University of Oulu

Järvelä, I., Määttä, T., Acharya, A. et al. Exome sequencing reveals predominantly de novo variants in disorders with intellectual disability (ID) in the founder population of Finland. Hum Genet 140, 1011–1029 (2021).

Exome sequencing reveals predominantly de novo variants in disorders with intellectual disability (ID) in the founder population of Finland

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Author: Järvelä, Irma1; Määttä, Tuomo2; Acharya, Anushree3;
Organizations: 1Department of Medical Genetics, University of Helsinki, P.O. Box 720, 00251, Helsinki, Finland
2Disability Services, Joint Authority for Kainuu, Kajaani, Finland
3Center for Statistical Genetics, Sergievsky Center, Taub Institute for Alzheimer’s Disease and the Aging Brain, and the Department of Neurology, Columbia University Medical Center, New York, NY, USA
4Eskoo The Center for Disability Empowerment, Seinäjoki, Finland
5Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA
6KTO-Special Welfare District of Varsinais-Suomi, Paimio, Finland
7Päijät-Häme Joint Municipal Authority, Lahti, Finland
8PEDEGO, University of Oulu, Oulu, Finland
9Department of Clinical Genetics, Turku University Hospital, Turku, Finland
10Kanta-Häme Central Hospital, Hämeenlinna, Finland
11Department of Clinical Genetics, University of Turku, Turku, Finland
12Northern Finland Laboratory Centre NordLab and Medical Research Centre, Oulu University Hospital and University of Oulu, Oulu, Finland
13Department of Radiology, Helsinki University Hospital, Helsinki, Finland
14Baylor College of Medicine, Houston, TX, 77030, USA
15Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA
16Department of Child Neurology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
17Institute of Clinical Medicine, School of Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland
18Kuopio Epilepsy Center, Kuopio University Hospital, Neurocenter, Finland
19Department of Child Neurology, Vaasa Central Hospital, Vaasa, Finland
20Division of Biology and Biomedical Sciences, Washington University in St. Louis, St. Louis, MO, 63110, USA
21Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA
22Texas Children’s Hospital, Houston, TX, 77030, USA
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 0.7 MB)
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Language: English
Published: Springer Nature, 2021
Publish Date: 2021-09-08


The genetics of autosomal recessive intellectual disability (ARID) has mainly been studied in consanguineous families, however, founder populations may also be of interest to study intellectual disability (ID) and the contribution of ARID. Here, we used a genotype-driven approach to study the genetic landscape of ID in the founder population of Finland. A total of 39 families with syndromic and non-syndromic ID were analyzed using exome sequencing, which revealed a variant in a known ID gene in 27 families. Notably, 75% of these variants in known ID genes were de novo or suspected de novo (64% autosomal dominant; 11% X-linked) and 25% were inherited (14% autosomal recessive; 7% X-linked; and 4% autosomal dominant). A dual molecular diagnosis was suggested in two families (5%). Via additional analysis and molecular testing, we identified three cases with an abnormal molecular karyotype, including chr21q22.12q22.2 uniparental disomy with a mosaic interstitial 2.7 Mb deletion covering DYRK1A and KCNJ6. Overall, a pathogenic or likely pathogenic variant was identified in 64% (25/39) of the families. Last, we report an alternate inheritance model for 3 known ID genes (UBA7, DDX47, DHX58) and discuss potential candidate genes for ID, including SYPL1 and ERGIC3 with homozygous founder variants and de novo variants in POLR2F and DNAH3. In summary, similar to other European populations, de novo variants were the most common variants underlying ID in the studied Finnish population, with limited contribution of ARID to ID etiology, though mainly driven by founder and potential founder variation in the latter case.

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Series: Human genetics
ISSN: 0340-6717
ISSN-E: 1432-1203
ISSN-L: 0340-6717
Volume: 140
Issue: 7
Pages: 1011 - 1029
DOI: 10.1007/s00439-021-02268-1
Type of Publication: A1 Journal article – refereed
Field of Science: 1184 Genetics, developmental biology, physiology
3124 Neurology and psychiatry
3123 Gynaecology and paediatrics
Funding: Open access funding provided by University of Helsinki including Helsinki University Central Hospital.. This study was funded in part by the US National Human Genome Research Institute (NHGRI)/National Heart Lung and Blood Institute UM1 HG006542 to the Baylor-Hopkins Center for Mendelian Genomics. JEP was funded by US NHGRI K08 HG008986.
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