The prevalence, genetic complexity and population-specific founder effects of human autosomal recessive disorders

Qingyang Xiao,Volker M Lauschke

doi:10.1038/s41525-021-00203-x

Abstract

Autosomal recessive (AR) disorders pose a significant burden for public health. However, despite their clinical importance, epidemiology and molecular genetics of many AR diseases remain poorly characterized. Here, we analyzed the genetic variability of 508 genes associated with AR disorders based on sequencing data from 141,456 individuals across seven ethnogeographic groups by integrating variants with documented pathogenicity from ClinVar, with stringent functionality predictions for variants with unknown pathogenicity. We first validated our model using 85 diseases for which population-specific prevalence data were available and found that our estimates strongly correlated with the respective clinically observed disease frequencies (r = 0.68; p < 0.0001). We found striking differences in population-specific disease prevalence with 101 AR diseases (27%) being limited to specific populations, while an additional 305 diseases (68%) differed more than tenfold across major ethnogeographic groups. Furthermore, by analyzing genetic AR disease complexity, we confirm founder effects for cystic fibrosis and Stargardt disease, and provide strong evidences for >25 additional population-specific founder mutations. The presented analyses reveal the molecular genetics of AR diseases with unprecedented resolution and provide insights into epidemiology, complexity, and population-specific founder effects. These data can serve as a powerful resource for clinical geneticists to inform population-adjusted genetic screening programs, particularly in otherwise understudied ethnogeographic groups.

Highlights

Autosomal recessive (AR) diseases constitute a subset of genetic disorders that are responsible for a considerable disease burden, affecting ~1.7–5 in 1000 neonates[1]
The landscape of pathogenic variation associated with human autosomal recessive disorders Across 508 genes associated with 450 AR diseases, we identified a total of 574,524 variants of which 46,935 were putatively pathogenic (Fig. 1a, b and Supplementary Data 1)
The largest number of pathogenic variants were found in ABCA4 (Stargardt disease; OMIM 248200; n = 528), SI, HSPG2 (Schwartz–Jampel syndrome; OMIM 255800; n = 438) and CFTR, while 18 genes harbored less than ten pathogenic variants (Fig. 1d and Supplementary Data 2)

Summary

INTRODUCTION

Autosomal recessive (AR) diseases constitute a subset of genetic disorders that are responsible for a considerable disease burden, affecting ~1.7–5 in 1000 neonates (compared to 1.4 in 1000 for autosomal dominant disorders)[1]. By integrating all pathogenic variants from ClinVar with highly stringent functionality predictions for rare and novel variants with unknown or conflicting pathogenicity annotations, we identified a total of 46,935 putatively disease-causing variations Based on their variant frequencies, we modeled the incidences of all human AR diseases. We validated the method using 85 diseases with available prevalence data and showed that our model yielded accurate predictions of population-specific disease frequencies for monogenic disorders (r = 0.68; p < 0.0001). Using this resource for rare disease epidemiology, we provide quantitative ethnogeographic maps of human AR disease prevalence and pinpoint variant panels, with maximal test effectiveness to guide the design of. We calculated the genetic complexity of all 450 analyzed AR diseases and find >25 diseases with pronounced population-specific founder effects, most of which have not been previously described

RESULTS

DISCUSSION

CODE AVAILABILITY