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

TitleExome sequencing reveals predominantly de novo variants in disorders with intellectual disability (ID) in the founder population of Finland.
Publication TypeJournal Article
Year of Publication2021
AuthorsJärvelä, I, Määttä, T, Acharya, A, Leppälä, J, Jhangiani, SN, Arvio, M, Siren, A, Kankuri-Tammilehto, M, Kokkonen, H, Palomäki, M, Varilo, T, Fang, M, Hadley, TD, Jolly, A, Linnankivi, T, Paetau, R, Saarela, A, Kälviäinen, R, Olme, J, Nouel-Saied, LM, Cornejo-Sanchez, DM, Llaci, L, Lupski, JR, Posey, JE, Leal, SM, Schrauwen, I
JournalHum Genet
Volume140
Issue7
Pagination1011-1029
Date Published2021 Jul
ISSN1432-1203
KeywordsExome, Family, Female, Finland, Genes, Recessive, Genetic Predisposition to Disease, Genotype, Homozygote, Humans, Intellectual Disability, Male, Pedigree, Whole Exome Sequencing
Abstract

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.

DOI10.1007/s00439-021-02268-1
Alternate JournalHum Genet
PubMed ID33710394
PubMed Central IDPMC8197721
Grant ListK08 HG008986 / HG / NHGRI NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States
US NHGRI K08 HG008986 / / U.S. Department of Health and Human Services /