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De Novo Coding Variants Are Strongly Associated with Tourette Disorder
Neuron (Cambridge, Mass.), 2017-05, Vol.94 (3), p.486-499.e9
2017
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Details

Autor(en) / Beteiligte
Titel
De Novo Coding Variants Are Strongly Associated with Tourette Disorder
Ist Teil von
  • Neuron (Cambridge, Mass.), 2017-05, Vol.94 (3), p.486-499.e9
Ort / Verlag
United States: Elsevier Inc
Erscheinungsjahr
2017
Quelle
MEDLINE
Beschreibungen/Notizen
  • Whole-exome sequencing (WES) and de novo variant detection have proven a powerful approach to gene discovery in complex neurodevelopmental disorders. We have completed WES of 325 Tourette disorder trios from the Tourette International Collaborative Genetics cohort and a replication sample of 186 trios from the Tourette Syndrome Association International Consortium on Genetics (511 total). We observe strong and consistent evidence for the contribution of de novo likely gene-disrupting (LGD) variants (rate ratio [RR] 2.32, p = 0.002). Additionally, de novo damaging variants (LGD and probably damaging missense) are overrepresented in probands (RR 1.37, p = 0.003). We identify four likely risk genes with multiple de novo damaging variants in unrelated probands: WWC1 (WW and C2 domain containing 1), CELSR3 (Cadherin EGF LAG seven-pass G-type receptor 3), NIPBL (Nipped-B-like), and FN1 (fibronectin 1). Overall, we estimate that de novo damaging variants in approximately 400 genes contribute risk in 12% of clinical cases. [Display omitted] •Exome sequencing links damaging de novo sequence variants with Tourette disorder•De novo variants in approximately 400 genes contribute risk in 12% of clinical cases•Recurrent de novo variants identify one high-confidence TD risk gene: WWC1•Gene discovery will exponentially increase as additional cohorts are sequenced Gene discovery by identifying recurrent de novo variants with whole-exome sequencing has proven effective in neurodevelopmental disorders like autism, epilepsy, and intellectual disability. Willsey et al. apply this approach to Tourette disorder, associate de novo variants, and identify genes.
Sprache
Englisch
Identifikatoren
ISSN: 0896-6273
eISSN: 1097-4199
DOI: 10.1016/j.neuron.2017.04.024
Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5769876
Format
–
Schlagworte
Adult, Attention deficit hyperactivity disorder, Autism, Cadherins, Cadherins - genetics, Cell Cycle Proteins, Celsr3 protein, Child, Cohort Studies, Consortia, de novo variants, Female, Fibronectin, Fibronectins - genetics, gene discovery, Genes, Genetic Predisposition to Disease, Genetic Variation, Genetics, Genomes, Genomics, Gilles de la Tourette syndrome, Humans, Intracellular Signaling Peptides and Proteins - genetics, Male, Mutation, Neural coding, Neurodevelopmental disorders, Neurosciences, Obsessive compulsive disorder, Odds Ratio, Parents, Pathogenesis, Phosphoproteins - genetics, Proteins - genetics, Quality control, Receptors, Cell Surface - genetics, Sequence Analysis, DNA, Siblings, Signal transduction, TIC Genetics, Tourette disorder, Tourette syndrome, Tourette Syndrome - genetics, TSAICG, whole-exome sequencing

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