Publications by authors named "Jennifer Howe"

32 Publications

INZ-701 Prevents Ectopic Tissue Calcification and Restores Bone Architecture and Growth in ENPP1-Deficient Mice.

J Bone Miner Res 2021 Apr 26. Epub 2021 Apr 26.

Inozyme Pharma, Boston, MA, USA.

Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is the major enzyme that cleaves extracellular adenosine triphosphate (ATP) to generate pyrophosphate (PPi), an inorganic metabolite with potent anticalcification activity. Loss-of-function mutations cause hypopyrophosphatemia and lead to a state of ENPP1 deficiency, which has an acute infantile phase known as generalized arterial calcification of infancy (GACI) and a pediatric to adult phase known as autosomal-recessive hypophosphatemic rickets type 2 (ARHR2). ENPP1 deficiency manifests as ectopic calcification of multiple tissues, neointimal proliferation, premature mortality, impaired growth, and bone deformities. INZ-701, a human ENPP1-Fc protein, is in clinical development as an enzyme replacement therapy for the treatment of ENPP1 deficiency. The pharmacokinetic and pharmacodynamic profile and therapeutic effect of INZ-701 were investigated in Enpp1 mice, a murine model of ENPP1 deficiency. Enpp1 mice have undetectable plasma PPi, lower plasma phosphate, and higher FGF23 levels compared with wild-type (WT) mice. Enpp1 mice on the acceleration diet, containing high phosphate and low magnesium, quickly develop clinical signs, including dehydration, rough hair coat, pinned ears, stiffed legs, and hunched back. Enpp1 mice treated with vehicle had aforementioned clinical signs plus severe ectopic calcification in multiple tissues and bone defects, characteristics of the clinical phenotype observed in GACI and ARHR2 patients. Our results showed a durable PPi response for more than 3 days after a single dose of INZ-701. Treatment of ENPP1-deficient mice every other day with INZ-701 for 8 weeks restored circulating levels of PPi, prevented pathological calcification in all the tested organs, restored growth parameters, corrected bone defects, improved clinical signs, and decreased mortality in Enpp1 mice, demonstrating the potential of INZ-701 to treat ENPP1 deficiency. © 2021 American Society for Bone and Mineral Research (ASBMR).
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http://dx.doi.org/10.1002/jbmr.4315DOI Listing
April 2021

RCL1 copy number variants are associated with a range of neuropsychiatric phenotypes.

Mol Psychiatry 2021 05 17;26(5):1706-1718. Epub 2021 Feb 17.

The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA, USA.

Mendelian and early-onset severe psychiatric phenotypes often involve genetic variants having a large effect, offering opportunities for genetic discoveries and early therapeutic interventions. Here, the index case is an 18-year-old boy, who at 14 years of age had a decline in cognitive functioning over the course of a year and subsequently presented with catatonia, auditory and visual hallucinations, paranoia, aggression, mood dysregulation, and disorganized thoughts. Exome sequencing revealed a stop-gain mutation in RCL1 (NM_005772.4:c.370 C > T, p.Gln124Ter), encoding an RNA 3'-terminal phosphate cyclase-like protein that is highly conserved across eukaryotic species. Subsequent investigations across two academic medical centers identified eleven additional cases of RCL1 copy number variations (CNVs) with varying neurodevelopmental or psychiatric phenotypes. These findings suggest that dosage variation of RCL1 contributes to a range of neurological and clinical phenotypes.
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http://dx.doi.org/10.1038/s41380-021-01035-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159744PMC
May 2021

Sleep phenotype of individuals with autism spectrum disorder bearing mutations in the PER2 circadian rhythm gene.

Am J Med Genet A 2021 04 20;185(4):1120-1130. Epub 2021 Jan 20.

Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.

The Per family of genes functions as a primary circadian rhythm maintenance in the brain. Mutations in PER2 are associated with familial advanced sleep-phase syndrome 1 (FASPS1), and recently suggested in delayed sleep phase syndrome and idiopathic hypersomnia. The detection of PER2 variants in individuals with autism spectrum disorder (ASD) and without reported sleep disorders, has suggested a role of circadian-relevant genes in the pathophysiology of ASD. It remains unclear whether these individuals may have, in addition to ASD, an undiagnosed circadian rhythm sleep disorder. The MSSNG database was used to screen whole genome sequencing data of 5,102 individuals with ASD for putative mutations in PER2. Families identified were invited to complete sleep phenotyping consisting of a structured interview and two standardized sleep questionnaires: the Pittsburgh Sleep Quality Index and the Morningness-Eveningness Questionnaire. From 5,102 individuals with ASD, two nonsense, one frameshift, and one de novo missense PER2 variants were identified (0.08%). Of these four, none had a diagnosed sleep disorder. Three reported either a history of, or ongoing sleep disturbances, and one had symptoms highly suggestive of FASPS1 (as did a mutation carrier father without ASD). The individual with the missense variant did not report sleep concerns. The ASD and cognitive profiles of these individuals varied in severity and symptoms. The results support a possible role of PER2-related circadian rhythm disturbances in the dysregulation of sleep overall and sometimes FASPS1. The relationship between dysregulated sleep and the pathophysiology of ASD require further exploration.
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http://dx.doi.org/10.1002/ajmg.a.62086DOI Listing
April 2021

Adaptation and validation of the Genetic Counseling Outcome Scale for autism spectrum disorders and related conditions.

J Genet Couns 2021 Feb 6;30(1):305-318. Epub 2020 Sep 6.

Azrieli Centre for Autism Research, Montreal Neurological Institute-Hospital, McGill University, Montreal, QC, Canada.

The genetics care pathway experienced by families affected by autism spectrum disorder (ASD) around the time of diagnosis is currently uncharacterized and potentially variable across contexts. The lack of consensus on outcome measures to capture the impact of genetic services for these families shows a gap in understanding and optimizing this genetics care pathway. The Genetic Counseling Outcome Scale (GCOS-24) is a validated outcome measure of clinical genetics services. The current study aims to adapt and validate the GCOS-24 as an outcome measure in the context routine genetic testing in ASD and related conditions. Families seen for their child's developmental evaluation for ASD and related conditions were invited to participate in a genomics cohort between 2016 and 2018. Families (n = 111) completed the mGCOS-24 (modified GCOS-24), adapted from the original GCOS-24 by clinicians working in the target population's routine care pathway. The mGCOS-24 has acceptable internal consistency (Cronbach's α = 0.84) and high test-retest reliability (ICC = 0.88). It also inversely correlates with stress as measured by Perceived Stress Scale (PSS-10) and distress, as measured by the Distress Thermometer, rs ≥ 0.39, ps < 0.001. The mGCOS-24 had adequate readability, as supported by cognitive interviews completed by a sub-sample of five mothers of a child with ASD. Together, our findings show that the mGCOS-24 has good validity for the target population. Preliminary characterization of the genetics care pathway in this population revealed remarkable variability in pre-test counseling and limited post-test counseling. The use of the mGCOS-24 as an outcome measure is useful in filling some of these gaps by offering a way to assess, and in the future, optimize the genetics care pathway for families affected by autism and related neurodevelopmental conditions.
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http://dx.doi.org/10.1002/jgc4.1323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891368PMC
February 2021

Genome-wide detection of tandem DNA repeats that are expanded in autism.

Nature 2020 10 27;586(7827):80-86. Epub 2020 Jul 27.

Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada.

Tandem DNA repeats vary in the size and sequence of each unit (motif). When expanded, these tandem DNA repeats have been associated with more than 40 monogenic disorders. Their involvement in disorders with complex genetics is largely unknown, as is the extent of their heterogeneity. Here we investigated the genome-wide characteristics of tandem repeats that had motifs with a length of 2-20 base pairs in 17,231 genomes of families containing individuals with autism spectrum disorder (ASD) and population control individuals. We found extensive polymorphism in the size and sequence of motifs. Many of the tandem repeat loci that we detected correlated with cytogenetic fragile sites. At 2,588 loci, gene-associated expansions of tandem repeats that were rare among population control individuals were significantly more prevalent among individuals with ASD than their siblings without ASD, particularly in exons and near splice junctions, and in genes related to the development of the nervous system and cardiovascular system or muscle. Rare tandem repeat expansions had a prevalence of 23.3% in children with ASD compared with 20.7% in children without ASD, which suggests that tandem repeat expansions make a collective contribution to the risk of ASD of 2.6%. These rare tandem repeat expansions included previously undescribed ASD-linked expansions in DMPK and FXN, which are associated with neuromuscular conditions, and in previously unknown loci such as FGF14 and CACNB1. Rare tandem repeat expansions were associated with lower IQ and adaptive ability. Our results show that tandem DNA repeat expansions contribute strongly to the genetic aetiology and phenotypic complexity of ASD.
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http://dx.doi.org/10.1038/s41586-020-2579-zDOI Listing
October 2020

Segregating patterns of copy number variations in extended autism spectrum disorder (ASD) pedigrees.

Am J Med Genet B Neuropsychiatr Genet 2020 07 6;183(5):268-276. Epub 2020 May 6.

Centre for Addiction and Mental Health, The Hospital for Sick Children & University of Toronto, Toronto, Ontario, Canada.

Autism spectrum disorder (ASD) is a relatively common childhood onset neurodevelopmental disorder with a complex genetic etiology. While progress has been made in identifying the de novo mutational landscape of ASD, the genetic factors that underpin the ASD's tendency to run in families are not well understood. In this study, nine extended pedigrees each with three or more individuals with ASD, and others with a lesser autism phenotype, were phenotyped and genotyped in an attempt to identify heritable copy number variants (CNVs). Although these families have previously generated linkage signals, no rare CNV segregated with these signals in any family. A small number of clinically relevant CNVs were identified. Only one CNV was identified that segregated with ASD phenotype; namely, a duplication overlapping DLGAP2 in three male offspring each with an ASD diagnosis. This gene encodes a synaptic scaffolding protein, part of a group of proteins known to be pathologically implicated in ASD. On the whole, however, the heritable nature of ASD in the families studied remains poorly understood.
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http://dx.doi.org/10.1002/ajmg.b.32785DOI Listing
July 2020

A framework for an evidence-based gene list relevant to autism spectrum disorder.

Nat Rev Genet 2020 06 21;21(6):367-376. Epub 2020 Apr 21.

The Centre for Applied Genomics, Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.

Autism spectrum disorder (ASD) is often grouped with other brain-related phenotypes into a broader category of neurodevelopmental disorders (NDDs). In clinical practice, providers need to decide which genes to test in individuals with ASD phenotypes, which requires an understanding of the level of evidence for individual NDD genes that supports an association with ASD. Consensus is currently lacking about which NDD genes have sufficient evidence to support a relationship to ASD. Estimates of the number of genes relevant to ASD differ greatly among research groups and clinical sequencing panels, varying from a few to several hundred. This Roadmap discusses important considerations necessary to provide an evidence-based framework for the curation of NDD genes based on the level of information supporting a clinically relevant relationship between a given gene and ASD.
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http://dx.doi.org/10.1038/s41576-020-0231-2DOI Listing
June 2020

Perceived utility of biological testing for autism spectrum disorder is associated with child and family functioning.

Res Dev Disabil 2020 May 28;100:103605. Epub 2020 Feb 28.

Azrieli Centre for Autism Research, Montreal Neurological Institute-Hospital, McGill University, Montreal, Canada; Research Institute of the McGill University Health Centre, Montreal, Canada. Electronic address:

Background: The clinical integration of chromosomal microarray testing promises improvements in diagnostic yields in Autism Spectrum Disorder (ASD). While the impact on clinical management is promising for some families, the utility perceived by families, including the majority for whom results are negative, is unclear. With next generation genomic sequencing technologies poised for integration, along with promising ASD biomarkers being developed, there is a need to understand the extent to which genomic and other biological testing would have utility for the target recipients of these tests and their families. The purpose of the present cross-sectional study was to examine the predictors of perceived utility of biological testing among parents of a child with ASD.

Methods: The Perceived Utility of Biotesting (PUB) Questionnaire was developed based on literature review and integrating family review. Following their child's diagnosis, families participating in an ongoing prospective study completed the PUB questionnaire along with self-reported measures of parent stress, child and family functioning, and family-centered care prior to undergoing genetic testing for both clinical and research purposes.

Results: Based on n = 85 families, psychometric properties of the Perceived Utility of Biotesting questionnaire suggest a reliable and valid instrument. A stepwise regression analysis reveals that lower levels of child emotional and behavioural functioning and higher levels of family functioning correlated with higher perceived utility for biological testing.

Limitations: A main limitation in the study is the participation rate of 50 %, thus the possibility of self-selection bias cannot be ruled out. We also chose to assess perceived utility among parents rather than the individuals with ASD themselves: modifying the questionnaire to capture perceived utility from autistic individuals across the lifespan would prove essential in future studies. Finally, ongoing validation of the PUB by assessing the PUB's discriminant and convergent validity is still needed.

Conclusions: We conclude that the utility of biological testing perceived by families whose child is undergoing genetic testing around ASD diagnosis depends on their unique child and family characteristics. This signifies that engaging families in biomarker discovery for improving the impact of research and care requires systematic input from a representative sample of families.
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http://dx.doi.org/10.1016/j.ridd.2020.103605DOI Listing
May 2020

Precision Health Resource of Control iPSC Lines for Versatile Multilineage Differentiation.

Stem Cell Reports 2019 12;13(6):1126-1141

Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address:

Induced pluripotent stem cells (iPSC) derived from healthy individuals are important controls for disease-modeling studies. Here we apply precision health to create a high-quality resource of control iPSCs. Footprint-free lines were reprogrammed from four volunteers of the Personal Genome Project Canada (PGPC). Multilineage-directed differentiation efficiently produced functional cortical neurons, cardiomyocytes and hepatocytes. Pilot users demonstrated versatility by generating kidney organoids, T lymphocytes, and sensory neurons. A frameshift knockout was introduced into MYBPC3 and these cardiomyocytes exhibited the expected hypertrophic phenotype. Whole-genome sequencing-based annotation of PGPC lines revealed on average 20 coding variants. Importantly, nearly all annotated PGPC and HipSci lines harbored at least one pre-existing or acquired variant with cardiac, neurological, or other disease associations. Overall, PGPC lines were efficiently differentiated by multiple users into cells from six tissues for disease modeling, and variant-preferred healthy control lines were identified for specific disease settings.
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http://dx.doi.org/10.1016/j.stemcr.2019.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6915802PMC
December 2019

A large data resource of genomic copy number variation across neurodevelopmental disorders.

NPJ Genom Med 2019 7;4:26. Epub 2019 Oct 7.

Hamilton Health Sciences, Ron Joyce Children's Health Centre, Hamilton, On Canada.

Copy number variations (CNVs) are implicated across many neurodevelopmental disorders (NDDs) and contribute to their shared genetic etiology. Multiple studies have attempted to identify shared etiology among NDDs, but this is the first genome-wide CNV analysis across autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), schizophrenia (SCZ), and obsessive-compulsive disorder (OCD) at once. Using microarray (Affymetrix CytoScan HD), we genotyped 2,691 subjects diagnosed with an NDD (204 SCZ, 1,838 ASD, 427 ADHD and 222 OCD) and 1,769 family members, mainly parents. We identified rare CNVs, defined as those found in <0.1% of 10,851 population control samples. We found clinically relevant CNVs (broadly defined) in 284 (10.5%) of total subjects, including 22 (10.8%) among subjects with SCZ, 209 (11.4%) with ASD, 40 (9.4%) with ADHD, and 13 (5.6%) with OCD. Among all NDD subjects, we identified 17 (0.63%) with aneuploidies and 115 (4.3%) with known genomic disorder variants. We searched further for genes impacted by different CNVs in multiple disorders. Examples of NDD-associated genes linked across more than one disorder (listed in order of occurrence frequency) are , , , , , , , , , , and long non-coding RNAs: and . We demonstrated that CNVs impacting the same genes could potentially contribute to the etiology of multiple NDDs. The CNVs identified will serve as a useful resource for both research and diagnostic laboratories for prioritization of variants.
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http://dx.doi.org/10.1038/s41525-019-0098-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779875PMC
October 2019

Association between distress and knowledge among parents of autistic children.

PLoS One 2019 26;14(9):e0223119. Epub 2019 Sep 26.

Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.

Understanding the overall utility of biological testing for autism spectrum disorder (ASD) is essential for the development and integration of biomarkers into routine care. One measure related to the overall utility of biological testing is the knowledge that a person has about the condition he/she suffers from. However, a major gap towards understanding the role of knowledge in overall utility is the absence of studies that have assessed knowledge of autism along with its predictors within a representative sample of families within the context of routine care. The objective of this study was to measure knowledge of ASD among families within the routine care pathway for biological testing in ASD by examining the association between knowledge with potential correlates of knowledge namely sociodemographic factors, parental stress and distress, and time since diagnosis among parents whose child with ASD is undergoing clinical genetic testing. Parents of a child diagnosed with ASD (n = 85, Mage = 39.0, SD = 7.7) participating in an ongoing prospective genomics study completed the ASD Quiz prior to undergoing genetic testing for clinical and research purposes. Parents also completed self-reported measures of stress and distress. Parent stress and distress was each independently correlated with knowledge of ASD, rs ≥ 0.26, ps < 0.05. Stepwise regression analysis revealed a significant model accounting for 7.8% of the variance in knowledge, F (1, 82) = 8.02, p = 0.006. The only factor significantly associated with knowledge was parental distress, β = 0.30, p = 0.006. Parental stress, time since diagnosis, and sociodemographic factors were not significant predictors in this model. We concluded that families require tailored support prior to undergoing genetic testing to address either knowledge gaps or high distress. Ongoing appraisal of the testing process among families of diverse backgrounds is essential in offering optimal care for families undergoing genetic testing.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0223119PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6763195PMC
April 2020

or human iPSC-derived neurons from individuals with autism develop hyperactive neuronal networks.

Elife 2019 02 12;8. Epub 2019 Feb 12.

Genetics & Genome Biology Program, The Hospital for Sick Children, Toronto, Canada.

Induced pluripotent stem cell (iPSC)-derived neurons are increasingly used to model Autism Spectrum Disorder (ASD), which is clinically and genetically heterogeneous. To study the complex relationship of penetrant and weaker polygenic risk variants to ASD, 'isogenic' iPSC-derived neurons are critical. We developed a set of procedures to control for heterogeneity in reprogramming and differentiation, and generated 53 different iPSC-derived glutamatergic neuronal lines from 25 participants from 12 unrelated families with ASD. Heterozygous de novo and rare-inherited presumed-damaging variants were characterized in ASD risk genes/loci. Combinations of putative etiologic variants ( or ) in separate families were modeled. We used a multi-electrode array, with patch-clamp recordings, to determine a reproducible synaptic phenotype in 25% of the individuals with ASD (other relevant data on the remaining lines was collected). Our most compelling new results revealed a consistent spontaneous network hyperactivity in neurons deficient for or The biobank of iPSC-derived neurons and accompanying genomic data are available to accelerate ASD research.

Editorial Note: This article has been through an editorial process in which authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).
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http://dx.doi.org/10.7554/eLife.40092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6372285PMC
February 2019

Complete Disruption of Autism-Susceptibility Genes by Gene Editing Predominantly Reduces Functional Connectivity of Isogenic Human Neurons.

Stem Cell Reports 2018 11 1;11(5):1211-1225. Epub 2018 Nov 1.

Genetics & Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 3H7, Canada; McLaughlin Centre, University of Toronto, Toronto, ON M5S 3H7, Canada. Electronic address:

Autism spectrum disorder (ASD) is phenotypically and genetically heterogeneous. We present a CRISPR gene editing strategy to insert a protein tag and premature termination sites creating an induced pluripotent stem cell (iPSC) knockout resource for functional studies of ten ASD-relevant genes (AFF2/FMR2, ANOS1, ASTN2, ATRX, CACNA1C, CHD8, DLGAP2, KCNQ2, SCN2A, TENM1). Neurogenin 2 (NGN2)-directed induction of iPSCs allowed production of excitatory neurons, and mutant proteins were not detectable. RNA sequencing revealed convergence of several neuronal networks. Using both patch-clamp and multi-electrode array approaches, the electrophysiological deficits measured were distinct for different mutations. However, they culminated in a consistent reduction in synaptic activity, including reduced spontaneous excitatory postsynaptic current frequencies in AFF2/FMR2-, ASTN2-, ATRX-, KCNQ2-, and SCN2A-null neurons. Despite ASD susceptibility genes belonging to different gene ontologies, isogenic stem cell resources can reveal common functional phenotypes, such as reduced functional connectivity.
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http://dx.doi.org/10.1016/j.stemcr.2018.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235011PMC
November 2018

A genome-wide linkage study of autism spectrum disorder and the broad autism phenotype in extended pedigrees.

J Neurodev Disord 2018 06 11;10(1):20. Epub 2018 Jun 11.

Centre for Addiction and Mental Health, The Hospital for Sick Children and University of Toronto, Toronto, ON, Canada.

Background: Although several genetic variants for autism spectrum disorder (ASD) have now been identified, these largely occur sporadically or are de novo. Much less progress has been made in identifying inherited variants, even though the disorder itself is familial in the majority of cases. The objective of this study was to identify chromosomal regions that harbor inherited variants increasing the risk for ASD using an approach that examined both ASD and the broad autism phenotype (BAP) among a unique sample of extended pedigrees.

Methods: ASD and BAP were assessed using standardized tools in 28 pedigrees from Canada and the USA, each with at least three ASD-diagnosed individuals from two nuclear families. Genome-wide linkage analysis was performed using the posterior probability of linkage (PPL) statistic, a quasi-Bayesian method that provides strength of evidence for or against linkage in an essentially model-free manner, with outcomes on the probability scale.

Results: The results confirm appreciable interfamilial heterogeneity as well as a high level of intrafamilial heterogeneity. Both ASD and combined ASD/BAP specific loci are apparent.

Conclusions: Inclusion of subclinical phenotypes such as BAP should be more widely employed in genetic studies of ASD as a way of identifying inherited genetic variants for the disorder. Moreover, the results underscore the need for approaches to identifying genetic risk factors in extended pedigrees that are robust to high levels of inter/intrafamilial locus and allelic heterogeneity.
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http://dx.doi.org/10.1186/s11689-018-9238-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5996536PMC
June 2018

The Personal Genome Project Canada: findings from whole genome sequences of the inaugural 56 participants.

CMAJ 2018 02;190(5):E126-E136

The Centre for Applied Genomics (Reuter, Walker, Thiruvahindrapuram, Whitney, Yuen, Trost, Paton, Pereira, Herbrick, Wintle, Merico, Howe, MacDonald, Lu, Nalpathamkalam, Sung, Wang, Patel, Pellecchia, J. Wei, Strug, Bell, Kellam, Mahtani, Hosseini, Fiume, Marshall, Buchanan, Scherer); Divisions of Clinical Pharmacology and Toxicology (I. Cohn), or Clinical, and Metabolic Genetics (Sondheimer, Weksberg, Shuman, Bowdin, Meyn, Monfared), The Hospital for Sick Children; Departments of Paediatrics (Sondheimer, R. Cohn) and Molecular Genetics (Yuen, Weksberg, Shuman, R. Cohn, Ellis, Meyn), University of Toronto; Deep Genomics Inc. (Merico); Department of Psychiatry (Bassett), University Health Network and Centre for Addiction and Mental Health, University of Toronto; Li Ka Shing Knowledge Institute (Bombard), St. Michael's Hospital; Institute of Health Policy, Management and Evaluation (Bombard), University of Toronto; Centre for Genetic Medicine (Stavropoulos, Bowdin, Ray, Monfared); Molecular Genetics Laboratory (Stavropoulos, Ray, Marshall), Division of Genome Diagnostics, Paediatric Laboratory Medicine; Developmental and Stem Cell Biology (Hildebrandt, W. Wei, Romm, Pasceri, Ellis); Ted Rogers Cardiac Genome Clinic (Hosseini); Cytogenetics Laboratory (Joseph-George), Division of Genome Diagnostics, Paediatric Laboratory Medicine, The Hospital for Sick Children; Departments of Biochemistry and Laboratory Medicine, and Pathobiology (Keeley), University of Toronto; DNAstack (Cook, Fiume); McLaughlin Centre (Lee, Scherer), University of Toronto; Medcan Health Management Inc. (Davies, Hazell); Dalla Lana School of Public Health (Szego), Department of Family and Community Medicine, and The Joint Centre for Bioethics, University of Toronto; Centre for Clinical Ethics (Szego), St. Joseph's Health Centre, Toronto, Ont.

Background: The Personal Genome Project Canada is a comprehensive public data resource that integrates whole genome sequencing data and health information. We describe genomic variation identified in the initial recruitment cohort of 56 volunteers.

Methods: Volunteers were screened for eligibility and provided informed consent for open data sharing. Using blood DNA, we performed whole genome sequencing and identified all possible classes of DNA variants. A genetic counsellor explained the implication of the results to each participant.

Results: Whole genome sequencing of the first 56 participants identified 207 662 805 sequence variants and 27 494 copy number variations. We analyzed a prioritized disease-associated data set ( = 1606 variants) according to standardized guidelines, and interpreted 19 variants in 14 participants (25%) as having obvious health implications. Six of these variants (e.g., in or mosaic loss of an X chromosome) were pathogenic or likely pathogenic. Seven were risk factors for cancer, cardiovascular or neurobehavioural conditions. Four other variants - associated with cancer, cardiac or neurodegenerative phenotypes - remained of uncertain significance because of discrepancies among databases. We also identified a large structural chromosome aberration and a likely pathogenic mitochondrial variant. There were 172 recessive disease alleles (e.g., 5 individuals carried mutations for cystic fibrosis). Pharmacogenomics analyses revealed another 3.9 potentially relevant genotypes per individual.

Interpretation: Our analyses identified a spectrum of genetic variants with potential health impact in 25% of participants. When also considering recessive alleles and variants with potential pharmacologic relevance, all 56 participants had medically relevant findings. Although access is mostly limited to research, whole genome sequencing can provide specific and novel information with the potential of major impact for health care.
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http://dx.doi.org/10.1503/cmaj.171151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5798982PMC
February 2018

Mutations in in individuals with intellectual disability, autism spectrum disorder, and macrocephaly.

Mol Autism 2017 9;8:59. Epub 2017 Nov 9.

Program in Genetics and Genome Biology, The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON Canada.

Background: Autism spectrum disorder (ASD), a developmental disorder of early childhood onset, affects males four times more frequently than females, suggesting a role for the sex chromosomes. In this study, we describe a family with ASD in which a predicted pathogenic nonsense mutation in the X-chromosome gene segregates with ASD phenotype.

Methods: Clinical phenotyping, microarray, and whole genome sequencing (WGS) were performed on the five members of this family. Maternal and female sibling X inactivation ratio was calculated, and phase was investigated. Mutant-induced pluripotent stem cells engineered for an exon 2 nonsense mutation were generated and differentiated into cortical neurons for expression and pathway analyses.

Results: Two males with an inherited mutation both presented with macrocephaly, intellectual disability (ID), and ASD. Their female sibling with the same mutation presented with ID and a broad autism phenotype. In contrast, their transmitting mother has no neurodevelopmental diagnosis. Our investigation of phase indicated maternal preferential inactivation of the mutated allele, with no such bias observed in the female sibling. We offer the explanation that this bias in X inactivation may explain the absence of a neurocognitive phenotype in the mother. Our cellular knockout model of revealed an impact on expression in differentiated neurons for several genes implicated in brain development and function, supported by our pathway enrichment analysis.

Conclusions: Penetrance for ASD is high among males but more variable among females with mutations. A critical role for this gene in brain development and function is demonstrated.
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http://dx.doi.org/10.1186/s13229-017-0175-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5679329PMC
February 2018

Variable phenotype expression in a family segregating microdeletions of the and autism spectrum disorder susceptibility genes.

NPJ Genom Med 2017 May;2

Program in Genetics and Genome Biology, The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, Canada.

Autism Spectrum Disorder (ASD) is a developmental condition of early childhood onset, which impacts socio-communicative functioning and is principally genetic in etiology. Currently, more than 50 genomic loci are deemed to be associated with susceptibility to ASD, showing and inherited unbalanced copy number variants (CNVs) and smaller insertions and deletions (indels), more complex structural variants (SVs), as well as single nucleotide variants (SNVs) deemed of pathological significance. However, the phenotypes associated with many of these genes are variable, and penetrance is largely unelaborated in clinical descriptions. This case report describes a family harboring two CNV microdeletions, which affect regions of and - each well-established in association with risk of ASD and other neurodevelopmental disorders. Although each CNV would likely be categorized as pathologically significant, both genomic alterations are transmitted in this family from an unaffected father to the proband, and shared by an unaffected sibling. This family case illustrates the importance of recognizing that phenotype can vary among exon overlapping variants of the same gene, and the need to evaluate penetrance of such variants in order to properly inform on risks.
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http://dx.doi.org/10.1038/s41525-017-0020-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482711PMC
May 2017

Genome-wide characteristics of mutations in autism.

NPJ Genom Med 2016 Aug;1:160271-1602710

BGI-Shenzhen, Yantian, Shenzhen, China.

mutations (DNMs) are important in Autism Spectrum Disorder (ASD), but so far analyses have mainly been on the ~1.5% of the genome encoding genes. Here, we performed whole genome sequencing (WGS) of 200 ASD parent-child trios and characterized germline and somatic DNMs. We confirmed that the majority of germline DNMs (75.6%) originated from the father, and these increased significantly with paternal age only (p=4.2×10). However, when clustered DNMs (those within 20kb) were found in ASD, not only did they mostly originate from the mother (p=7.7×10), but they could also be found adjacent to copy number variations (CNVs) where the mutation rate was significantly elevated (p=2.4×10). By comparing DNMs detected in controls, we found a significant enrichment of predicted damaging DNMs in ASD cases (p=8.0×10; OR=1.84), of which 15.6% (p=4.3×10) and 22.5% (p=7.0×10) were in the non-coding or genic non-coding, respectively. The non-coding elements most enriched for DNM were untranslated regions of genes, boundaries involved in exon-skipping and DNase I hypersensitive regions. Using microarrays and a novel outlier detection test, we also found aberrant methylation profiles in 2/185 (1.1%) of ASD cases. These same individuals carried independently identified DNMs in the ASD risk- and epigenetic- genes and Our data begins to characterize different genome-wide DNMs, and highlight the contribution of non-coding variants, to the etiology of ASD.
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http://dx.doi.org/10.1038/npjgenmed.2016.27DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4980121PMC
August 2016

Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder.

JAMA 2015 Sep;314(9):895-903

Disciplines of Genetics and Medicine, Memorial University of Newfoundland, St John's, Newfoundland and Labrador, Canada.

Importance: The use of genome-wide tests to provide molecular diagnosis for individuals with autism spectrum disorder (ASD) requires more study.

Objective: To perform chromosomal microarray analysis (CMA) and whole-exome sequencing (WES) in a heterogeneous group of children with ASD to determine the molecular diagnostic yield of these tests in a sample typical of a developmental pediatric clinic.

Design, Setting, And Participants: The sample consisted of 258 consecutively ascertained unrelated children with ASD who underwent detailed assessments to define morphology scores based on the presence of major congenital abnormalities and minor physical anomalies. The children were recruited between 2008 and 2013 in Newfoundland and Labrador, Canada. The probands were stratified into 3 groups of increasing morphological severity: essential, equivocal, and complex (scores of 0-3, 4-5, and ≥6).

Exposures: All probands underwent CMA, with WES performed for 95 proband-parent trios.

Main Outcomes And Measures: The overall molecular diagnostic yield for CMA and WES in a population-based ASD sample stratified in 3 phenotypic groups.

Results: Of 258 probands, 24 (9.3%, 95%CI, 6.1%-13.5%) received a molecular diagnosis from CMA and 8 of 95 (8.4%, 95%CI, 3.7%-15.9%) from WES. The yields were statistically different between the morphological groups. Among the children who underwent both CMA and WES testing, the estimated proportion with an identifiable genetic etiology was 15.8% (95%CI, 9.1%-24.7%; 15/95 children). This included 2 children who received molecular diagnoses from both tests. The combined yield was significantly higher in the complex group when compared with the essential group (pairwise comparison, P = .002). [table: see text].

Conclusions And Relevance: Among a heterogeneous sample of children with ASD, the molecular diagnostic yields of CMA and WES were comparable, and the combined molecular diagnostic yield was higher in children with more complex morphological phenotypes in comparison with the children in the essential category. If replicated in additional populations, these findings may inform appropriate selection of molecular diagnostic testing for children affected by ASD.
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http://dx.doi.org/10.1001/jama.2015.10078DOI Listing
September 2015

Whole-genome sequencing of quartet families with autism spectrum disorder.

Nat Med 2015 Feb 26;21(2):185-91. Epub 2015 Jan 26.

1] The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada. [2] Department of Molecular Genetics and McLaughlin Centre, University of Toronto, Toronto, Ontario, Canada.

Autism spectrum disorder (ASD) is genetically heterogeneous, with evidence for hundreds of susceptibility loci. Previous microarray and exome-sequencing studies have examined portions of the genome in simplex families (parents and one ASD-affected child) having presumed sporadic forms of the disorder. We used whole-genome sequencing (WGS) of 85 quartet families (parents and two ASD-affected siblings), consisting of 170 individuals with ASD, to generate a comprehensive data resource encompassing all classes of genetic variation (including noncoding variants) and accompanying phenotypes, in apparently familial forms of ASD. By examining de novo and rare inherited single-nucleotide and structural variations in genes previously reported to be associated with ASD or other neurodevelopmental disorders, we found that some (69.4%) of the affected siblings carried different ASD-relevant mutations. These siblings with discordant mutations tended to demonstrate more clinical variability than those who shared a risk variant. Our study emphasizes that substantial genetic heterogeneity exists in ASD, necessitating the use of WGS to delineate all genic and non-genic susceptibility variants in research and in clinical diagnostics.
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http://dx.doi.org/10.1038/nm.3792DOI Listing
February 2015

Using extended pedigrees to identify novel autism spectrum disorder (ASD) candidate genes.

Hum Genet 2015 Feb 29;134(2):191-201. Epub 2014 Nov 29.

Department of Psychiatry and Behavioural Neurosciences, McMaster University, Chedoke Campus (Evel Building, Room 457), Hamilton, ON, Canada,

Copy number variation has emerged as an important cause of phenotypic variation, particularly in relation to some complex disorders. Autism spectrum disorder (ASD) is one such disorder, in which evidence is emerging for an etiological role for some rare penetrant de novo and rare inherited copy number variants (CNVs). De novo variation, however, does not always explain the familial nature of ASD, leaving a gap in our knowledge concerning the heritable genetic causes of this disorder. Extended pedigrees, in which several members have ASD, provide an opportunity to investigate inherited genetic risk factors. In this current study, we recruited 19 extended ASD pedigrees, and, using the Illumina HumanOmni2.5 BeadChip, conducted genome-wide CNV interrogation. We found no definitive evidence of an etiological role for segregating CNVs in these pedigrees, and no evidence that linkage signals in these pedigrees are explained by segregating CNVs. However, a small number of putative de novo variants were transmitted from BAP parents to their ASD offspring, and evidence emerged for a rare duplication CNV at 11p13.3 harboring two putative 'developmental/neuropsychiatric' susceptibility gene(s), GSTP1 and NDUFV1.
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http://dx.doi.org/10.1007/s00439-014-1513-6DOI Listing
February 2015

Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: a gradient of severity in cognitive impairments.

PLoS Genet 2014 Sep 4;10(9):e1004580. Epub 2014 Sep 4.

Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Département de Génétique et de Cytogénétique, Unité fonctionnelle de génétique clinique, Paris, France; Centre de Référence "Déficiences intellectuelles de causes rares", Paris, France and Groupe de Recherche Clinique "Déficience intellectuelle et autisme", UPMC, Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpital Armand Trousseau, Service de Neuropédiatrie, Paris, France.

SHANK genes code for scaffold proteins located at the post-synaptic density of glutamatergic synapses. In neurons, SHANK2 and SHANK3 have a positive effect on the induction and maturation of dendritic spines, whereas SHANK1 induces the enlargement of spine heads. Mutations in SHANK genes have been associated with autism spectrum disorders (ASD), but their prevalence and clinical relevance remain to be determined. Here, we performed a new screen and a meta-analysis of SHANK copy-number and coding-sequence variants in ASD. Copy-number variants were analyzed in 5,657 patients and 19,163 controls, coding-sequence variants were ascertained in 760 to 2,147 patients and 492 to 1,090 controls (depending on the gene), and, individuals carrying de novo or truncating SHANK mutations underwent an extensive clinical investigation. Copy-number variants and truncating mutations in SHANK genes were present in ∼1% of patients with ASD: mutations in SHANK1 were rare (0.04%) and present in males with normal IQ and autism; mutations in SHANK2 were present in 0.17% of patients with ASD and mild intellectual disability; mutations in SHANK3 were present in 0.69% of patients with ASD and up to 2.12% of the cases with moderate to profound intellectual disability. In summary, mutations of the SHANK genes were detected in the whole spectrum of autism with a gradient of severity in cognitive impairment. Given the rare frequency of SHANK1 and SHANK2 deleterious mutations, the clinical relevance of these genes remains to be ascertained. In contrast, the frequency and the penetrance of SHANK3 mutations in individuals with ASD and intellectual disability-more than 1 in 50-warrant its consideration for mutation screening in clinical practice.
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http://dx.doi.org/10.1371/journal.pgen.1004580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4154644PMC
September 2014

Convergence of genes and cellular pathways dysregulated in autism spectrum disorders.

Am J Hum Genet 2014 May 24;94(5):677-94. Epub 2014 Apr 24.

Academic Centre on Rare Diseases, School of Medicine and Medical Science, University College Dublin, Dublin 4, Ireland; Children's University Hospital Temple Street, Dublin 1, Ireland.

Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.
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http://dx.doi.org/10.1016/j.ajhg.2014.03.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4067558PMC
May 2014

Disruption of the ASTN2/TRIM32 locus at 9q33.1 is a risk factor in males for autism spectrum disorders, ADHD and other neurodevelopmental phenotypes.

Hum Mol Genet 2014 May 30;23(10):2752-68. Epub 2013 Dec 30.

The Centre for Applied Genomics.

Rare copy number variants (CNVs) disrupting ASTN2 or both ASTN2 and TRIM32 have been reported at 9q33.1 by genome-wide studies in a few individuals with neurodevelopmental disorders (NDDs). The vertebrate-specific astrotactins, ASTN2 and its paralog ASTN1, have key roles in glial-guided neuronal migration during brain development. To determine the prevalence of astrotactin mutations and delineate their associated phenotypic spectrum, we screened ASTN2/TRIM32 and ASTN1 (1q25.2) for exonic CNVs in clinical microarray data from 89 985 individuals across 10 sites, including 64 114 NDD subjects. In this clinical dataset, we identified 46 deletions and 12 duplications affecting ASTN2. Deletions of ASTN1 were much rarer. Deletions near the 3' terminus of ASTN2, which would disrupt all transcript isoforms (a subset of these deletions also included TRIM32), were significantly enriched in the NDD subjects (P = 0.002) compared with 44 085 population-based controls. Frequent phenotypes observed in individuals with such deletions include autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), speech delay, anxiety and obsessive compulsive disorder (OCD). The 3'-terminal ASTN2 deletions were significantly enriched compared with controls in males with NDDs, but not in females. Upon quantifying ASTN2 human brain RNA, we observed shorter isoforms expressed from an alternative transcription start site of recent evolutionary origin near the 3' end. Spatiotemporal expression profiling in the human brain revealed consistently high ASTN1 expression while ASTN2 expression peaked in the early embryonic neocortex and postnatal cerebellar cortex. Our findings shed new light on the role of the astrotactins in psychopathology and their interplay in human neurodevelopment.
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http://dx.doi.org/10.1093/hmg/ddt669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3990173PMC
May 2014

Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing.

Am J Hum Genet 2013 Aug 11;93(2):249-63. Epub 2013 Jul 11.

Department of Paediatrics and Neurobiology, Duke University School of Medicine, Durham, NC 27710, USA.

Autism Spectrum Disorder (ASD) demonstrates high heritability and familial clustering, yet the genetic causes remain only partially understood as a result of extensive clinical and genomic heterogeneity. Whole-genome sequencing (WGS) shows promise as a tool for identifying ASD risk genes as well as unreported mutations in known loci, but an assessment of its full utility in an ASD group has not been performed. We used WGS to examine 32 families with ASD to detect de novo or rare inherited genetic variants predicted to be deleterious (loss-of-function and damaging missense mutations). Among ASD probands, we identified deleterious de novo mutations in six of 32 (19%) families and X-linked or autosomal inherited alterations in ten of 32 (31%) families (some had combinations of mutations). The proportion of families identified with such putative mutations was larger than has been previously reported; this yield was in part due to the comprehensive and uniform coverage afforded by WGS. Deleterious variants were found in four unrecognized, nine known, and eight candidate ASD risk genes. Examples include CAPRIN1 and AFF2 (both linked to FMR1, which is involved in fragile X syndrome), VIP (involved in social-cognitive deficits), and other genes such as SCN2A and KCNQ2 (linked to epilepsy), NRXN1, and CHD7, which causes ASD-associated CHARGE syndrome. Taken together, these results suggest that WGS and thorough bioinformatic analyses for de novo and rare inherited mutations will improve the detection of genetic variants likely to be associated with ASD or its accompanying clinical symptoms.
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http://dx.doi.org/10.1016/j.ajhg.2013.06.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3738824PMC
August 2013

Individual common variants exert weak effects on the risk for autism spectrum disorders.

Hum Mol Genet 2012 Nov 26;21(21):4781-92. Epub 2012 Jul 26.

Autism Genetics Group, Department of Psychiatry, School of Medicine, Trinity College, Dublin 8, Ireland.

While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest.
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http://dx.doi.org/10.1093/hmg/dds301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3471395PMC
November 2012

Utilization of preventive care services and their effect on cardiovascular outcomes in the United States.

Risk Manag Healthc Policy 2011 19;4:1-7. Epub 2011 Jan 19.

Pharmacy Health Care Administration, Department of Pharmacy Practice, University of Toledo College of Pharmacy, Toledo, OH, USA.

Objective: To describe and analyze utilization of preventive care services and their effect on cardiovascular outcomes in the United States.

Methods: Data from the 2007 Medical Expenditure Panel Survey (MEPS) were used to analyze utilization of preventive care services and their effect on cardiovascular outcomes. Recommendations by the Seventh Report of the Joint Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure and the National Cholesterol Education Program were used to determine appropriate levels of preventive care utilization. Utilization of blood pressure screening and cholesterol checkup services were used as the dependent variable, while age, gender, race, ethnicity, insurance status, and perceived health status were used as independent variables. Since guidelines differ for people with elevated blood pressure, respondents with elevated blood pressure were identified in the MEPS database by self-reported diagnosis. Descriptive statistics were used to describe the population, while a multivariate logistic regression model was built to predict odds of utilizing appropriate levels of preventive services.

Results: Total number of adult respondents for which data were available for blood pressure checkup and cholesterol checkup was 20,523 and 15,784, respectively. Overall, MEPS respondents were found to adhere to guideline recommendations for preventive care utilization. Multivariate logistic regression showed that odds of utilization of preventive care services were higher for elderly patients (age >65 years) for blood pressure (odds ratio [OR] = 2.39, 95% confidence interval [CI]: 1.92-2.97) and cholesterol (OR = 3.05, 95% CI: 2.18-4.27) preventive services compared with younger population (age 18-54 years). Males had much lower odds of getting blood pressure (OR = 0.33, 95% CI: 0.30-0.37) and cholesterol (OR = 0.59, 95% CI: 0.50-0.70) checks done compared with females. Odds of utilization were nearly similar for all races. Uninsured had lower odds for blood pressure (OR = 0.26, 95% CI: 0.23-0.30) and cholesterol (OR = 0.30, 95% CI: 0.24-0.39) checks compared with privately insured people. Asians had lower odds of getting blood pressure checkups compared to Whites (OR = 0.49, 95% CI: 0.39-0.63). Similar trends were recorded for other covariates such as race and perceived health status.

Conclusion: The study was successful in identifying existing age, race, income, and insurance-status related disparities in preventive care utilization within a US population.
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http://dx.doi.org/10.2147/RMHP.S15777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3270932PMC
August 2012

Rare copy number variation discovery and cross-disorder comparisons identify risk genes for ADHD.

Sci Transl Med 2011 Aug;3(95):95ra75

The Centre for Applied Genomics and Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.

Attention deficit hyperactivity disorder (ADHD) is a common and persistent condition characterized by developmentally atypical and impairing inattention, hyperactivity, and impulsiveness. We identified de novo and rare copy number variations (CNVs) in 248 unrelated ADHD patients using million-feature genotyping arrays. We found de novo CNVs in 3 of 173 (1.7%) ADHD patients for whom we had DNA from both parents. These CNVs affected brain-expressed genes: DCLK2, SORCS1, SORCS3, and MACROD2. We also detected rare inherited CNVs in 19 of 248 (7.7%) ADHD probands, which were absent in 2357 controls and which either overlapped previously implicated ADHD loci (for example, DRD5 and 15q13 microduplication) or identified new candidate susceptibility genes (ASTN2, CPLX2, ZBBX, and PTPRN2). Among these de novo and rare inherited CNVs, there were also examples of genes (ASTN2, GABRG1, and CNTN5) previously implicated by rare CNVs in other neurodevelopmental conditions including autism spectrum disorder (ASD). To further explore the overlap of risks in ADHD and ASD, we used the same microarrays to test for rare CNVs in an independent, newly collected cohort of 349 unrelated individuals with a primary diagnosis of ASD. Deletions of the neuronal ASTN2 and the ASTN2-intronic TRIM32 genes yielded the strongest association with ADHD and ASD, but numerous other shared candidate genes (such as CHCHD3, MACROD2, and the 16p11.2 region) were also revealed. Our results provide support for a role for rare CNVs in ADHD risk and reinforce evidence for the existence of common underlying susceptibility genes for ADHD, ASD, and other neuropsychiatric disorders.
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http://dx.doi.org/10.1126/scitranslmed.3002464DOI Listing
August 2011

A genome-wide scan for common alleles affecting risk for autism.

Hum Mol Genet 2010 Oct 27;19(20):4072-82. Epub 2010 Jul 27.

Department of Psychiatry, School of Medicine, Trinity College, Dublin 8, Ireland.

Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10(-8). When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10(-8) threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C.
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http://dx.doi.org/10.1093/hmg/ddq307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2947401PMC
October 2010
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