Genotype–phenotype correlation in contactin-associated protein-like 2 (CNTNAP-2) developmental disorder
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Published:2023-05-14
Issue:7
Volume:142
Page:909-925
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ISSN:0340-6717
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Container-title:Human Genetics
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language:en
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Short-container-title:Hum Genet
Author:
D’Onofrio Gianluca, Accogli Andrea, Severino Mariasavina, Caliskan Haluk, Kokotović Tomislav, Blazekovic Antonela, Jercic Kristina Gotovac, Markovic Silvana, Zigman Tamara, Goran Krnjak, Barišić Nina, Duranovic Vlasta, Ban Ana, Borovecki Fran, Ramadža Danijela Petković, Barić Ivo, Fazeli Walid, Herkenrath Peter, Marini Carla, Vittorini Roberta, Gowda Vykuntaraju, Bouman Arjan, Rocca Clarissa, Alkhawaja Issam Azmi, Murtaza Bibi Nazia, Rehman Malik Mujaddad Ur, Al Alam Chadi, Nader Gisele, Mancardi Maria Margherita, Giacomini Thea, Srivastava Siddharth, Alvi Javeria Raza, Tomoum Hoda, Matricardi Sara, Iacomino Michele, Riva Antonella, Scala Marcello, Madia Francesca, Pistorio Angela, Salpietro Vincenzo, Minetti Carlo, Rivière Jean-Baptiste, Srour Myriam, Efthymiou Stephanie, Maroofian Reza, Houlden Henry, Vernes Sonja Catherine, Zara Federico, Striano Pasquale, Nagy VanjaORCID
Abstract
AbstractContactin-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.
Funder
Università degli Studi di Genova
Publisher
Springer Science and Business Media LLC
Subject
Genetics (clinical),Genetics
Reference45 articles.
1. Alarcón M, Abrahams BS, Stone JL, Duvall JA, Perederiy JV, Bomar JM, Sebat J, Wigler M, Martin CL, Ledbetter DH, Nelson SF, Cantor RM, Geschwind DH (2008) Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene. Am J Hum Genet 82(1):150–159. https://doi.org/10.1016/j.ajhg.2007.09.005 2. Al-Murrani A, Ashton F, Aftimos S, George AM, Love DR (2012) Amino-terminal microdeletion within the CNTNAP2 gene associated with variable expressivity of speech delay. Case Rep Genet 2012:172408. https://doi.org/10.1155/2012/172408 3. Anderson GR, Galfin T, Xu W, Aoto J, Malenka RC, Südhof TC (2012) Candidate autism gene screen identifies critical role for cell-adhesion molecule CASPR2 in dendritic arborization and spine development. Proc Natl Acad Sci USA 109(44):18120–18125. https://doi.org/10.1073/pnas.1216398109 4. Arking DE, Cutler DJ, Brune CW, Teslovich TM, West K, Ikeda M, Rea A, Guy M, Lin S, Cook EH, Chakravarti A (2008) A common genetic variant in the neurexin superfamily member CNTNAP2 increases familial risk of autism. Am J Hum Genet 82(1):160–164. https://doi.org/10.1016/j.ajhg.2007.09.015 5. Badshah N, Mattison KA, Ahmad S, Chopra P, Johnston HR, Ahmad S, Khan SH, Sarwar MT, Cutler DJ, Taylor M, Vadlamani G, Zwick ME, Escayg A (2022) Novel missense CNTNAP2 variant identified in two consanguineous Pakistani families with developmental delay, epilepsy, intellectual disability, and aggressive behavior. Front Neurol 13:918022. https://doi.org/10.3389/fneur.2022.918022
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