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Biallelic SYNE2 Missense Mutations Leading to Nesprin-2 Giant Hypo-Expression Are Associated with Intellectual Disability and Autism

Young, Natalie; Asif, Maria; Jackson, Matthew; Fernández-Mayoralas, Daniel Martín; de la Peña, Mar Jimenez; Calleja-Pérez, Beatriz; Álvarez, Sara; Hunter-Featherstone, Eve; Noegel, Angelika A.; Höhne, Wolfgang; Nürnberg, Peter; Obara, Boguslaw; Hussain, Muhammad Sajid; Karakesisoglou, Iakowos; Fernández-Jaén, Alberto

Biallelic SYNE2 Missense Mutations Leading to Nesprin-2 Giant Hypo-Expression Are Associated with Intellectual Disability and Autism Thumbnail


Maria Asif

Matthew Jackson

Daniel Martín Fernández-Mayoralas

Mar Jimenez de la Peña

Beatriz Calleja-Pérez

Sara Álvarez

Eve Hunter-Featherstone

Angelika A. Noegel

Wolfgang Höhne

Peter Nürnberg

Boguslaw Obara

Muhammad Sajid Hussain

Alberto Fernández-Jaén


Autism spectrum disorder (ASD) is a group of neurological and developmental disabilities characterised by clinical and genetic heterogeneity. The current study aimed to expand ASD genotyping by investigating potential associations with SYNE2 mutations. Specifically, the disease-causing variants of SYNE2 in 410 trios manifesting neurodevelopmental disorders using whole-exome sequencing were explored. The consequences of the identified variants were studied at the transcript level using quantitative polymerase chain reaction (qPCR). For validation, immunofluorescence and immunoblotting were performed to analyse mutational effects at the protein level. The compound heterozygous variants of SYNE2 (NM_182914.3:c.2483T>G; p.(Val828Gly) and NM_182914.3:c.2362G>A; p.(Glu788Lys)) were identified in a 4.5-year-old male, clinically diagnosed with autism spectrum disorder, developmental delay and intellectual disability. Both variants reside within the nesprin-2 giant spectrin repeat (SR5) domain and are predicted to be highly damaging using in silico tools. Specifically, a significant reduction of nesprin-2 giant protein levels is revealed in patient cells. SYNE2 transcription and the nuclear envelope localisation of the mutant proteins was however unaffected as compared to parental control cells. Collectively, these data provide novel insights into the cardinal role of the nesprin-2 giant in neurodevelopment and suggest that the biallelic hypomorphic SYNE2 mutations may be a new cause of intellectual disability and ASD.

Journal Article Type Article
Acceptance Date Aug 20, 2021
Online Publication Date Aug 24, 2021
Publication Date 2021-09
Deposit Date Jan 26, 2022
Publicly Available Date Jan 27, 2022
Journal Genes
Publisher MDPI
Peer Reviewed Peer Reviewed
Volume 12
Issue 9
Article Number 1294
Public URL


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Copyright Statement
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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