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

Irma Järvelä,Reetta Kälviäinen,Tuomo Määttä,Juha Leppälä,Maarit Palomäki,Ritva Paetau,Tarja Linnankivi,Hannaleena Kokkonen,Jan Olme,Auli Sirén ,Anni Saarela,Liz M Nouel-Saied ,Diana M Cornejo-Sanchez ,Trevor D Hadley ,Minna Kankuri-Tammilehto,Mary Fang,Teppo Varilo,Angad Jolly,Jennifer E Posey,James R Lupski,Anushree Acharya,Maria Arvio,Suzanne M Leal,Shalini N Jhangiani,Lorida Llaci,Isabelle Schrauwen

doi:10.1007/s00439-021-02268-1

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.

Highlights

It is estimated that variants that affect the functions of more than 2500 genes can give rise to intellectual disability (ID), and roughly half of these genes remain unknown
Our study demonstrates that de novo variants are the most common cause of ID in the founder population of Finland
We suggested a phenotypic extension in five families (13%), an alternate inheritance model in three families (8%), and an abnormal molecular karyotype finding in three families (8%)

Summary

Introduction

It is estimated that variants that affect the functions of more than 2500 genes can give rise to ID, and roughly half of these genes remain unknown. Most evidence for ARID genes has been obtained from populations where consanguineous marriages are common (Monies et al 2017; Martin et al 2018) whereas data about genetic variants underlying ARID are rare in outbred populations (Martin et al 2018). Founder populations can serve as a middle ground between mixed and consanguineous populations in the identification of ARID genes where the enrichment of a disease allele is strongly affected by genetic drift, and founder effects. The Finnish population represents a founder population where nearly 40 rare autosomal recessive (AR) diseases with one founder variant have enriched (Peltonen et al 1999). To further dissect the landscape of the genetic causes underlying ID in a founder population, a genomic sequencebased approach of exome sequencing (ES) was used

Methods

Results

Conclusion