A1 Refereed original research article in a scientific journal
Exome sequencing reveals predominantly de novo variants in disorders with intellectual disability (ID) in the founder population of Finland
Authors: Järvelä Irma, Määttä Tuomo, Acharya Anushree, Leppälä Juha, Jhangiani Shalini N., Arvio Maria, Siren Auli, Kankuri-Tammilehto Minna, Kokkonen Hannaleena, Palomäki Maarit, Varilo Teppo, Fang Mary, Hadley Trevor D., Jolly Angad, Linnankivi Tarja, Paetau Ritva, Saarela Anni, Kälviäinen Reetta, Olme Jan, Nouel-Saied Liz M., Cornejo-Sanchez Diana M., Llaci Lorida, Lupski James R., Posey Jennifer E., Leal Suzanne M., Schrauwen Isabelle
Publisher: SPRINGER
Publication year: 2021
Journal: Human Genetics
Journal name in source: HUMAN GENETICS
Journal acronym: HUM GENET
Volume: 140
First page : 1011
Last page: 1029
Number of pages: 19
ISSN: 0340-6717
eISSN: 1432-1203
DOI: https://doi.org/10.1007/s00439-021-02268-1
Web address : https://link.springer.com/article/10.1007/s00439-021-02268-1
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/53653639
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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