Exploring the genomics of cognitive impairment: whole-genome SNP genotyping experience in Estonian patients and general population
Date
2012-08-14
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Abstract
Intellektipuue on raske arenguhäire, mis arenenud riikides esineb ligikaudse sagedusega 2% üldpopulatsioonist. Intellektipuude tekkepõhjused võivad olla väga erinevad ning ligi pooltel patsientidest on häire põhjus jäänud koguni teadmata. Viimastel aastatel teaduses kasutusele võetud kogu-genoomi analüüsimeetodid on näidanud, et inimgenoomis esinevad laialdaselt DNA koopiaarvu variatisoonid (CNV) - kromosoomsegmendid, mille koopiate arv on ümberkorralduse tõttu genoomis tavapärasest suurem või väiksem. On leitud, et CNV-d võivad olulisel osal patsientidest vastutada intellektipuude ja teiste kaasasündinud arenguhäirete eest ning olla riskifaktoriks erinevate komplekshaiguste kujunemisel. Samas esinevad CNV-d ka (näiliselt) tervetel inimestel, mis muudab nende kliinilise tähtsuse hindamise sageli keeruliseks ning enamuse CNV-de mõju inimese tervisele ja arengule on praegusel ajal veel ebaselge.
Käesolev töö on esimene ulatuslik uurimus CNV-de haigusseoselisest rollist intellektipuudega Eesti perekondades. Kuna rea genoomsete muutuste puhul võib nende mõju haigustunnuste avaldumisele olla varieeruv, teostati CNV-de täpsema rolli analüüsimiseks sama uuring ka Tartu Ülikooli Eesti Geenivaramu geenidoonoritele. Töö tulemusena leiti 18 peres intellektipuuet põhjustav CNV ehk geneetiline diagnoos määrati 23% uuritud patsientidest, kellel seni oli nende haiguse põhjus teadmata. Eesti Geenivaramu geenidoonorite hulgast leiti neuropsühholoogiliste häiretega seotud CNV-d 19 indiviidil. Vastavalt Eesti Geenivaramu küsimustikule on enamus neist inimestest kannatanud aastaid erinevate tervisehäirete (näiteks tugev rasvumine, epilepsia, kõnearengu häired, depressioon, teised neuroloogilised ja psühhiaatrilised probleemid) teadmata, et nende genoomis esineb vastavate haiguste riski suurendavaid variatsioone. Samuti oli uuringuandmetel oluline roll kahe kromosoomregiooniga, 7q11.23 ja 16p11.2, seotud uute genoomsete sündroomide iseloomustamisel. Kokkuvõtlikult näitas käesolev uuring CNV-de olulist rolli neuropsühholoogiliste häirete kujunemisel ning genoomse analüüsi efektiivsust teaduses ja diagnostikas.
Intellectual disability (ID) is a neurodevelopmental disorder with a population prevalence of approximately 2% and high socio-economical burden on the patients’ families and the society. Due to the heterogeneous aetiology of ID, disease-causative factors have remained unknown in about half of patients with cognitive impairment. Over the recent years, the biotechnological progress in human genomics has enabled a whole-genome approaches to study the genetic background of diseases and revealed small chromosomal gains and losses - DNA copy number variations (CNVs) - as one of the major contributors to the aetiology of developmental disorders. However, these CNVs can also be harmless variants in the human genome or act as susceptibility factors for common diseases and phenotypic traits. Moreover, numerous CNVs initially detected in patients with brain-related disorders also occur with lower frequency in apparently normal individuals. Thus, challenging the assessment of the consequence of CNVs on individual’s health and development. The current study was the first comprehensive effort to investigate genomic causes of cognitive impairment and associated complex phenotypes in Estonian patients with unexplained ID and general population individuals. As a result of the study, genetic diagnosis was established in 18 investigated families (the diagnostic yield of 23%) and rare CNVs of neuropsychological relevance were found in 19 Estonian general population individuals. By participating in collaborative investigations, the core clinical features were established for novel genomic disorders associated with regions 7q11.23 and 16p11.2 in the human genome. In summary, the results of this study demonstrated the importance of rare CNVs in the aetiology of neurodevelopmental disorders and proved that whole-genome screening for genomic rearrangments is an effective tool in research and diagnostics.
Intellectual disability (ID) is a neurodevelopmental disorder with a population prevalence of approximately 2% and high socio-economical burden on the patients’ families and the society. Due to the heterogeneous aetiology of ID, disease-causative factors have remained unknown in about half of patients with cognitive impairment. Over the recent years, the biotechnological progress in human genomics has enabled a whole-genome approaches to study the genetic background of diseases and revealed small chromosomal gains and losses - DNA copy number variations (CNVs) - as one of the major contributors to the aetiology of developmental disorders. However, these CNVs can also be harmless variants in the human genome or act as susceptibility factors for common diseases and phenotypic traits. Moreover, numerous CNVs initially detected in patients with brain-related disorders also occur with lower frequency in apparently normal individuals. Thus, challenging the assessment of the consequence of CNVs on individual’s health and development. The current study was the first comprehensive effort to investigate genomic causes of cognitive impairment and associated complex phenotypes in Estonian patients with unexplained ID and general population individuals. As a result of the study, genetic diagnosis was established in 18 investigated families (the diagnostic yield of 23%) and rare CNVs of neuropsychological relevance were found in 19 Estonian general population individuals. By participating in collaborative investigations, the core clinical features were established for novel genomic disorders associated with regions 7q11.23 and 16p11.2 in the human genome. In summary, the results of this study demonstrated the importance of rare CNVs in the aetiology of neurodevelopmental disorders and proved that whole-genome screening for genomic rearrangments is an effective tool in research and diagnostics.
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Keywords
vaimne alaareng, DNA koopiaarvu variatsioonid, geeniuuringud, kromosoomid, populatsioonigeneetika, mental retardation, DNA copy number variations, genetic research, chromosomes, population genetics