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

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 disorder...

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Autores principales:	Qingyang Xiao, Volker M. Lauschke
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Genetics QH426-470
Acceso en línea:	https://doaj.org/article/f7d08ecf18b04035bbcda70b35c01a50
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spelling	oai:doaj.org-article:f7d08ecf18b04035bbcda70b35c01a502021-12-02T17:51:22ZThe prevalence, genetic complexity and population-specific founder effects of human autosomal recessive disorders10.1038/s41525-021-00203-x2056-7944https://doaj.org/article/f7d08ecf18b04035bbcda70b35c01a502021-06-01T00:00:00Zhttps://doi.org/10.1038/s41525-021-00203-xhttps://doaj.org/toc/2056-7944Abstract 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.Qingyang XiaoVolker M. LauschkeNature PortfolioarticleMedicineRGeneticsQH426-470ENnpj Genomic Medicine, Vol 6, Iss 1, Pp 1-7 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Genetics QH426-470
spellingShingle	Medicine R Genetics QH426-470 Qingyang Xiao Volker M. Lauschke The prevalence, genetic complexity and population-specific founder effects of human autosomal recessive disorders
description	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.
format	article
author	Qingyang Xiao Volker M. Lauschke
author_facet	Qingyang Xiao Volker M. Lauschke
author_sort	Qingyang Xiao
title	The prevalence, genetic complexity and population-specific founder effects of human autosomal recessive disorders
title_short	The prevalence, genetic complexity and population-specific founder effects of human autosomal recessive disorders
title_full	The prevalence, genetic complexity and population-specific founder effects of human autosomal recessive disorders
title_fullStr	The prevalence, genetic complexity and population-specific founder effects of human autosomal recessive disorders
title_full_unstemmed	The prevalence, genetic complexity and population-specific founder effects of human autosomal recessive disorders
title_sort	prevalence, genetic complexity and population-specific founder effects of human autosomal recessive disorders
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/f7d08ecf18b04035bbcda70b35c01a50
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The prevalence, genetic complexity and population-specific founder effects of human autosomal recessive disorders

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