Cargando…
Genotype–phenotype correlation in contactin-associated protein-like 2 (CNTNAP-2) developmental disorder
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 heter...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Berlin Heidelberg
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10329570/ https://www.ncbi.nlm.nih.gov/pubmed/37183190 http://dx.doi.org/10.1007/s00439-023-02552-2 |
_version_ | 1785070046691721216 |
---|---|
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, Vanja |
author_facet | 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, Vanja |
author_sort | D’Onofrio, Gianluca |
collection | PubMed |
description | 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00439-023-02552-2. |
format | Online Article Text |
id | pubmed-10329570 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-103295702023-07-10 Genotype–phenotype correlation in contactin-associated protein-like 2 (CNTNAP-2) developmental disorder 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, Vanja Hum Genet Original Investigation 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00439-023-02552-2. Springer Berlin Heidelberg 2023-05-14 2023 /pmc/articles/PMC10329570/ /pubmed/37183190 http://dx.doi.org/10.1007/s00439-023-02552-2 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access 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/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Original Investigation 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, Vanja Genotype–phenotype correlation in contactin-associated protein-like 2 (CNTNAP-2) developmental disorder |
title | Genotype–phenotype correlation in contactin-associated protein-like 2 (CNTNAP-2) developmental disorder |
title_full | Genotype–phenotype correlation in contactin-associated protein-like 2 (CNTNAP-2) developmental disorder |
title_fullStr | Genotype–phenotype correlation in contactin-associated protein-like 2 (CNTNAP-2) developmental disorder |
title_full_unstemmed | Genotype–phenotype correlation in contactin-associated protein-like 2 (CNTNAP-2) developmental disorder |
title_short | Genotype–phenotype correlation in contactin-associated protein-like 2 (CNTNAP-2) developmental disorder |
title_sort | genotype–phenotype correlation in contactin-associated protein-like 2 (cntnap-2) developmental disorder |
topic | Original Investigation |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10329570/ https://www.ncbi.nlm.nih.gov/pubmed/37183190 http://dx.doi.org/10.1007/s00439-023-02552-2 |
work_keys_str_mv | AT donofriogianluca genotypephenotypecorrelationincontactinassociatedproteinlike2cntnap2developmentaldisorder AT accogliandrea genotypephenotypecorrelationincontactinassociatedproteinlike2cntnap2developmentaldisorder AT severinomariasavina genotypephenotypecorrelationincontactinassociatedproteinlike2cntnap2developmentaldisorder AT caliskanhaluk genotypephenotypecorrelationincontactinassociatedproteinlike2cntnap2developmentaldisorder AT kokotovictomislav genotypephenotypecorrelationincontactinassociatedproteinlike2cntnap2developmentaldisorder AT blazekovicantonela genotypephenotypecorrelationincontactinassociatedproteinlike2cntnap2developmentaldisorder AT jercickristinagotovac genotypephenotypecorrelationincontactinassociatedproteinlike2cntnap2developmentaldisorder AT markovicsilvana genotypephenotypecorrelationincontactinassociatedproteinlike2cntnap2developmentaldisorder AT zigmantamara genotypephenotypecorrelationincontactinassociatedproteinlike2cntnap2developmentaldisorder AT gorankrnjak genotypephenotypecorrelationincontactinassociatedproteinlike2cntnap2developmentaldisorder AT barisicnina genotypephenotypecorrelationincontactinassociatedproteinlike2cntnap2developmentaldisorder AT duranovicvlasta genotypephenotypecorrelationincontactinassociatedproteinlike2cntnap2developmentaldisorder AT banana genotypephenotypecorrelationincontactinassociatedproteinlike2cntnap2developmentaldisorder AT boroveckifran genotypephenotypecorrelationincontactinassociatedproteinlike2cntnap2developmentaldisorder AT ramadzadanijelapetkovic genotypephenotypecorrelationincontactinassociatedproteinlike2cntnap2developmentaldisorder AT baricivo genotypephenotypecorrelationincontactinassociatedproteinlike2cntnap2developmentaldisorder AT fazeliwalid genotypephenotypecorrelationincontactinassociatedproteinlike2cntnap2developmentaldisorder AT herkenrathpeter genotypephenotypecorrelationincontactinassociatedproteinlike2cntnap2developmentaldisorder AT marinicarla genotypephenotypecorrelationincontactinassociatedproteinlike2cntnap2developmentaldisorder AT vittoriniroberta genotypephenotypecorrelationincontactinassociatedproteinlike2cntnap2developmentaldisorder AT gowdavykuntaraju genotypephenotypecorrelationincontactinassociatedproteinlike2cntnap2developmentaldisorder AT boumanarjan genotypephenotypecorrelationincontactinassociatedproteinlike2cntnap2developmentaldisorder AT roccaclarissa genotypephenotypecorrelationincontactinassociatedproteinlike2cntnap2developmentaldisorder AT alkhawajaissamazmi genotypephenotypecorrelationincontactinassociatedproteinlike2cntnap2developmentaldisorder AT murtazabibinazia genotypephenotypecorrelationincontactinassociatedproteinlike2cntnap2developmentaldisorder AT rehmanmalikmujaddadur genotypephenotypecorrelationincontactinassociatedproteinlike2cntnap2developmentaldisorder AT alalamchadi genotypephenotypecorrelationincontactinassociatedproteinlike2cntnap2developmentaldisorder AT nadergisele genotypephenotypecorrelationincontactinassociatedproteinlike2cntnap2developmentaldisorder AT mancardimariamargherita genotypephenotypecorrelationincontactinassociatedproteinlike2cntnap2developmentaldisorder AT giacominithea genotypephenotypecorrelationincontactinassociatedproteinlike2cntnap2developmentaldisorder AT srivastavasiddharth genotypephenotypecorrelationincontactinassociatedproteinlike2cntnap2developmentaldisorder AT alvijaveriaraza genotypephenotypecorrelationincontactinassociatedproteinlike2cntnap2developmentaldisorder AT tomoumhoda genotypephenotypecorrelationincontactinassociatedproteinlike2cntnap2developmentaldisorder AT matricardisara genotypephenotypecorrelationincontactinassociatedproteinlike2cntnap2developmentaldisorder AT iacominomichele genotypephenotypecorrelationincontactinassociatedproteinlike2cntnap2developmentaldisorder AT rivaantonella genotypephenotypecorrelationincontactinassociatedproteinlike2cntnap2developmentaldisorder AT scalamarcello genotypephenotypecorrelationincontactinassociatedproteinlike2cntnap2developmentaldisorder AT madiafrancesca genotypephenotypecorrelationincontactinassociatedproteinlike2cntnap2developmentaldisorder AT pistorioangela genotypephenotypecorrelationincontactinassociatedproteinlike2cntnap2developmentaldisorder AT salpietrovincenzo genotypephenotypecorrelationincontactinassociatedproteinlike2cntnap2developmentaldisorder AT minetticarlo genotypephenotypecorrelationincontactinassociatedproteinlike2cntnap2developmentaldisorder AT rivierejeanbaptiste genotypephenotypecorrelationincontactinassociatedproteinlike2cntnap2developmentaldisorder AT srourmyriam genotypephenotypecorrelationincontactinassociatedproteinlike2cntnap2developmentaldisorder AT efthymioustephanie genotypephenotypecorrelationincontactinassociatedproteinlike2cntnap2developmentaldisorder AT maroofianreza genotypephenotypecorrelationincontactinassociatedproteinlike2cntnap2developmentaldisorder AT houldenhenry genotypephenotypecorrelationincontactinassociatedproteinlike2cntnap2developmentaldisorder AT vernessonjacatherine genotypephenotypecorrelationincontactinassociatedproteinlike2cntnap2developmentaldisorder AT zarafederico genotypephenotypecorrelationincontactinassociatedproteinlike2cntnap2developmentaldisorder AT strianopasquale genotypephenotypecorrelationincontactinassociatedproteinlike2cntnap2developmentaldisorder AT nagyvanja genotypephenotypecorrelationincontactinassociatedproteinlike2cntnap2developmentaldisorder |