Integrating healthcare and research genetic data empowers the discovery of 49 novel developmental disorders

Kaplanis, Joanna; Samocha, Kaitlin E.; Wiel, Laurens; Zhang, Zhancheng; Arvai, Kevin J.; Eberhardt, Ruth Y; Gallone, Giuseppe; Lelieveld, Stefan H.; Martin, Hilary C.; McRae, Jeremy F.; Short, Patrick; Torene, Rebecca; Boer, Elke de; Danecek, Petr; Gardner, Eugene J.; Huang, Ni; Lord, Jenny; Pfundt, Rolph; Reijnders, Margot R.F.; Yeung, Alison; Vissers, Lisenka E.L.M.; Juusola, Jane; Wright, Caroline F.; Brunner, Han G.; Firth, Helen V.; FitzPatrick, David R.; Barrett, Jeffrey C.; Hurles, Matthew E.; Gilissen, Christian; Retterer, Kyle

doi:10.1101/258723

Cited by 15 publications

(17 citation statements)

References 62 publications

(68 reference statements)

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“…Singletons in classes 3 and 4 show the same mutational spectrum as the genomic background, suggesting that these represent independent mutation events whose spacing is mainly driven by variation in local ancestry. Since multi-nucleotide mutations are uniquely implicated in the genetic architecture of complex diseases 46 and the evolutionary history of the genome 47 , our findings illustrate how the TOPMed sample will facilitate more refined and robust approaches to interpreting patterns of genetic diversity.…”

Section: Insights Into Mutation Processesmentioning

confidence: 82%

Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program

Taliun¹,

Harris²,

Kessler³

et al. 2019

Preprint

481

665

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Summary paragraphThe Trans-Omics for Precision Medicine (TOPMed) program seeks to elucidate the genetic architecture and disease biology of heart, lung, blood, and sleep disorders, with the ultimate goal of improving diagnosis, treatment, and prevention. The initial phases of the program focus on whole genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here, we describe TOPMed goals and design as well as resources and early insights from the sequence data. The resources include a variant browser, a genotype imputation panel, and sharing of genomic and phenotypic data via dbGaP. In 53,581 TOPMed samples, >400 million single-nucleotide and insertion/deletion variants were detected by alignment with the reference genome. Additional novel variants are detectable through assembly of unmapped reads and customized analysis in highly variable loci. Among the >400 million variants detected, 97% have frequency <1% and 46% are singletons. These rare variants provide insights into mutational processes and recent human evolutionary history. The nearly complete catalog of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and non-coding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and extends the reach of nearly all genome-wide association studies to include variants down to ~0.01% in frequency.

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Section: Insights Into Mutation Processesmentioning

confidence: 82%

Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program

Taliun¹,

Harris²,

Kessler³

et al. 2019

Preprint

481

665

View full text Add to dashboard Cite

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“…Another recent study found a significant enrichment of de novo missense variants in PRKAR1B in a large sample of 31,058 trio-exomes of children with developmental disorders and their unaffected parents 16 .…”

Section: Introductionmentioning

confidence: 96%

“…perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted September 11, 2020. ; https://doi.org/10.1101/2020.09.10.20190314 doi: medRxiv preprint parents 16 .…”

Section: Introductionmentioning

confidence: 99%

Variants in PRKAR1B cause a neurodevelopmental disorder with autism spectrum disorder,apraxia, and insensitivity to pain

Marbach

Stoyanov

Erger

et al. 2020

Preprint

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Purpose: We characterize the phenotypes of six unrelated individuals with intellectual disability and autism spectrum disorder, who carry heterozygous missense-variants of the PRKAR1B gene. Methods: Variants of PRKAR1B were identified by single-exome or trio-exome analysis. We contacted the families and physicians of the six individuals in order to collect clinical and phenotypic information. Results: PRKAR1B encodes the R1β subunit of the cyclic AMP-dependent protein kinase A (PKA), and is predominantly expressed in the central nervous system. Recent studies of patient cohorts with neurodevelopmental disorders found significant enrichment of de novo missense variants in PRKAR1B, and in vivo studies of the murine ortholog demonstrated altered hippocampal function and reduced neurogenic inflammation and long-term nociceptive pain in R1β-deficient mice. In our study, de novo origin of the PRKAR1B-variants could be confirmed in five out of six individuals, and four carried the same heterozygous de novo variant c.1003C>T (p. Arg335Trp; NM_001164760). Global developmental delay, autism spectrum disorder, and apraxia/dyspraxia has been reported in all six, and reduced pain sensitivity was found in three individuals carrying the c.1003C>T variant. Conclusion: Our study provides strong evidence for a novel, PRKAR1B-related neurodevelopmental disorder.

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“…Developmental disorders (DD) are a class of diseases frequently caused by pathogenic mutations in protein coding genes 28 that often disrupt the normal process of neocortical development. Therefore, we asked how a set of 299 DD-associated genes that were recently discovered from exome sequencing of DD parent-offspring trios 29 distributed on our spatial LT trajectory. A total of 74 of the 299 DD-associated genes were found in the spatial LT gene set (1.87-fold enrichment, p = 3.2x10 -8 ).…”

mentioning

confidence: 99%

Sensitive spatial genome wide expression profiling at cellular resolution

Stickels

Murray

Kumar

et al. 2020

Preprint

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The precise spatial localization of molecular signals within tissues richly informs the mechanisms of tissue formation and function. Previously, we developed Slide-seq, a technology which enables transcriptome-wide measurements with 10-micron spatial resolution. Here, we report new modifications to Slide-seq library generation, bead synthesis, and array indexing that markedly improve the mRNA capture sensitivity of the technology, approaching the efficiency of droplet-based single-cell RNAseq techniques. We demonstrate how this modified protocol, which we have termed Slide-seqV2, can be used effectively in biological contexts where high detection sensitivity is important. First, we deploy Slide-seqV2 to identify new dendritically localized mRNAs in the mouse hippocampus. Second, we integrate the spatial information of Slide-seq data with single-cell trajectory analysis tools to characterize the spatiotemporal development of the mouse neocortex. The combination of near-cellular resolution and high transcript detection will enable broad utility of Slide-seq across many experimental contexts. Main text:The ab initio identification of spatially defined gene expression patterns can provide powerful insights into the development and maintenance of complex tissue architectures, and the molecular characterization of pathological states. Recently, we developed Slide-seq 1 , a spatial genomics technology that quantifies expression genome-wide with high (10-micron)

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Integrating healthcare and research genetic data empowers the discovery of 49 novel developmental disorders

Cited by 15 publications

References 62 publications

Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program

Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program

Variants in PRKAR1B cause a neurodevelopmental disorder with autism spectrum disorder,apraxia, and insensitivity to pain

Sensitive spatial genome wide expression profiling at cellular resolution

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