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Article: Clinical actionability of genetic findings in cerebral palsy.

Lewis, Sara A / Chopra, Maya / Cohen, Julie S / Bain, Jennifer / Aravamuthan, Bhooma / Carmel, Jason B / Fahey, Michael C / Segel, Reeval / Wintle, Richard F / Zech, Michael / May, Halie / Haque, Nahla / Fehlings, Darcy / Srivastava, Siddharth / Kruer, Michael C

medRxiv : the preprint server for health sciences

2023

Abstract: Background and objectives: Single gene mutations are increasingly recognized as causes of cerebral palsy (CP) phenotypes, yet there is currently no standardized framework for measuring their clinical impact. We evaluated Pathogenic/Likely Pathogenic (P/ ... ...

Abstract	Background and objectives: Single gene mutations are increasingly recognized as causes of cerebral palsy (CP) phenotypes, yet there is currently no standardized framework for measuring their clinical impact. We evaluated Pathogenic/Likely Pathogenic (P/LP) variants identified in individuals with CP to determine how frequently genetic testing results would prompt changes in care. Methods: We analyzed published P/LP variants in OMIM genes identified in clinical (n = 1,345 individuals) or research (n = 496) cohorts using exome sequencing of CP patients. We established a working group of clinical and research geneticists, developmental pediatricians, genetic counselors, and neurologists and performed a systematic review of existing literature for evidence of clinical management approaches linked to genetic disorders. Scoring rubrics were adapted, and a modified Delphi approach was used to build consensus and establish the anticipated impact on patient care. Overall Results: We found 140/1,841 (8%) of individuals in published CP cohorts had a genetic diagnosis classified as Discussion: Our findings indicate that actionable genetic findings occur in 8% of individuals referred for genetic testing with CP. Evaluation of potential
Language	English
Publishing date	2023-09-11
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.09.08.23295195
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Article ; Online: VikNGS: a C++ variant integration kit for next generation sequencing association analysis.

Baskurt, Zeynep / Mastromatteo, Scott / Gong, Jiafen / Wintle, Richard F / Scherer, Stephen W / Strug, Lisa J

Bioinformatics (Oxford, England)

2019 Volume 36, Issue 4, Page(s) 1283–1285

Abstract: Summary: Integration of next generation sequencing data (NGS) across different research studies can improve the power of genetic association testing by increasing sample size and can obviate the need for sequencing controls. If differential genotype ... ...

Abstract	Summary: Integration of next generation sequencing data (NGS) across different research studies can improve the power of genetic association testing by increasing sample size and can obviate the need for sequencing controls. If differential genotype uncertainty across studies is not accounted for, combining datasets can produce spurious association results. We developed the Variant Integration Kit for NGS (VikNGS), a fast cross-platform software package, to enable aggregation of several datasets for rare and common variant genetic association analysis of quantitative and binary traits with covariate adjustment. VikNGS also includes a graphical user interface, power simulation functionality and data visualization tools. Availability and implementation: The VikNGS package can be downloaded at http://www.tcag.ca/tools/index.html. Supplementary information: Supplementary data are available at Bioinformatics online.
MeSH term(s)	Data Visualization ; Genotype ; High-Throughput Nucleotide Sequencing ; Phenotype ; Software
Language	English
Publishing date	2019-10-02
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1422668-6
ISSN	1367-4811 ; 1367-4803
ISSN (online)	1367-4811
ISSN	1367-4803
DOI	10.1093/bioinformatics/btz716
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Article ; Online: Mutational Landscape of Autism Spectrum Disorder Brain Tissue.

Woodbury-Smith, Marc / Lamoureux, Sylvia / Begum, Ghausia / Nassir, Nasna / Akter, Hosneara / O'Rielly, Darren D / Rahman, Proton / Wintle, Richard F / Scherer, Stephen W / Uddin, Mohammed

Genes

2022 Volume 13, Issue 2

Abstract: Rare post-zygotic mutations in the brain are now known to contribute to several neurodevelopmental disorders, including autism spectrum disorder (ASD). However, due to the limited availability of brain tissue, most studies rely on estimates of mosaicism ... ...

Abstract	Rare post-zygotic mutations in the brain are now known to contribute to several neurodevelopmental disorders, including autism spectrum disorder (ASD). However, due to the limited availability of brain tissue, most studies rely on estimates of mosaicism from peripheral samples. In this study, we undertook whole exome sequencing on brain tissue from 26 ASD brain donors from the Harvard Brain Tissue Resource Center (HBTRC) and ascertained the presence of post-zygotic and germline mutations categorized as pathological, including those impacting known ASD-implicated genes. Although quantification did not reveal enrichment for post-zygotic mutations compared with the controls (
MeSH term(s)	Autism Spectrum Disorder/genetics ; Autism Spectrum Disorder/pathology ; Brain/pathology ; Calcium-Binding Proteins/genetics ; Genetic Predisposition to Disease ; Humans ; Membrane Proteins/genetics ; Mutation ; Whole Exome Sequencing
Chemical Substances	CLSTN3 protein, human ; Calcium-Binding Proteins ; Membrane Proteins
Language	English
Publishing date	2022-01-24
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527218-4
ISSN	2073-4425 ; 2073-4425
ISSN (online)	2073-4425
ISSN	2073-4425
DOI	10.3390/genes13020207
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Article ; Online: Chromosomal-level reference genome assembly of the North American wolverine (Gulo gulo luscus): a resource for conservation genomics.

Lok, Si / Lau, Timothy N H / Trost, Brett / Tong, Amy H Y / Wintle, Richard F / Engstrom, Mark D / Stacy, Elise / Waits, Lisette P / Scrafford, Matthew / Scherer, Stephen W

G3 (Bethesda, Md.)

2022 Volume 12, Issue 8

Abstract: We report a chromosomal-level genome assembly of a male North American wolverine (Gulo gulo luscus) from the Kugluktuk region of Nunavut, Canada. The genome was assembled directly from long-reads, comprising: 758 contigs with a contig N50 of 36.6 Mb; ... ...

Abstract	We report a chromosomal-level genome assembly of a male North American wolverine (Gulo gulo luscus) from the Kugluktuk region of Nunavut, Canada. The genome was assembled directly from long-reads, comprising: 758 contigs with a contig N50 of 36.6 Mb; contig L50 of 20; base count of 2.39 Gb; and a near complete representation (99.98%) of the BUSCO 5.2.2 set of 9,226 genes. A presumptive chromosomal-level assembly was generated by scaffolding against two chromosomal-level Mustelidae reference genomes, the ermine and the Eurasian river otter, to derive a final scaffold N50 of 144.0 Mb and a scaffold L50 of 7. We annotated a comprehensive set of genes that have been associated with models of aggressive behavior, a trait which the wolverine is purported to have in the popular literature. To support an integrated, genomics-based wildlife management strategy at a time of environmental disruption from climate change, we annotated the principal genes of the innate immune system to provide a resource to study the wolverine's susceptibility to new infectious and parasitic diseases. As a resource, we annotated genes involved in the modality of infection by the coronaviruses, an important class of viral pathogens of growing concern as shown by the recent spillover infections by severe acute respiratory syndrome coronavirus-2 to naïve wildlife. Tabulation of heterozygous single nucleotide variants in our specimen revealed a heterozygosity level of 0.065%, indicating a relatively diverse genetic pool that would serve as a baseline for the genomics-based conservation of the wolverine, a rare cold-adapted carnivore now under threat.
MeSH term(s)	Animals ; COVID-19 ; Chromosomes ; Genomics ; Humans ; Male ; Mustelidae/genetics ; North America
Language	English
Publishing date	2022-06-08
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2629978-1
ISSN	2160-1836 ; 2160-1836
ISSN (online)	2160-1836
ISSN	2160-1836
DOI	10.1093/g3journal/jkac138
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Article: Mutational Landscape of Autism Spectrum Disorder Brain Tissue

Woodbury-Smith, Marc / Lamoureux, Sylvia / Begum, Ghausia / Nassir, Nasna / Akter, Hosneara / O’Rielly, Darren D. / Rahman, Proton / Wintle, Richard F. / Scherer, Stephen W. / Uddin, Mohammed

Genes. 2022 Jan. 24, v. 13, no. 2

2022

Abstract	Rare post-zygotic mutations in the brain are now known to contribute to several neurodevelopmental disorders, including autism spectrum disorder (ASD). However, due to the limited availability of brain tissue, most studies rely on estimates of mosaicism from peripheral samples. In this study, we undertook whole exome sequencing on brain tissue from 26 ASD brain donors from the Harvard Brain Tissue Resource Center (HBTRC) and ascertained the presence of post-zygotic and germline mutations categorized as pathological, including those impacting known ASD-implicated genes. Although quantification did not reveal enrichment for post-zygotic mutations compared with the controls (n = 15), a small number of pathogenic, potentially ASD-implicated mutations were identified, notably in TRAK1 and CLSTN3. Furthermore, germline mutations were identified in the same tissue samples in several key ASD genes, including PTEN, SC1A, CDH13, and CACNA1C. The establishment of tissue resources that are available to the scientific community will facilitate the discovery of new mutations for ASD and other neurodevelopmental disorders.
Keywords	autism ; brain ; germ cells ; mutation
Language	English
Dates of publication	2022-0124
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2527218-4
ISSN	2073-4425
ISSN	2073-4425
DOI	10.3390/genes13020207
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Article ; Online: The development of the pediatric stroke neuroimaging platform (PEDSNIP).

Domi, Trish / Robertson, Amanda / Lee, Wayne / Wintle, Richard F / Stence, Nicholas / Bernard, Timothy / Kirton, Adam / Carlson, Helen / Andrade, Andrea / Rafay, Mubeen F / Bjornson, Bruce / Kim, Danny / Dowling, Michael / Bonnett, Wilmot / Rivkin, Michael / Krishnan, Pradeep / Shroff, Manohar / Ertl-Wagner, Birgit / Strother, Stephen /

Arnott, Steven / Wintermark, Max / Kassner, Andrea / deVeber, Gabrielle / Dlamini, Nomazulu

NeuroImage. Clinical

2023 Volume 39, Page(s) 103438

Abstract: Childhood stroke occurs from birth to 18 years of age, ranks among the top ten childhood causes of death, and leaves lifelong neurological impairments. Arterial ischemic stroke in infancy and childhood occurs due to arterial occlusion in the brain, ... ...

Abstract	Childhood stroke occurs from birth to 18 years of age, ranks among the top ten childhood causes of death, and leaves lifelong neurological impairments. Arterial ischemic stroke in infancy and childhood occurs due to arterial occlusion in the brain, resulting in a focal lesion. Our understanding of mechanisms of injury and repair associated with focal injury in the developing brain remains rudimentary. Neuroimaging can reveal important insights into these mechanisms. In adult stroke population, multi-center neuroimaging studies are common and have accelerated the translation process leading to improvements in treatment and outcome. These studies are centered on the growing evidence that neuroimaging measures and other biomarkers (e.g., from blood and cerebrospinal fluid) can enhance our understanding of mechanisms of risk and injury and be used as complementary outcome markers. These factors have yet to be studied in pediatric stroke because most neuroimaging studies in this population have been conducted in single-centred, small cohorts. By pooling neuroimaging data across multiple sites, larger cohorts of patients can significantly boost study feasibility and power in elucidating mechanisms of brain injury, repair and outcomes. These aims are particularly relevant in pediatric stroke because of the decreased incidence rates and the lack of mechanism-targeted trials. Toward these aims, we developed the Pediatric Stroke Neuroimaging Platform (PEDSNIP) in 2015, funded by The Brain Canada Platform Support Grant, to focus on three identified neuroimaging priorities. These were: developing and harmonizing multisite clinical protocols, creating the infrastructure and methods to import, store and organize the large clinical neuroimaging dataset from multiple sites through the International Pediatric Stroke Study (IPSS), and enabling central searchability. To do this, developed a two-pronged approach that included building 1) A Clinical-MRI Data Repository (standard of care imaging) linked to clinical data and longitudinal outcomes and 2) A Research-MRI neuroimaging data set acquired through our extensive collaborative, multi-center, multidisciplinary network. This dataset was collected prospectively in eight North American centers to test the feasibility and implementation of harmonized advanced Research-MRI, with the addition of clinical information, genetic and proteomic studies, in a cohort of children presenting with acute ischemic stroke. Here we describe the process that enabled the development of PEDSNIP built to provide the infrastructure to support neuroimaging research priorities in pediatric stroke. Having built this Platform, we are now able to utilize the largest neuroimaging and clinical data pool on pediatric stroke data worldwide to conduct hypothesis-driven research. We are actively working on a bioinformatics approach to develop predictive models of risk, injury and repair and accelerate breakthrough discoveries leading to mechanism-targeted treatments that improve outcomes and minimize the burden following childhood stroke. This unique transformational resource for scientists and researchers has the potential to result in a paradigm shift in the management, outcomes and quality of life in children with stroke and their families, with far-reaching benefits for other brain conditions of people across the lifespan.
MeSH term(s)	Adult ; Child ; Humans ; Ischemic Stroke ; Proteomics ; Quality of Life ; Stroke/diagnostic imaging ; Stroke/therapy ; Neuroimaging
Language	English
Publishing date	2023-05-19
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2701571-3
ISSN	2213-1582 ; 2213-1582
ISSN (online)	2213-1582
ISSN	2213-1582
DOI	10.1016/j.nicl.2023.103438
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Article ; Online: Gene copy number variation and pediatric mental health/neurodevelopment in a general population.

Zarrei, Mehdi / Burton, Christie L / Engchuan, Worrawat / Higginbotham, Edward J / Wei, John / Shaikh, Sabah / Roslin, Nicole M / MacDonald, Jeffrey R / Pellecchia, Giovanna / Nalpathamkalam, Thomas / Lamoureux, Sylvia / Manshaei, Roozbeh / Howe, Jennifer / Trost, Brett / Thiruvahindrapuram, Bhooma / Marshall, Christian R / Yuen, Ryan K C / Wintle, Richard F / Strug, Lisa J /

Stavropoulos, Dimitri J / Vorstman, Jacob A S / Arnold, Paul / Merico, Daniele / Woodbury-Smith, Marc / Crosbie, Jennifer / Schachar, Russell J / Scherer, Stephen W

Human molecular genetics

2023 Volume 32, Issue 15, Page(s) 2411–2421

Abstract: We assessed the relationship of gene copy number variation (CNV) in mental health/neurodevelopmental traits and diagnoses, physical health and cognition in a community sample of 7100 unrelated children and youth of European or East Asian ancestry (Spit ... ...

Abstract	We assessed the relationship of gene copy number variation (CNV) in mental health/neurodevelopmental traits and diagnoses, physical health and cognition in a community sample of 7100 unrelated children and youth of European or East Asian ancestry (Spit for Science). Clinically significant or susceptibility CNVs were present in 3.9% of participants and were associated with elevated scores on a continuous measure of attention-deficit/hyperactivity disorder (ADHD) traits (P = 5.0 × 10-3), longer response inhibition (a cognitive deficit found in several mental health and neurodevelopmental disorders; P = 1.0 × 10-2) and increased prevalence of mental health diagnoses (P = 1.9 × 10-6, odds ratio: 3.09), specifically ADHD, autism spectrum disorder anxiety and learning problems/learning disorder (P's < 0.01). There was an increased burden of rare deletions in gene-sets related to brain function or expression in brain associated with more ADHD traits. With the current mental health crisis, our data established a baseline for delineating genetic contributors in pediatric-onset conditions.
MeSH term(s)	Adolescent ; Humans ; Child ; Mental Health ; DNA Copy Number Variations/genetics ; Autism Spectrum Disorder/genetics ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Attention Deficit Disorder with Hyperactivity/epidemiology ; Attention Deficit Disorder with Hyperactivity/genetics ; Gene Dosage
Language	English
Publishing date	2023-10-05
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1108742-0
ISSN	1460-2083 ; 0964-6906
ISSN (online)	1460-2083
ISSN	0964-6906
DOI	10.1093/hmg/ddad074
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Article: A Distributed Whole Genome Sequencing Benchmark Study.

Frontiers in genetics

2020 Volume 11, Page(s) 612515

Abstract: Population sequencing often requires collaboration across a distributed network of sequencing centers for the timely processing of thousands of samples. In such massive efforts, it is important that participating scientists can be confident that the ... ...

Abstract	Population sequencing often requires collaboration across a distributed network of sequencing centers for the timely processing of thousands of samples. In such massive efforts, it is important that participating scientists can be confident that the accuracy of the sequence data produced is not affected by which center generates the data. A study was conducted across three established sequencing centers, located in Montreal, Toronto, and Vancouver, constituting Canada's Genomics Enterprise (www.cgen.ca). Whole genome sequencing was performed at each center, on three genomic DNA replicates from three well-characterized cell lines. Secondary analysis pipelines employed by each site were applied to sequence data from each of the sites, resulting in three datasets for each of four variables (cell line, replicate, sequencing center, and analysis pipeline), for a total of 81 datasets. These datasets were each assessed according to multiple quality metrics including concordance with benchmark variant truth sets to assess consistent quality across all three conditions for each variable. Three-way concordance analysis of variants across conditions for each variable was performed. Our results showed that the variant concordance between datasets differing only by sequencing center was similar to the concordance for datasets differing only by replicate, using the same analysis pipeline. We also showed that the statistically significant differences between datasets result from the analysis pipeline used, which can be unified and updated as new approaches become available. We conclude that genome sequencing projects can rely on the quality and reproducibility of aggregate data generated across a network of distributed sites.
Language	English
Publishing date	2020-12-01
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606823-0
ISSN	1664-8021
ISSN	1664-8021
DOI	10.3389/fgene.2020.612515
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Article ; Online: Comprehensive whole-genome sequence analyses provide insights into the genomic architecture of cerebral palsy.

Fehlings, Darcy L / Zarrei, Mehdi / Engchuan, Worrawat / Sondheimer, Neal / Thiruvahindrapuram, Bhooma / MacDonald, Jeffrey R / Higginbotham, Edward J / Thapa, Ritesh / Behlim, Tarannum / Aimola, Sabrina / Switzer, Lauren / Ng, Pamela / Wei, John / Danthi, Prakroothi S / Pellecchia, Giovanna / Lamoureux, Sylvia / Ho, Karen / Pereira, Sergio L / de Rijke, Jill /

Sung, Wilson W L / Mowjoodi, Alireza / Howe, Jennifer L / Nalpathamkalam, Thomas / Manshaei, Roozbeh / Ghaffari, Siavash / Whitney, Joseph / Patel, Rohan V / Hamdan, Omar / Shaath, Rulan / Trost, Brett / Knights, Shannon / Samdup, Dawa / McCormick, Anna / Hunt, Carolyn / Kirton, Adam / Kawamura, Anne / Mesterman, Ronit / Gorter, Jan Willem / Dlamini, Nomazulu / Merico, Daniele / Hilali, Murto / Hirschfeld, Kyle / Grover, Kritika / Bautista, Nelson X / Han, Kara / Marshall, Christian R / Yuen, Ryan K C / Subbarao, Padmaja / Azad, Meghan B / Turvey, Stuart E / Mandhane, Piush / Moraes, Theo J / Simons, Elinor / Maxwell, George / Shevell, Michael / Costain, Gregory / Michaud, Jacques L / Hamdan, Fadi F / Gauthier, Julie / Uguen, Kevin / Stavropoulos, Dimitri J / Wintle, Richard F / Oskoui, Maryam / Scherer, Stephen W

Nature genetics

2024 Volume 56, Issue 4, Page(s) 585–594

Abstract: We performed whole-genome sequencing (WGS) in 327 children with cerebral palsy (CP) and their biological parents. We classified 37 of 327 (11.3%) children as having pathogenic/likely pathogenic (P/LP) variants and 58 of 327 (17.7%) as having variants of ... ...

Abstract	We performed whole-genome sequencing (WGS) in 327 children with cerebral palsy (CP) and their biological parents. We classified 37 of 327 (11.3%) children as having pathogenic/likely pathogenic (P/LP) variants and 58 of 327 (17.7%) as having variants of uncertain significance. Multiple classes of P/LP variants included single-nucleotide variants (SNVs)/indels (6.7%), copy number variations (3.4%) and mitochondrial mutations (1.5%). The COL4A1 gene had the most P/LP SNVs. We also analyzed two pediatric control cohorts (n = 203 trios and n = 89 sib-pair families) to provide a baseline for de novo mutation rates and genetic burden analyses, the latter of which demonstrated associations between de novo deleterious variants and genes related to the nervous system. An enrichment analysis revealed previously undescribed plausible candidate CP genes (SMOC1, KDM5B, BCL11A and CYP51A1). A multifactorial CP risk profile and substantial presence of P/LP variants combine to support WGS in the diagnostic work-up across all CP and related phenotypes.
MeSH term(s)	Humans ; Child ; DNA Copy Number Variations/genetics ; Cerebral Palsy/genetics ; Mutation ; Whole Genome Sequencing ; Genomics
Language	English
Publishing date	2024-03-29
Publishing country	United States
Document type	Journal Article
ZDB-ID	1108734-1
ISSN	1546-1718 ; 1061-4036
ISSN (online)	1546-1718
ISSN	1061-4036
DOI	10.1038/s41588-024-01686-x
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Article ; Online: Cerebral palsy and genomics: an international consortium.

MacLennan, Alastair H / Kruer, Michael C / Baynam, Gareth / Moreno-De-Luca, Andres / Wilson, Yana A / Zhu, Changlian / Wintle, Richard F / Gecz, Jozef

Developmental medicine and child neurology

2018 Volume 60, Issue 2, Page(s) 209–210

MeSH term(s)	Cerebral Palsy/genetics ; Genomics/methods ; Humans ; International Cooperation
Language	English
Publishing date	2018
Publishing country	England
Document type	Letter
ZDB-ID	80369-8
ISSN	1469-8749 ; 0012-1622
ISSN (online)	1469-8749
ISSN	0012-1622
DOI	10.1111/dmcn.13643
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