title: Enrichment of rare variants in population isolates: single AICDA mutation responsible for hyper-IgM syndrome type 2 in Finland.
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.
authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
authors.forename: Luca
authors.initials: L
authors.lastname: Trotta
authors.affiliation: Department of Internal Medicine, Oulu University Hospital, Oulu, Finland.
authors.forename: Timo
authors.initials: T
authors.lastname: Hautala
authors.affiliation: Department of Internal Medicine, Kuopio University Hospital, Kuopio, Finland.
authors.forename: Sari
authors.initials: S
authors.lastname: Hämäläinen
authors.affiliation: Department of Internal Medicine, Tampere University Hospital, Tampere, Finland.
authors.forename: Jaana
authors.initials: J
authors.lastname: Syrjänen
authors.affiliation: Department of Internal Medicine, Tampere University Hospital, Tampere, Finland.|Department of Virology, University of Tampere, School of Medicine, Tampere, Finland.
authors.forename: Hanna
authors.initials: H
authors.lastname: Viskari
authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
authors.forename: Henrikki
authors.initials: H
authors.lastname: Almusa
authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
authors.forename: Maija
authors.initials: M
authors.lastname: Lepisto
authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
authors.forename: Meri
authors.initials: M
authors.lastname: Kaustio
authors.affiliation: Hematology Research Unit, Biomedicum Helsinki and Hematology Division, Comprehensive Cancer Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Kimmo
authors.initials: K
authors.lastname: Porkka
authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: Aarno
authors.initials: A
authors.lastname: Palotie
authors.affiliation: Rare Disease Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.|Adult Immunodeficiency Unit, Inflammation Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Mikko
authors.initials: M
authors.lastname: Seppänen
authors.affiliation: Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
authors.forename: Janna
authors.initials: J
authors.lastname: Saarela
mesh_terms: D000328:Adult; D002648:Child; D003564:Cytidine Deaminase / Q000235:genetics*; D005260:Female; D005387:Finland; D018703:Founder Effect; D005787:Gene Frequency; D006239:Haplotypes; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D053306:Hyper-IgM Immunodeficiency Syndrome / Q000175:diagnosis / Q000235:genetics*; D007223:Infant; D008297:Male; D009154:Mutation; D010375:Pedigree; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase