Identification of NCAN as a candidate gene for developmental dyslexia

Elisabet Einarsdottir,Nancy Yiu-Lin Yu,Fahimeh Darki,Antti-Jussi Ämmälä,Linnea Karlsson,Riitta Parkkola,Katri Kantojärvi,Hans Matsson,Jaana Nopola-Hemmi,Noora M Scheinin,Myriam Peyrard-Janvid,Torkel Klingberg,Eira Leinonen,Harri Merisaari,Jetro J Tuulari,Tiina Paunio,Juha Kere,Hasse Karlsson,Jani Saunavaara

doi:10.1038/s41598-017-10175-7

Abstract

A whole-genome linkage analysis in a Finnish pedigree of eight cases with developmental dyslexia (DD) revealed several regions shared by the affected individuals. Analysis of coding variants from two affected individuals identified rs146011974G > A (Ala1039Thr), a rare variant within the NCAN gene co-segregating with DD in the pedigree. This variant prompted us to consider this gene as a putative candidate for DD. The RNA expression pattern of the NCAN gene in human tissues was highly correlated (R > 0.8) with that of the previously suggested DD susceptibility genes KIAA0319, CTNND2, CNTNAP2 and GRIN2B. We investigated the association of common variation in NCAN to brain structures in two data sets: young adults (Brainchild study, Sweden) and infants (FinnBrain study, Finland). In young adults, we found associations between a common genetic variant in NCAN, rs1064395, and white matter volume in the left and right temporoparietal as well as the left inferior frontal brain regions. In infants, this same variant was found to be associated with cingulate and prefrontal grey matter volumes. Our results suggest NCAN as a new candidate gene for DD and indicate that NCAN variants affect brain structure.

Highlights

A whole-genome linkage analysis in a Finnish pedigree of eight cases with developmental dyslexia (DD) revealed several regions shared by the affected individuals
Structural brain imaging has repeatedly highlighted certain regions in the left hemisphere correlated with DD, e.g.5, 18, 21–23, and white matter changes related to allelic variation in the DD susceptibility genes DYX1C1, DCDC2 and KIAA0319 are a recurring observation
We used linkage analysis to prioritize potential candidate regions for autosomal dominant DD in a multiplex pedigree, followed up by evaluation of exome-sequencing data in those regions. This allowed us to highlight a new plausible candidate gene for DD, NCAN. Neither this gene nor genomic region have been previously suggested by linkage or GWA studies as a susceptibility locus or gene for dyslexia

Summary

Introduction

A whole-genome linkage analysis in a Finnish pedigree of eight cases with developmental dyslexia (DD) revealed several regions shared by the affected individuals. We found associations between a common genetic variant in NCAN, rs1064395, and white matter volume in the left and right temporoparietal as well as the left inferior frontal brain regions. Detection of chromosomal abnormalities such as balanced translocations in families has led to the identification of at least three DD susceptibility genes (DYX1C1, ROBO1, CYP19A1)[2,3,4] This approach has been used to identify genes implicated in learning difficulties similar to DD (e.g. CTNND2)[5]. Structural brain imaging has repeatedly highlighted certain regions in the left hemisphere correlated with DD, e.g.5, 18, 21–23, and white matter changes related to allelic variation in the DD susceptibility genes DYX1C1, DCDC2 and KIAA0319 are a recurring observation. In their recent review, provide an overview of what is known regarding the mechanism of language acquisition and its impact on the brain[26]

Objectives

Methods

Results

Conclusion