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Tiivistelmä Suomesta on löytynyt peittyvästi periytyvä, aivojen paksupoimuisuutta aiheuttava aivosairaus, joka johtaa lievään tai keskivaikeaan kehitysvammaisuuteen. Taudin ensioireena todetaan yleensä puheen kehityksen viivästyminen, ja aivojen magneettikuvauksessa havaitaan otsa- ja ohimolohkojen alueelle painottuva aivokuoren paksupoimuisuus eli pakygyria. Nuorella aikuisiällä alkavia neuropsykiatrisia oireita esiintyy noin puolella potilaista. Taudin aiheuttaa CRADD-geenin perustajageenivirhe c.509G>A p.Arg170His. Kyseinen geenivirhe on rikastunut Pohjois-Pohjanmaan ja Kainuun alueelle, jolla sen kantajataajuus on 1:80. Kaikilta suomalaisilta potilailta on löytynyt sama geenivirhe homotsygoottisena, ja se voidaan todeta kohdennetulla geenitestillä. CRADD-geenin tehtävä on muun muassa edistää hermosolujen ohjelmoitunutta solukuolemaa. Suomalaista alkuperää olevia potilaita on löytynyt tähän mennessä 23, joten CRADD-geenivirheen aiheuttaman aivojen paksupoimuisuuden voidaan katsoa kuuluvan suomalaiseen tautiperintöön.
Abstract Background: The genetic architecture of hearing impairment in Finland is largely unknown. Here, we investigated two Finnish families with autosomal recessive nonsyndromic symmetrical moderate-to-severe hearing impairment. Methods: Exome and custom capture next-generation sequencing were used to detect the underlying cause of hearing impairment. Results: In both Finnish families, we identified a homozygous pathogenic splice site variant c.637+1G>T in CABP2 that is known to cause autosomal recessive nonsyndromic hearing impairment. Four CABP2 variants have been reported to underlie autosomal recessive nonsyndromic hearing impairment in eight families from Iran, Turkey, Pakistan, Italy, and Denmark. Of these variants, the pathogenic splice site variant c.637+1Ggt;T is the most prevalent. The c.637+1Ggt;T variant is enriched in the Finnish population, which has undergone multiple bottlenecks that can lead to the higher frequency of certain variants including those involved in disease. Conclusion: We report two Finnish families with hearing impairment due to the CABP2 splice site variant c.637+1Ggt;T.
Abstract Isolated populations have been valuable for the discovery of rare monogenic diseases and their causative genetic variants. Finnish disease heritage (FDH) is an example of a group of hereditary monogenic disorders caused by single major, usually autosomal-recessive, variants enriched in the population due to several past genetic drift events. Interestingly, distinct subpopulations have remained in Finland and have maintained their unique genetic repertoire. Thus, FDH diseases have persisted, facilitating vigorous research on the underlying molecular mechanisms and development of treatment options. This Review summarizes the current status of FDH, including the most recently discovered FDH disorders, and introduces a set of other recently identified diseases that share common features with the traditional FDH diseases. The Review also discusses a new era for population-based studies, which combine various forms of big data to identify novel genotype–phenotype associations behind more complex conditions, as exemplified here by the FinnGen project. In addition to the pathogenic variants with an unequivocal causative role in the disease phenotype, several risk alleles that correlate with certain phenotypic features have been identified among the Finns, further emphasizing the broad value of studying genetically isolated populations.