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Population-level deficit of homozygosity unveils CPSF3 as an intellectual disability syndrome gene

Population-level deficit of homozygosity unveils CPSF3 as an intellectual disability syndrome gene


Title: Population-level deficit of homozygosity unveils CPSF3 as an intellectual disability syndrome gene
Author: Arnadottir, Gudny A.
Oddsson, Asmundur   orcid.org/0000-0002-4606-5163
Jensson, Brynjar O.
Gisladottir, Svanborg
Simon, Mariella T.
Arnthorsson, Asgeir O.
Katrinardottir, Hildigunnur
Fridriksdottir, Run
Ivarsdottir, Erna V.
Jonasdottir, Adalbjorg
... 23 more authors Show all authors
Date: 2022-02-04
Language: English
Scope:
University/Institute: Landspitali - The National University Hospital of Iceland
Department: Faculty of Medicine
Clinical Laboratory Services, Diagnostics and Blood Bank
Women's and Childrens's Services
Series: Nature Communications; 13(1)
ISSN: 2041-1723
DOI: https://doi.org/10.1038/s41467-022-28330-8
Subject: Meinafræði; Lífefna- og sameindalíffræði; Barnalæknisfræði; Cleavage And Polyadenylation Specificity Factor; Intellectual Disability; Genotype; Chemistry (all); Biochemistry, Genetics and Molecular Biology (all); Physics and Astronomy (all)
URI: https://hdl.handle.net/20.500.11815/3032

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Citation:

Arnadottir , G A , Oddsson , A , Jensson , B O , Gisladottir , S , Simon , M T , Arnthorsson , A O , Katrinardottir , H , Fridriksdottir , R , Ivarsdottir , E V , Jonasdottir , A , Jonasdottir , A , Barrick , R , Saemundsdottir , J , le Roux , L , Oskarsson , G R , Asmundsson , J , Steffensen , T , Gudmundsson , K R , Ludvigsson , P , Jonsson , J J , Masson , G , Jonsdottir , I , Holm , H , Jonasson , J G , Magnusson , O T , Thorarensen , O , Abdenur , J , Norddahl , G L , Gudbjartsson , D F , Bjornsson , H T , Thorsteinsdottir , U , Sulem , P & Stefansson , K 2022 , ' Population-level deficit of homozygosity unveils CPSF3 as an intellectual disability syndrome gene ' , Nature Communications , vol. 13 , no. 1 , 705 . https://doi.org/10.1038/s41467-022-28330-8

Abstract:

Predicting the pathogenicity of biallelic missense variants can be challenging. Here, we use a deficit of observed homozygous carriers of missense variants, versus an expected number in a set of 153,054 chip-genotyped Icelanders, to identify potentially pathogenic genotypes. We follow three missense variants with a complete deficit of homozygosity and find that their pathogenic effect in homozygous state ranges from severe childhood disease to early embryonic lethality. One of these variants is in CPSF3, a gene not previously linked to disease. From a set of clinically sequenced Icelanders, and by sequencing archival samples targeted through the Icelandic genealogy, we find four homozygous carriers. Additionally, we find two homozygous carriers of Mexican descent of another missense variant in CPSF3. All six homozygous carriers of missense variants in CPSF3 show severe intellectual disability, seizures, microcephaly, and abnormal muscle tone. Here, we show how the absence of certain homozygous genotypes from a large population set can elucidate causes of previously unexplained recessive diseases and early miscarriage.

Description:

Funding Information: We wish to thank the patients and family members followed in this study, and all other individuals who participated in the study and whose contribution made this work possible. M.T.S. was supported by a grant from the Sacchi Foundation. Publisher Copyright: © 2022, The Author(s).

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