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. 2020 Apr 1;143(4):1099-1105.
doi: 10.1093/brain/awaa051.

A catalogue of new incidence estimates of monogenic neurodevelopmental disorders caused by de novo variants

Javier A López-Rivera  1   2   3 , Eduardo Pérez-Palma  2   4 , Joseph Symonds  5   6 , Amanda S Lindy  7 , Dianalee A McKnight  7 , Costin Leu  2   3 , Sameer Zuberi  5   6 , Andreas Brunklaus  5   6 , Rikke S Møller  8   9 , Dennis Lal  1   2   3   4   10   11
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A catalogue of new incidence estimates of monogenic neurodevelopmental disorders caused by de novo variants

Javier A López-Rivera et al. Brain. .

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 τ = 0.093, P-value = 6.9 × 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.

Keywords: autism; epilepsy; incidence; neurodevelopmental disorder.

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Figures

Figure 1 Gene-variant intolerance.
Figure 1 Gene-variant intolerance.
(A) Distribution of intolerance to protein-coding variation of established de novo NDD genes by intolerance type. MV = missense variant intolerant; MV & PTV = intolerant to both missense and truncating variants. (B) Total predicted sporadic disease incidence due to established de novo variant-associated disease genes. Error bars represent 90% CIs.
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