Genotype-phenotype correlation in contactin-associated protein-like 2 (CNTNAP-2) developmental disorder
Abstract
Contactin-associated protein-like 2 (CNTNAP2) gene encodes for CASPR2, a presynaptic type 1 transmembrane protein, involved in cell–cell adhesion and synaptic interactions. Biallelic CNTNAP2 loss has been associated with “Pitt-Hopkins-like syndrome-1” (MIM#610042), while the pathogenic role of heterozygous variants remains controversial. We report 22 novel patients harboring mono- (n = 2) and bi-allelic (n = 20) CNTNAP2 variants and carried out a literature review to characterize the genotype–phenotype correlation. Patients (M:F 14:8) were aged between 3 and 19 years and affected by global developmental delay (GDD) (n = 21), moderate to profound intellectual disability (n = 17) and epilepsy (n = 21). Seizures mainly started in the first two years of life (median 22.5 months). Antiseizure medications were successful in controlling the seizures in about two-thirds of the patients. Autism spectrum disorder (ASD) and/or other neuropsychiatric comorbidities were present in nine patients (40.9%). Nonspecific midline brain anomalies were noted in most patients while focal signal abnormalities in the temporal lobes were noted in three subjects. Genotype–phenotype correlation was performed by also including 50 previously published patients (15 mono- and 35 bi-allelic variants). Overall, GDD (p < 0.0001), epilepsy (p < 0.0001), hyporeflexia (p = 0.012), ASD (p = 0.009), language impairment (p = 0.020) and severe cognitive impairment (p = 0.031) were significantly associated with the presence of biallelic versus monoallelic variants. We have defined the main features associated with biallelic CNTNAP2 variants, as severe cognitive impairment, epilepsy and behavioral abnormalities. We propose CASPR2-deficiency neurodevelopmental disorder as an exclusively recessive disease while the contribution of heterozygous variants is less likely to follow an autosomal dominant inheritance pattern.
Citation
D'Onofrio , G , Accogli , A , Severino , M , Caliskan , H , Kokotović , T , Blazekovic , A , Jercic , K G , Markovic , S , Zigman , T , Goran , K , Barišić , N , Duranovic , V , Ban , A , Borovecki , F , Ramadža , D P , Barić , I , Fazeli , W , Herkenrath , P , Marini , C , Vittorini , R , Gowda , V , Bouman , A , Rocca , C , Alkhawaja , I A , Murtaza , B N , Rehman , M M U , Al Alam , C , Nader , G , Mancardi , M M , Giacomini , T , Srivastava , S , Alvi , J R , Tomoum , H , Matricardi , S , Iacomino , M , Riva , A , Scala , M , Madia , F , Pistorio , A , Salpietro , V , Minetti , C , Rivière , J-B , Srour , M , Efthymiou , S , Maroofian , R , Houlden , H , Vernes , S C , Zara , F , Striano , P & Nagy , V 2023 , ' Genotype-phenotype correlation in contactin-associated protein-like 2 ( CNTNAP-2 ) developmental disorder ' , Human Genetics . https://doi.org/10.1007/s00439-023-02552-2
Publication
Human Genetics
Status
Peer reviewed
ISSN
0340-6717Type
Journal article
Rights
Copyright © The Author(s) 2023. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Description
Funding: Open access funding provided by Università degli Studi di Genova within the CRUI-CARE Agreement. SS receives funding from the National Institutes of Health National Institute of Neurological Disorders and Stroke (K23NS119666). VN is supported by the Ludwig Boltzmann Gesellschaft core funding, the Austrian Science Fund (FWF): P 32924 and TAI 202 1000 Ideas Project.Collections
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