We did expression studies in human fibroblasts from one individual by real-time PCR and western blot analysis, and in mouse tissues by immunohistochemistry and real-time PCR.

Findings: 26 families were included in the study. We did exome sequencing in the first 17 enrolled families; we screened for TBC1D24 by Sanger sequencing in subsequent families. We identified TBC1D24 mutations in 11 individuals from nine families (by exome sequencing in seven families, and Sanger sequencing in two families). 18 families had individuals with all five main features of DOORS syndrome, and TBC1D24 mutations were identified in half of these families. The seizure types in individuals with TBC1D24 mutations included generalised tonic-clonic, complex partial, focal clonic, and infantile spasms. Of the 18 individuals with DOORS syndrome from 17 families without TBC1D24 mutations, eight did not have seizures and three did not have deafness. In expression studies, some mutations abrogated TBC1D24 mRNA stability. We also detected Tbc1d24 expression in mouse phalangeal chondrocytes and calvaria, which suggests a role of TBC1D24 in skeletogenesis.

Interpretation: Our findings suggest that mutations in TBC1D24 seem to be an important cause of DOORS syndrome and can cause diverse phenotypes. Thus, individuals with DOORS syndrome without deafness and seizures but with the other features should still be screened for TBC1D24 mutations. More information is needed to understand the cellular roles of TBC1D24 and identify the genes responsible for DOORS phenotypes in individuals who do not have a mutation in TBC1D24.

Funding: US National Institutes of Health, the CIHR (Canada), the NIHR (UK), the Wellcome Trust, the Henry Smith Charity, and Action Medical Research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1474-4422(13)70265-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895324PMC
January 2014

Palate abnormalities in Chilean patients with chromosome 22q11 microdeletion syndrome.

Int J Pediatr Otorhinolaryngol 2012 Dec 29;76(12):1726-8. Epub 2012 Aug 29.

Center for Human Genetics, Facultad de Medicina, Clínica Alemana-Universidad del Desarrollo, Chile.

Objective: Chromosome 22q11 microdeletion syndrome (del22q11) is the most frequent microdeletion syndrome in humans, with an estimated incidence of 1/4000. It is recognized as a common identifiable cause of cleft palate. We characterized palatal abnormalities in a large cohort of Chilean patients with del22q11.

Methods: Patients with the deletion were evaluated by geneticists and speech pathologists, including nasopharyngoscopy when indicated. Comparisons between groups with and without palatal abnormalities were performed using Fisher's exact test and Mann-Whitney U test.

Results: Two hundred and one patients were included in the study. Palate abnormalities were present in 154 patients (76.6%). The most frequent finding was submucous cleft palate (both classic and occult forms) seen in 80 patients (39.8% of the total group). Overt cleft palate or cleft lip/palate was seen in 30 patients (14.9%). Patients without palate abnormalities had significantly greater frequency of congenital heart disease and higher mortality.

Conclusions: Our data show a high frequency of palate abnormalities without significant association with congenital heart disease. The most common types of palate defects seen in this series are usually not evident on physical examination and thus require a high index of suspicion and active evaluation through nasopharyngoscopy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijporl.2012.08.010DOI Listing
December 2012

De Novo COL7A1 mutation in a patient with trisomy 21: coexistence of dystrophic epidermolysis bullosa and Down syndrome.

Int J Dermatol 2012 Sep;51(9):1078-81

Dystrophic Epidermolysis Bullosa Research Association (DEBRA)-Chile.

Background: Down syndrome (DS) is the most common autosomal chromosomal disorder. Epidermolysis bullosa (EB) is a rare genodermatosis characterized by skin and mucous membrane fragility, with formation of blisters and erosions after minor trauma. Dystrophic EB (DEB) is inherited as an autosomal dominant (DDEB) or recessive (RDEB) trait. Both forms are caused by mutations in COL7A1, the gene coding for the type VII collagen. We report a patient affected by both conditions: DS and DDEB.

Methods: A patient with DS developed generalized blisters at the age of three months. Cytogenetic study was performed to confirm DS. Skin biopsies were examined with immunohistochemical and electron microscopy techniques to determine EB subtype. Genomic DNA was extracted from peripheral blood samples. COL7A1 mutations were screened by heteroduplex analysis using conformation-sensitive gel electrophoresis and sequencing.

Results: Karyotype analysis revealed trisomy 21. Histological study agreed with a DEB diagnosis. Mutational analysis showed a heterozygous c.6127G>T mutation in COL7A1, which is compatible with DDEB. Parental study suggests that c.6127G>T arises as a de novo mutation.

Conclusions: This report demonstrates that EB can be associated with other common conditions and reports the case of a patient who suffered two de novo independent genetic conditions. It also contributes to expanding the knowledge and database of clinical and molecular aspects of DDEB.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1365-4632.2011.05428.xDOI Listing
September 2012