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

Gudny A. Arnadottir, Asmundur Oddsson, Brynjar O. Jensson, Svanborg Gisladottir, Mariella T. Simon, Asgeir O. Arnthorsson, Hildigunnur Katrinardottir, Run Fridriksdottir, Erna V. Ivarsdottir, Adalbjorg Jonasdottir, Aslaug Jonasdottir, Rebekah Barrick, Jona Saemundsdottir, Louise Roux, Gudjon R. Oskarsson, Jurate Asmundsson, Thora Steffensen, Kjartan R. Gudmundsson, Petur Ludvigsson, Jon J. Jonsson, Gisli Masson, Ingileif Jonsdottir, Hilma Holm, Jon G. Jonasson, Olafur Th. Magnusson, Olafur Thorarensen, Jose Abdenur, Gudmundur L. Norddahl, Daniel F. Gudbjartsson, Hans T. Bjornsson, Unnur Thorsteinsdottir, Patrick Sulem () and Kari Stefansson ()
Additional contact information
Gudny A. Arnadottir: deCODE Genetics/Amgen, Inc.
Asmundur Oddsson: deCODE Genetics/Amgen, Inc.
Brynjar O. Jensson: deCODE Genetics/Amgen, Inc.
Svanborg Gisladottir: The National University Hospital of Iceland
Mariella T. Simon: Children’s Hospital of Orange County
Asgeir O. Arnthorsson: deCODE Genetics/Amgen, Inc.
Hildigunnur Katrinardottir: deCODE Genetics/Amgen, Inc.
Run Fridriksdottir: deCODE Genetics/Amgen, Inc.
Erna V. Ivarsdottir: deCODE Genetics/Amgen, Inc.
Adalbjorg Jonasdottir: deCODE Genetics/Amgen, Inc.
Aslaug Jonasdottir: deCODE Genetics/Amgen, Inc.
Rebekah Barrick: Children’s Hospital of Orange County
Jona Saemundsdottir: deCODE Genetics/Amgen, Inc.
Louise Roux: deCODE Genetics/Amgen, Inc.
Gudjon R. Oskarsson: deCODE Genetics/Amgen, Inc.
Jurate Asmundsson: The National University Hospital of Iceland
Thora Steffensen: The National University Hospital of Iceland
Kjartan R. Gudmundsson: deCODE Genetics/Amgen, Inc.
Petur Ludvigsson: The National University Hospital of Iceland
Jon J. Jonsson: University of Iceland
Gisli Masson: deCODE Genetics/Amgen, Inc.
Ingileif Jonsdottir: deCODE Genetics/Amgen, Inc.
Hilma Holm: deCODE Genetics/Amgen, Inc.
Jon G. Jonasson: University of Iceland
Olafur Th. Magnusson: deCODE Genetics/Amgen, Inc.
Olafur Thorarensen: The National University Hospital of Iceland
Jose Abdenur: Children’s Hospital of Orange County
Gudmundur L. Norddahl: deCODE Genetics/Amgen, Inc.
Daniel F. Gudbjartsson: deCODE Genetics/Amgen, Inc.
Hans T. Bjornsson: University of Iceland
Unnur Thorsteinsdottir: deCODE Genetics/Amgen, Inc.
Patrick Sulem: deCODE Genetics/Amgen, Inc.
Kari Stefansson: deCODE Genetics/Amgen, Inc.

Nature Communications, 2022, vol. 13, issue 1, 1-9

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-28330-8

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