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

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.

Genome sequencing is a sensitive first-line test to diagnose individuals with intellectual disability

“…In cohort 1, parental analysis was performed in 26 cases and of those, 14 variants were de novo (54%) of which, 3 were first classified as VUS. This de novo fraction is lower than in a recent study from Finland using a trio-ES approach reporting a de novo rate of 75%, 36 providing further support that a higher diagnostic yield could be obtained with trios.…”

“…Intellectual disability (ID), defined as limitations in both intellectual function and adaptive behavior, affects approximately 1% of the world population. [1][2][3] Depending on the cognitive ability (as measured by an IQ test), individuals are subdivided into 4 groups: mild (IQ 50-70), moderate (IQ [35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50], severe (IQ [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35], and profound (IQ < 20). 4 The etiology of ID is heterogeneous and includes environmental factors, such as congenital infections or hypoxic encephalopathy, and genetic factors.…”

RNA Helicases in Microsatellite Repeat Expansion Disorders and Neurodegeneration

“…Additionally, autoinflammatory responses in the Aicardi-Guotieres or Singleton Merten syndromes and ID have been attributed to mutations which cluster around the ATP binding region of the RNA helicase IFIH1 ( Crow et al, 2015 ; Rice et al, 2020 ). Finally, exome sequencing has linked several other RNA helicases to rare cases of ID, including DDX47, DDX54, DHX8, DHX16, DHX34, DHX37 and DHX58 ( Paine et al, 2019 ; Järvelä et al, 2021 ). A diagram summarising the altered functions of RNA helicases in non-repeat neurodegenerative disorders is presented in Figure 3 .…”

Clan genomics: From OMIM phenotypic traits to genes and biology

“…(c) Studies in CMT genes including PMP22 (Roa, Garcia, Pentao, et al, 1993;Shy et al, 2006) and EGR2 (Warner et al, 1998) revealed both biallelic and monoallelic variants at the locus associated with AR and AD neuropathy traits, respectively. The PMP22 gene (horizontal rectangle) on two chromosome 17 homologues (horizontal lines); PMP22 T118M recessive DSP trait alleles and combinations of alleles at the CMT1A/HNPP locus (Jarvela et al, 2021). Perhaps as we learn how to characterize better these cognitive phenotypes, and rare variant smaller sized CNV, for example, <100 kb, additional potentially contributing variant alleles will be elucidated (Lupski, 2015a;Mannik et al, 2015).…”