A catalogue of new incidence estimates of monogenic neurodevelopmental disorders caused by de novo variants
Open Access
- 1 April 2020
- journal article
- research article
- Published by Oxford University Press (OUP) in Brain
- Vol. 143 (4), 1099-1105
- https://doi.org/10.1093/brain/awaa051
Abstract
A large fraction of rare and severe neurodevelopmental disorders are caused by sporadic de novo variants. Epidemiological disease estimates are not available for the vast majority of these de novo monogenic neurodevelopmental disorders because of phenotypic heterogeneity and the absence of large-scale genomic screens. Yet, knowledge of disease incidence is important for clinicians and researchers to guide health policy planning. Here, we adjusted a statistical method based on genetic data to predict, for the first time, the incidences of 101 known de novo variant-associated neurodevelopmental disorders as well as 3106 putative monogenic disorders. Two corroboration analyses supported the validity of the calculated estimates. First, greater predicted gene-disorder incidences positively correlated with larger numbers of pathogenic variants collected from patient variant databases (Kendall's tau = 0.093, P-value = 6.9 x 10(-6)). Second, for six of seven (86%) de novo variant associated monogenic disorders for which epidemiological estimates were available (SCN1A, SLC2A1, SALL1, TBX5, KCNQ2, and CDKL5), the predicted incidence estimates matched the reported estimates. We conclude that in the absence of epidemiological data, our catalogue of 3207 incidence estimates for disorders caused by de novo variants can guide patient advocacy groups, clinicians, researchers, and policymakers in strategic decision-making.Funding Information
- Molecular Medicine Ph.D. Program of Cleveland Clinic and Case Western Reserve University
- National Institute of General Medical Sciences (T32GM088088)
- Dravet Syndrome Foundation
This publication has 39 references indexed in Scilit:
- Incidence and phenotypes of childhood-onset genetic epilepsies: a prospective population-based national cohortBrain, 2019
- The Problem of Rarity: Estimation of Prevalence in Rare DiseaseValue in Health, 2018
- High Rate of Recurrent De Novo Mutations in Developmental and Epileptic EncephalopathiesAmerican Journal of Human Genetics, 2017
- Public variant databases: liability?Genetics in Medicine, 2017
- Analysis of protein-coding genetic variation in 60,706 humansNature, 2016
- Global Carrier Rates of Rare Inherited Disorders Using Population Exome SequencesPLOS ONE, 2016
- The origins, determinants, and consequences of human mutationsScience, 2015
- The incidence of SCN1A‐related Dravet syndrome in Denmark is 1:22,000: A population‐based study from 2004 to 2009Epilepsia, 2015
- A framework for the interpretation of de novo mutation in human diseaseNature Genetics, 2014
- De novo STXBP1 mutations in mental retardation and nonsyndromic epilepsyAnnals of Neurology, 2009