Enrichment of rare variants in population isolates : single AICDA mutation responsible for hyper-IgM syndrome type 2 in Finland

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http://hdl.handle.net/10138/167974

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Trotta , L , Hautala , T , Hamalainen , S , Syrjanen , J , Viskari , H , Almusa , H , Lepisto , M , Kaustio , M , Porkka , K , Palotie , A , Seppanen , M & Saarela , J 2016 , ' Enrichment of rare variants in population isolates : single AICDA mutation responsible for hyper-IgM syndrome type 2 in Finland ' , European Journal of Human Genetics , vol. 24 , no. 10 , pp. 1473-1478 . https://doi.org/10.1038/ejhg.2016.37

Title: Enrichment of rare variants in population isolates : single AICDA mutation responsible for hyper-IgM syndrome type 2 in Finland
Author: Trotta, Luca; Hautala, Timo; Hamalainen, Sari; Syrjanen, Jaana; Viskari, Hanna; Almusa, Henrikki; Lepisto, Maija; Kaustio, Meri; Porkka, Kimmo; Palotie, Aarno; Seppanen, Mikko; Saarela, Janna
Contributor: University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Clinicum
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Clinicum
University of Helsinki, Institute for Molecular Medicine Finland
Date: 2016-10
Language: eng
Number of pages: 6
Belongs to series: European Journal of Human Genetics
ISSN: 1018-4813
URI: http://hdl.handle.net/10138/167974
Abstract: Antibody class-switch recombination and somatic hypermutation critically depend on the function of activation-induced cytidine deaminase (AID). Rare variants in its gene AICDA have been reported to cause autosomal recessive AID deficiency (autosomal recessive hyper-IgM syndrome type 2 (HIGM2)). Exome sequencing of a multicase Finnish family with an HIGM2 phenotype identified a rare, homozygous, variant (c.416T > C, p.(Met139Thr)) in the AICDA gene, found to be significantly enriched in the Finnish population compared with other populations of European origin (38.56-fold, P <0.001). The population history of Finland, characterized by a restricted number of founders, isolation and several population bottlenecks, has caused enrichment of certain rare disease-causing variants and losses of others, as part of a phenomenon called the Finnish Disease Heritage. Accordingly, rare founder mutations cause the majority of observed Finnish cases in these mostly autosomal recessive disorders that consequently are more frequent in Finland than elsewhere. Screening of all currently known Finnish patients with an HIGM2 phenotype showed them to be homozygous for p.(Met139Thr). All the Finnish p.(Met139Thr) carriers with available data on their geographic descent originated from the eastern and northeastern parts of Finland. They were observed to share more of their genome identity by descent (IBD) than Finns in general (P <0.001), and they all carried a 207.5-kb ancestral haplotype containing the variant. In conclusion, the identified p.(Met139Thr) variant is significantly enriched in Finns and explains all thus far found AID deficiencies in Finland.
Subject: INDUCED CYTIDINE DEAMINASE
FINNISH-DISEASE HERITAGE
CARTILAGE-HAIR HYPOPLASIA
GENETIC-ANALYSIS
HUMAN GENOME
AID
DEFICIENCY
TOLERANCE
PHENOTYPE
UPDATE
1182 Biochemistry, cell and molecular biology
1184 Genetics, developmental biology, physiology
3111 Biomedicine
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