Publications by authors named "Hilary Coon"

113 Publications

Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction.

Am J Hum Genet 2021 02 28;108(2):346-356. Epub 2021 Jan 28.

Department of Rehabilitation and Development, Randall Children's Hospital at Legacy Emanuel Medical Center, Portland, OR 97227, USA.

Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression, and a severe phenotype. In contrast, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.
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http://dx.doi.org/10.1016/j.ajhg.2021.01.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895900PMC
February 2021

Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction.

Am J Hum Genet 2021 02 28;108(2):346-356. Epub 2021 Jan 28.

Department of Rehabilitation and Development, Randall Children's Hospital at Legacy Emanuel Medical Center, Portland, OR 97227, USA.

Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression, and a severe phenotype. In contrast, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.
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http://dx.doi.org/10.1016/j.ajhg.2021.01.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895900PMC
February 2021

Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction.

Am J Hum Genet 2021 02 28;108(2):346-356. Epub 2021 Jan 28.

Department of Rehabilitation and Development, Randall Children's Hospital at Legacy Emanuel Medical Center, Portland, OR 97227, USA.

Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression, and a severe phenotype. In contrast, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.
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http://dx.doi.org/10.1016/j.ajhg.2021.01.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895900PMC
February 2021

Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction.

Am J Hum Genet 2021 02 28;108(2):346-356. Epub 2021 Jan 28.

Department of Rehabilitation and Development, Randall Children's Hospital at Legacy Emanuel Medical Center, Portland, OR 97227, USA.

Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression, and a severe phenotype. In contrast, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.
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http://dx.doi.org/10.1016/j.ajhg.2021.01.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895900PMC
February 2021

The role of rare compound heterozygous events in autism spectrum disorder.

Transl Psychiatry 2020 06 22;10(1):204. Epub 2020 Jun 22.

Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

The identification of genetic variants underlying autism spectrum disorders (ASDs) may contribute to a better understanding of their underlying biology. To examine the possible role of a specific type of compound heterozygosity in ASD, namely, the occurrence of a deletion together with a functional nucleotide variant on the remaining allele, we sequenced 550 genes in 149 individuals with ASD and their deletion-transmitting parents. This approach allowed us to identify additional sequence variants occurring in the remaining allele of the deletion. Our main goal was to compare the rate of sequence variants in remaining alleles of deleted regions between probands and the deletion-transmitting parents. We also examined the predicted functional effect of the identified variants using Combined Annotation-Dependent Depletion (CADD) scores. The single nucleotide variant-deletion co-occurrence was observed in 13.4% of probands, compared with 8.1% of parents. The cumulative burden of sequence variants (n = 68) in pooled proband sequences was higher than the burden in pooled sequences from the deletion-transmitting parents (n = 41, X = 6.69, p = 0.0097). After filtering for those variants predicted to be most deleterious, we observed 21 of such variants in probands versus 8 in their deletion-transmitting parents (X = 5.82, p = 0.016). Finally, cumulative CADD scores conferred by these variants were significantly higher in probands than in deletion-transmitting parents (burden test, β = 0.13; p = 1.0 × 10). Our findings suggest that the compound heterozygosity described in the current study may be one of several mechanisms explaining variable penetrance of CNVs with known pathogenicity for ASD.
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http://dx.doi.org/10.1038/s41398-020-00866-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308334PMC
June 2020

The role of rare compound heterozygous events in autism spectrum disorder.

Transl Psychiatry 2020 06 22;10(1):204. Epub 2020 Jun 22.

Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

The identification of genetic variants underlying autism spectrum disorders (ASDs) may contribute to a better understanding of their underlying biology. To examine the possible role of a specific type of compound heterozygosity in ASD, namely, the occurrence of a deletion together with a functional nucleotide variant on the remaining allele, we sequenced 550 genes in 149 individuals with ASD and their deletion-transmitting parents. This approach allowed us to identify additional sequence variants occurring in the remaining allele of the deletion. Our main goal was to compare the rate of sequence variants in remaining alleles of deleted regions between probands and the deletion-transmitting parents. We also examined the predicted functional effect of the identified variants using Combined Annotation-Dependent Depletion (CADD) scores. The single nucleotide variant-deletion co-occurrence was observed in 13.4% of probands, compared with 8.1% of parents. The cumulative burden of sequence variants (n = 68) in pooled proband sequences was higher than the burden in pooled sequences from the deletion-transmitting parents (n = 41, X = 6.69, p = 0.0097). After filtering for those variants predicted to be most deleterious, we observed 21 of such variants in probands versus 8 in their deletion-transmitting parents (X = 5.82, p = 0.016). Finally, cumulative CADD scores conferred by these variants were significantly higher in probands than in deletion-transmitting parents (burden test, β = 0.13; p = 1.0 × 10). Our findings suggest that the compound heterozygosity described in the current study may be one of several mechanisms explaining variable penetrance of CNVs with known pathogenicity for ASD.
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http://dx.doi.org/10.1038/s41398-020-00866-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308334PMC
June 2020

Correction to: Early Second Trimester Maternal Serum Steroid‑Related Biomarkers Associated with Autism Spectrum Disorder.

J Autism Dev Disord 2019 Nov;49(11):4584

University of Utah, Salt Lake City, UT, 84108, USA.

The original version of the article has been published without funding source information.
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http://dx.doi.org/10.1007/s10803-019-04206-7DOI Listing
November 2019

Early Second Trimester Maternal Serum Steroid-Related Biomarkers Associated with Autism Spectrum Disorder.

J Autism Dev Disord 2019 Nov;49(11):4572-4583

University of Utah, Salt Lake City, UT, 84108, USA.

Epidemiologic studies link increased autism spectrum disorder (ASD) risk to obstetrical conditions associated with inflammation and steroid dysregulation, referred to as prenatal metabolic syndrome (PNMS). This pilot study measured steroid-related biomarkers in early second trimester maternal serum collected during the first and second trimester evaluation of risk study. ASD case and PNMS exposure status of index offspring were determined through linkage with autism registries and birth certificate records. ASD case (N = 53) and control (N = 19) groups were enriched for PNMS exposure. Higher estradiol and lower sex hormone binding globulin (SHBG) were significantly associated with increased ASD risk. Study findings provide preliminary evidence to link greater placental estradiol activity with ASD and support future investigations of the prenatal steroid environment in ASD.
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http://dx.doi.org/10.1007/s10803-019-04162-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814559PMC
November 2019

DiI-mediated analysis of presynaptic and postsynaptic structures in human postmortem brain tissue.

J Comp Neurol 2019 12 12;527(18):3087-3098. Epub 2019 Jun 12.

Department of Neurobiology and Anatomy, University of Utah School of Medicine, Salt Lake City, Utah.

Most cognitive and psychiatric disorders are thought to be disorders of the synapse, yet the precise synapse defects remain unknown. Because synapses are highly specialized anatomical structures, defects in synapse formation and function can often be observed as changes in microscale neuroanatomy. Unfortunately, few methods are available for accurate analysis of synaptic structures in human postmortem tissues. Here, we present a methodological pipeline for assessing presynaptic and postsynaptic structures in human postmortem tissue that is accurate, rapid, and relatively inexpensive. Our method uses small tissue blocks from postmortem human brains, immersion fixation, lipophilic dye (DiI) labeling, and confocal microscopy. As proof of principle, we analyzed presynaptic and postsynaptic structures from hippocampi of 13 individuals aged 4 months to 71 years. Our results indicate that postsynaptic CA1 dendritic spine shape and density do not change in adults, while presynaptic DG mossy fiber boutons undergo significant structural rearrangements with normal aging. This suggests that mossy fiber synapses, which play a major role in learning and memory, may remain dynamic throughout life. Importantly, we find that human CA1 spine densities observed using this method on tissue that is up to 28 h postmortem is comparable to prior studies using tissue with much shorter postmortem intervals. Thus, the ease of our protocol and suitability on tissue with longer postmortem intervals should facilitate higher-powered studies of human presynaptic and postsynaptic structures in healthy and diseased states.
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http://dx.doi.org/10.1002/cne.24722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6790174PMC
December 2019

DiI-mediated analysis of presynaptic and postsynaptic structures in human postmortem brain tissue.

J Comp Neurol 2019 12 12;527(18):3087-3098. Epub 2019 Jun 12.

Department of Neurobiology and Anatomy, University of Utah School of Medicine, Salt Lake City, Utah.

Most cognitive and psychiatric disorders are thought to be disorders of the synapse, yet the precise synapse defects remain unknown. Because synapses are highly specialized anatomical structures, defects in synapse formation and function can often be observed as changes in microscale neuroanatomy. Unfortunately, few methods are available for accurate analysis of synaptic structures in human postmortem tissues. Here, we present a methodological pipeline for assessing presynaptic and postsynaptic structures in human postmortem tissue that is accurate, rapid, and relatively inexpensive. Our method uses small tissue blocks from postmortem human brains, immersion fixation, lipophilic dye (DiI) labeling, and confocal microscopy. As proof of principle, we analyzed presynaptic and postsynaptic structures from hippocampi of 13 individuals aged 4 months to 71 years. Our results indicate that postsynaptic CA1 dendritic spine shape and density do not change in adults, while presynaptic DG mossy fiber boutons undergo significant structural rearrangements with normal aging. This suggests that mossy fiber synapses, which play a major role in learning and memory, may remain dynamic throughout life. Importantly, we find that human CA1 spine densities observed using this method on tissue that is up to 28 h postmortem is comparable to prior studies using tissue with much shorter postmortem intervals. Thus, the ease of our protocol and suitability on tissue with longer postmortem intervals should facilitate higher-powered studies of human presynaptic and postsynaptic structures in healthy and diseased states.
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http://dx.doi.org/10.1002/cne.24722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6790174PMC
December 2019

DiI-mediated analysis of presynaptic and postsynaptic structures in human postmortem brain tissue.

J Comp Neurol 2019 12 12;527(18):3087-3098. Epub 2019 Jun 12.

Department of Neurobiology and Anatomy, University of Utah School of Medicine, Salt Lake City, Utah.

Most cognitive and psychiatric disorders are thought to be disorders of the synapse, yet the precise synapse defects remain unknown. Because synapses are highly specialized anatomical structures, defects in synapse formation and function can often be observed as changes in microscale neuroanatomy. Unfortunately, few methods are available for accurate analysis of synaptic structures in human postmortem tissues. Here, we present a methodological pipeline for assessing presynaptic and postsynaptic structures in human postmortem tissue that is accurate, rapid, and relatively inexpensive. Our method uses small tissue blocks from postmortem human brains, immersion fixation, lipophilic dye (DiI) labeling, and confocal microscopy. As proof of principle, we analyzed presynaptic and postsynaptic structures from hippocampi of 13 individuals aged 4 months to 71 years. Our results indicate that postsynaptic CA1 dendritic spine shape and density do not change in adults, while presynaptic DG mossy fiber boutons undergo significant structural rearrangements with normal aging. This suggests that mossy fiber synapses, which play a major role in learning and memory, may remain dynamic throughout life. Importantly, we find that human CA1 spine densities observed using this method on tissue that is up to 28 h postmortem is comparable to prior studies using tissue with much shorter postmortem intervals. Thus, the ease of our protocol and suitability on tissue with longer postmortem intervals should facilitate higher-powered studies of human presynaptic and postsynaptic structures in healthy and diseased states.
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http://dx.doi.org/10.1002/cne.24722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6790174PMC
December 2019

Genome-wide de novo risk score implicates promoter variation in autism spectrum disorder.

Science 2018 12;362(6420)

Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, CA, USA.

Whole-genome sequencing (WGS) has facilitated the first genome-wide evaluations of the contribution of de novo noncoding mutations to complex disorders. Using WGS, we identified 255,106 de novo mutations among sample genomes from members of 1902 quartet families in which one child, but not a sibling or their parents, was affected by autism spectrum disorder (ASD). In contrast to coding mutations, no noncoding functional annotation category, analyzed in isolation, was significantly associated with ASD. Casting noncoding variation in the context of a de novo risk score across multiple annotation categories, however, did demonstrate association with mutations localized to promoter regions. We found that the strongest driver of this promoter signal emanates from evolutionarily conserved transcription factor binding sites distal to the transcription start site. These data suggest that de novo mutations in promoter regions, characterized by evolutionary and functional signatures, contribute to ASD.
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http://dx.doi.org/10.1126/science.aat6576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6432922PMC
December 2018

Genome-wide de novo risk score implicates promoter variation in autism spectrum disorder.

Science 2018 12;362(6420)

Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, CA, USA.

Whole-genome sequencing (WGS) has facilitated the first genome-wide evaluations of the contribution of de novo noncoding mutations to complex disorders. Using WGS, we identified 255,106 de novo mutations among sample genomes from members of 1902 quartet families in which one child, but not a sibling or their parents, was affected by autism spectrum disorder (ASD). In contrast to coding mutations, no noncoding functional annotation category, analyzed in isolation, was significantly associated with ASD. Casting noncoding variation in the context of a de novo risk score across multiple annotation categories, however, did demonstrate association with mutations localized to promoter regions. We found that the strongest driver of this promoter signal emanates from evolutionarily conserved transcription factor binding sites distal to the transcription start site. These data suggest that de novo mutations in promoter regions, characterized by evolutionary and functional signatures, contribute to ASD.
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http://dx.doi.org/10.1126/science.aat6576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6432922PMC
December 2018

Lineage: Visualizing Multivariate Clinical Data in Genealogy Graphs.

IEEE Trans Vis Comput Graph 2019 03 6;25(3):1543-1558. Epub 2018 Mar 6.

The majority of diseases that are a significant challenge for public and individual heath are caused by a combination of hereditary and environmental factors. In this paper we introduce Lineage, a novel visual analysis tool designed to support domain experts who study such multifactorial diseases in the context of genealogies. Incorporating familial relationships between cases with other data can provide insights into shared genomic variants and shared environmental exposures that may be implicated in such diseases. We introduce a data and task abstraction, and argue that the problem of analyzing such diseases based on genealogical, clinical, and genetic data can be mapped to a multivariate graph visualization problem. The main contribution of our design study is a novel visual representation for tree-like, multivariate graphs, which we apply to genealogies and clinical data about the individuals in these families. We introduce data-driven aggregation methods to scale to multiple families. By designing the genealogy graph layout to align with a tabular view, we are able to incorporate extensive, multivariate attributes in the analysis of the genealogy without cluttering the graph. We validate our designs by conducting case studies with our domain collaborators.
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http://dx.doi.org/10.1109/TVCG.2018.2811488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6170727PMC
March 2019

An analytical framework for whole-genome sequence association studies and its implications for autism spectrum disorder.

Nat Genet 2018 04 26;50(5):727-736. Epub 2018 Apr 26.

Department of Biology, Eastern Nazarene College, Quincy, MA, USA.

Genomic association studies of common or rare protein-coding variation have established robust statistical approaches to account for multiple testing. Here we present a comparable framework to evaluate rare and de novo noncoding single-nucleotide variants, insertion/deletions, and all classes of structural variation from whole-genome sequencing (WGS). Integrating genomic annotations at the level of nucleotides, genes, and regulatory regions, we define 51,801 annotation categories. Analyses of 519 autism spectrum disorder families did not identify association with any categories after correction for 4,123 effective tests. Without appropriate correction, biologically plausible associations are observed in both cases and controls. Despite excluding previously identified gene-disrupting mutations, coding regions still exhibited the strongest associations. Thus, in autism, the contribution of de novo noncoding variation is probably modest in comparison to that of de novo coding variants. Robust results from future WGS studies will require large cohorts and comprehensive analytical strategies that consider the substantial multiple-testing burden.
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http://dx.doi.org/10.1038/s41588-018-0107-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5961723PMC
April 2018

Allele-specific expression in a family quartet with autism reveals mono-to-biallelic switch and novel transcriptional processes of autism susceptibility genes.

Sci Rep 2018 03 9;8(1):4277. Epub 2018 Mar 9.

Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei, 10051, Taiwan.

Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder, and the exact causal mechanism is unknown. Dysregulated allele-specific expression (ASE) has been identified in persons with ASD; however, a comprehensive analysis of ASE has not been conducted in a family quartet with ASD. To fill this gap, we analyzed ASE using genomic DNA from parent and offspring and RNA from offspring's postmortem prefrontal cortex (PFC); one of the two offspring had been diagnosed with ASD. DNA- and RNA-sequencing revealed distinct ASE patterns from the PFC of both offspring. However, only the PFC of the offspring with ASD exhibited a mono-to-biallelic switch for LRP2BP and ZNF407. We also identified a novel site of RNA-editing in KMT2C in addition to new monoallelically-expressed genes and miRNAs. Our results demonstrate the prevalence of ASE in human PFC and ASE abnormalities in the PFC of a person with ASD. Taken together, these findings may provide mechanistic insights into the pathogenesis of ASD.
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http://dx.doi.org/10.1038/s41598-018-22753-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5844893PMC
March 2018

Novel pedigree analysis implicates DNA repair and chromatin remodeling in multiple myeloma risk.

PLoS Genet 2018 02 1;14(2):e1007111. Epub 2018 Feb 1.

University of Utah School of Medicine, Salt Lake City, Utah, United States of America.

The high-risk pedigree (HRP) design is an established strategy to discover rare, highly-penetrant, Mendelian-like causal variants. Its success, however, in complex traits has been modest, largely due to challenges of genetic heterogeneity and complex inheritance models. We describe a HRP strategy that addresses intra-familial heterogeneity, and identifies inherited segments important for mapping regulatory risk. We apply this new Shared Genomic Segment (SGS) method in 11 extended, Utah, multiple myeloma (MM) HRPs, and subsequent exome sequencing in SGS regions of interest in 1063 MM / MGUS (monoclonal gammopathy of undetermined significance-a precursor to MM) cases and 964 controls from a jointly-called collaborative resource, including cases from the initial 11 HRPs. One genome-wide significant 1.8 Mb shared segment was found at 6q16. Exome sequencing in this region revealed predicted deleterious variants in USP45 (p.Gln691* and p.Gln621Glu), a gene known to influence DNA repair through endonuclease regulation. Additionally, a 1.2 Mb segment at 1p36.11 is inherited in two Utah HRPs, with coding variants identified in ARID1A (p.Ser90Gly and p.Met890Val), a key gene in the SWI/SNF chromatin remodeling complex. Our results provide compelling statistical and genetic evidence for segregating risk variants for MM. In addition, we demonstrate a novel strategy to use large HRPs for risk-variant discovery more generally in complex traits.
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http://dx.doi.org/10.1371/journal.pgen.1007111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5794067PMC
February 2018

Mid-life social outcomes for a population-based sample of adults with ASD.

Autism Res 2018 01 20;11(1):142-152. Epub 2017 Dec 20.

University of Utah Department of Psychiatry, 501 Chipeta Way, Salt Lake City, Utah, 84108.

Adults with autism spectrum disorders (ASD) fall short of social outcomes of non-ASD peers in mid-life, as documented by currently published research. The aim of the current study was to extend what is known about social functioning, employment, independent living, and use of social services by examining details of the current life status for a population-based sample of adults with ASD (mean age = 35.5 years, range = 22.2-51.4). We collected outcome data via direct assessment and informant report for 169 individuals. Three-fourths of the sample had cognitive abilities in the intellectually disabled range. Social functioning outcomes, as a single measure, mirror those reported previously for other samples, including samples with a high proportion of individuals with normal range intellectual abilities, with 20% achieving the most independent outcomes and 46% requiring high levels of support across most life areas. Participant subgroups who achieved maximal outcomes represented a range of social and intellectual abilities for several outcome metrics. Participants used high levels of public and private supports, yet specific areas of clear, unmet need were also identified. Autism Res 2018, 11: 142-152. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.

Lay Summary: This paper describes the social functioning outcomes for 169 adults with autism spectrum disorders in mid-life. Adult participants spanned the full range of functional and cognitive ability levels, with over 75% functioning in the cognitively impaired range. While summary descriptions of outcomes for this sample were similar to those reported for other groups of adults, this report provides detailed information regarding employment outcomes, social relationships, leisure activities, participation in the community, residential situations, public service use, and involvement with law enforcement.
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http://dx.doi.org/10.1002/aur.1897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5924705PMC
January 2018

Mid-life social outcomes for a population-based sample of adults with ASD.

Autism Res 2018 01 20;11(1):142-152. Epub 2017 Dec 20.

University of Utah Department of Psychiatry, 501 Chipeta Way, Salt Lake City, Utah, 84108.

Adults with autism spectrum disorders (ASD) fall short of social outcomes of non-ASD peers in mid-life, as documented by currently published research. The aim of the current study was to extend what is known about social functioning, employment, independent living, and use of social services by examining details of the current life status for a population-based sample of adults with ASD (mean age = 35.5 years, range = 22.2-51.4). We collected outcome data via direct assessment and informant report for 169 individuals. Three-fourths of the sample had cognitive abilities in the intellectually disabled range. Social functioning outcomes, as a single measure, mirror those reported previously for other samples, including samples with a high proportion of individuals with normal range intellectual abilities, with 20% achieving the most independent outcomes and 46% requiring high levels of support across most life areas. Participant subgroups who achieved maximal outcomes represented a range of social and intellectual abilities for several outcome metrics. Participants used high levels of public and private supports, yet specific areas of clear, unmet need were also identified. Autism Res 2018, 11: 142-152. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.

Lay Summary: This paper describes the social functioning outcomes for 169 adults with autism spectrum disorders in mid-life. Adult participants spanned the full range of functional and cognitive ability levels, with over 75% functioning in the cognitively impaired range. While summary descriptions of outcomes for this sample were similar to those reported for other groups of adults, this report provides detailed information regarding employment outcomes, social relationships, leisure activities, participation in the community, residential situations, public service use, and involvement with law enforcement.
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http://dx.doi.org/10.1002/aur.1897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5924705PMC
January 2018

Genetic analysis of age at onset variation in spinocerebellar ataxia type 2.

Neurol Genet 2017 Jun 15;3(3):e155. Epub 2017 May 15.

Department of Neurology (K.P.F., S.-M.P.), Department of Psychiatry (H.C.), University of Utah, Salt Lake City; Department of Surgery (N.S.), University of Miami, FL; and Center for the Research and Rehabilitation of Hereditary Ataxias (L.V., L.A.M.), Holguin, Cuba.

Objective: To examine heritability of the residual variability of spinocerebellar ataxia type 2 (SCA2) age at onset (AO) after controlling for CAG repeat length.

Methods: From 1955 to 2001, dates of birth, CAG repeat lengths, AO, sex, familial inheritances, and clinical manifestations were collected for a large Cuban SCA2 cohort of 382 affected individuals, including 129 parent-child pairs and 69 sibships. Analyses were performed with log-transformed AO in the GENMOD procedure to predict AO using repeat length, taking into account family structure. Because all relationships were first degree, the model was implemented with an exchangeable correlation matrix. Familial correlations were estimated using the Pedigree Analysis Package to control for similarity due to genetic relatedness.

Results: For the entire sample, the mutant CAG repeat allele explained 69% of AO variance. When adjusted for pedigree structure, this decreased to 50%. Evidence for imprinting or sex-specific effects of the CAG repeat on AO was not found. For the entire sample, we determined an upper bound for heritability of the residual variance of 33% ( = 0.008). Heritability was higher in sib-sib pairs, especially in female sib-sib pairs, than in parent-child pairs.

Conclusions: We established that a large proportion of AO variance in SCA2 was determined by genetic modifiers in addition to CAG repeat length. The genetic structure of heritability of the residual AO variance was surprisingly similar to Huntington disease, suggesting the presence of recessive modifying alleles and possibly X-chromosome-linked modifiers.
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http://dx.doi.org/10.1212/NXG.0000000000000155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5432368PMC
June 2017

Sudden infant death "syndrome"-Insights and future directions from a Utah population database analysis.

Am J Med Genet A 2017 Jan 28;173(1):177-182. Epub 2016 Oct 28.

Division of Pediatric Pathology, Department of Pathology, School of Medicine, University of Utah, Salt Lake City, Utah.

"Sudden Infant Death syndrome" (SIDS) represents the commonest category of infant death after the first month of life. As genome scale sequencing greatly facilitates the identification of new candidate disease variants, the challenges of ascribing causation to these variants persists. In order to determine the extent to which SIDS occurs in related individuals and their pedigree structure we undertook an analysis of SIDS using the Utah Population Database, recording, for example, evidence of enrichment for genetic causation following the back-to-sleep recommendations of 1992 and 1994. Our evaluation of the pre- and post back-to-sleep incidence of SIDS in Utah showed a decrease in SIDS incidence on the order of eightfold following back-to-sleep. An odds ratio of 4.2 for SIDS recurrence among sibs was identified from 1968 to 2013 which was similar to the odds ratio of 4.84 for death due to other or unknown cause among sibs of SIDS cases for the same time period. Combining first through thid degree relatives yielded an odds ratio of SIDS recurrence of 9.29 in the post-back-to-sleep (1995-2013) subset of SIDS cases where similar calculations of first-third degree relatives for the entire time period of 1968-2013 showed an odds ratio of 2.95. Expanded multigenertional pedigrees showing enrichment for SIDS were also identified. Based on these findings we hypothesize that post back-to-sleep SIDS, especially recurrences within a family, are potentially enriched for genetic causes due to the impact of safe sleeping guidelines in mitigating environmental risk factors. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.a.37994DOI Listing
January 2017

VARPRISM: incorporating variant prioritization in tests of de novo mutation association.

Genome Med 2016 08 25;8(1):91. Epub 2016 Aug 25.

Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.

Background: Patients with certain genetic diseases, such as autism spectrum disorder, have increased rates of de novo mutations within some protein-coding genes.

Results: We introduce the VARiant PRIoritization SuM (VARPRISM), a software package which incorporates functional variant prioritization information to improve the power to detect de novo mutations influencing disease risk. VARPRISM evaluates the consequence of any given exonic mutation on the protein sequence to estimate the likelihood that the mutation is benign or damaging and conducts a likelihood ratio test on the gene level. We analyzed the Simons Simplex Collection of 2508 parent-offspring autism trios using VARPRISM, replicating 44 genes previously implicated in autism susceptibility and identifying 20 additional candidate genes, including MYO1E, KCND3, PDCD1, DLX3, and TSPAN4 (false discovery rate < 0.3).

Conclusion: By incorporating functional predictions, VARPRISM improved the statistical power to identify de novo mutations increasing disease risks. VARPRISM is available at http://www.hufflab.org/software/VARPRISM .
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http://dx.doi.org/10.1186/s13073-016-0341-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4997702PMC
August 2016

VARPRISM: incorporating variant prioritization in tests of de novo mutation association.

Genome Med 2016 08 25;8(1):91. Epub 2016 Aug 25.

Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.

Background: Patients with certain genetic diseases, such as autism spectrum disorder, have increased rates of de novo mutations within some protein-coding genes.

Results: We introduce the VARiant PRIoritization SuM (VARPRISM), a software package which incorporates functional variant prioritization information to improve the power to detect de novo mutations influencing disease risk. VARPRISM evaluates the consequence of any given exonic mutation on the protein sequence to estimate the likelihood that the mutation is benign or damaging and conducts a likelihood ratio test on the gene level. We analyzed the Simons Simplex Collection of 2508 parent-offspring autism trios using VARPRISM, replicating 44 genes previously implicated in autism susceptibility and identifying 20 additional candidate genes, including MYO1E, KCND3, PDCD1, DLX3, and TSPAN4 (false discovery rate < 0.3).

Conclusion: By incorporating functional predictions, VARPRISM improved the statistical power to identify de novo mutations increasing disease risks. VARPRISM is available at http://www.hufflab.org/software/VARPRISM .
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http://dx.doi.org/10.1186/s13073-016-0341-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4997702PMC
August 2016

VARPRISM: incorporating variant prioritization in tests of de novo mutation association.

Genome Med 2016 08 25;8(1):91. Epub 2016 Aug 25.

Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.

Background: Patients with certain genetic diseases, such as autism spectrum disorder, have increased rates of de novo mutations within some protein-coding genes.

Results: We introduce the VARiant PRIoritization SuM (VARPRISM), a software package which incorporates functional variant prioritization information to improve the power to detect de novo mutations influencing disease risk. VARPRISM evaluates the consequence of any given exonic mutation on the protein sequence to estimate the likelihood that the mutation is benign or damaging and conducts a likelihood ratio test on the gene level. We analyzed the Simons Simplex Collection of 2508 parent-offspring autism trios using VARPRISM, replicating 44 genes previously implicated in autism susceptibility and identifying 20 additional candidate genes, including MYO1E, KCND3, PDCD1, DLX3, and TSPAN4 (false discovery rate < 0.3).

Conclusion: By incorporating functional predictions, VARPRISM improved the statistical power to identify de novo mutations increasing disease risks. VARPRISM is available at http://www.hufflab.org/software/VARPRISM .
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http://dx.doi.org/10.1186/s13073-016-0341-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4997702PMC
August 2016
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