National survey on the prevalence of single-gene aetiologies for genetic developmental and epileptic encephalopathies in Italy

Abstract

Background: We aimed to estimate real-world evidence of the prevalence rate of genetic developmental and epileptic encephalopathies (DEEs) in the Italian population over a 11-year period.

Methods: Fifteen paediatric and adult tertiary Italian epilepsy centres participated in a survey related to 98 genes included in the molecular diagnostic workflows of most centres. We included patients with a clinical diagnosis of DEE, caused by a pathogenic or likely pathogenic variant in one of the selected genes, with a molecular diagnosis established between 2012 and 2022. These data were used as a proxy to estimate the prevalence rate of DEEs.

Results: We included 1568 unique patients and found a mean incidence proportion of 2.6 patients for 100.000 inhabitants (SD=1.13) with consistent values across most Italian regions. The number of molecular diagnoses showed a continuing positive trend, resulting in more than a 10-fold increase between 2012 and 2022. The mean age at molecular diagnosis was 11.2 years (range 0-75). Pathogenic or likely pathogenic variants in genes with an autosomal dominant inheritance pattern occurred in 77% (n=1207) patients; 17% (n=271) in X-linked genes and 6% (n=90) in genes with autosomal recessive inheritance. The most frequently reported genes in the survey were SCN1A (16%), followed by KCNQ2 (5.6%) and SCN2A (5%).

Conclusion: Our study provides a large dataset of patients with monogenic DEE, from a European country. This is essential for informing decision-makers in drug development on the appropriateness of initiatives aimed at developing precision medicine therapies and is instrumental in implementing disease-specific registries and natural history studies.

Keywords: Epilepsy; Genomics.

Figure 1. (A) Number of patients born in the 20 Italian regions and enrolled in the survey. (B) Mean incidence proportion of patients (2012–2022) per region normalised with the corresponding number of inhabitants. Similar blue intensities correspond to a similar mean incidence proportion of patients.

Figure 2. (A) Density plot of the age at the inclusion in the survey. (B) Density plot of the age at the inclusion in the survey grouped by sex. Vertical dashed grey line: median age (11 years); Vertical dotted grey line: mean age (13.7 years). Orange: female patients, light blue: male patients.

Figure 3. Per year distribution of the number of diagnoses reported in the survey. The dotted blue line depicts the polynomial (third order) trendline.

Figure 4. (A) Density plot of the age at molecular diagnosis. (B) Density plot of the age at molecular diagnosis grouped by sex. Vertical dashed grey line: median age (7 years); Vertical dotted grey line: mean age (10.2 years). Orange: female patients; light blue: male patients.