Genotype-phenotype correlation in contactin-associated protein-like 2 (CNTNAP-2) developmental disorder

Gianluca D'Onofrio; Andrea Accogli; Mariasavina Severino; Haluk Caliskan; Tomislav Kokotović; Antonela Blazekovic; Kristina Gotovac Jercic; Silvana Markovic; Tamara Zigman; Krnjak Goran; Nina Barišić; Vlasta Duranovic; Ana Ban; Fran Borovecki; Danijela Petković Ramadža; Ivo Barić; Walid Fazeli; Peter Herkenrath; Carla Marini; Roberta Vittorini; Vykuntaraju Gowda; Arjan Bouman; Clarissa Rocca; Issam Azmi Alkhawaja; Bibi Nazia Murtaza; Malik Mujaddad Ur Rehman; Chadi Al Alam; Gisele Nader; Maria Margherita Mancardi; Thea Giacomini; Siddharth Srivastava; Javeria Raza Alvi; Hoda Tomoum; Sara Matricardi; Michele Iacomino; Antonella Riva; Marcello Scala; Francesca Madia; Angela Pistorio; Vincenzo Salpietro; Carlo Minetti; Jean-Baptiste Rivière; Myriam Srour; Stephanie Efthymiou; Reza Maroofian; Henry Houlden; Sonja Catherine Vernes; Federico Zara; Pasquale Striano; Vanja Nagy

doi:10.1007/s00439-023-02552-2

Genotype-phenotype correlation in contactin-associated protein-like 2 (CNTNAP-2) developmental disorder

Gianluca D'Onofrio, Andrea Accogli, Mariasavina Severino, Haluk Caliskan, Tomislav Kokotović, Antonela Blazekovic, Kristina Gotovac Jercic, Silvana Markovic, Tamara Zigman, Krnjak Goran, Nina Barišić, Vlasta Duranovic, Ana Ban, Fran Borovecki, Danijela Petković Ramadža, Ivo Barić, Walid Fazeli, Peter Herkenrath, Carla Marini, Roberta VittoriniVykuntaraju Gowda, Arjan Bouman, Clarissa Rocca, Issam Azmi Alkhawaja, Bibi Nazia Murtaza, Malik Mujaddad Ur Rehman, Chadi Al Alam, Gisele Nader, Maria Margherita Mancardi, Thea Giacomini, Siddharth Srivastava, Javeria Raza Alvi, Hoda Tomoum, Sara Matricardi, Michele Iacomino, Antonella Riva, Marcello Scala, Francesca Madia, Angela Pistorio, Vincenzo Salpietro, Carlo Minetti, Jean-Baptiste Rivière, Myriam Srour, Stephanie Efthymiou, Reza Maroofian, Henry Houlden, Sonja Catherine Vernes, Federico Zara, Pasquale Striano^*, Vanja Nagy^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Number of pages	17
Journal	Human Genetics
DOIs	https://doi.org/10.1007/s00439-023-02552-2
Publication status	Published - 14 May 2023

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Sonja Vernes UKRI Future Leaders: Mammalian vocal communication as a model for human language; from genes and brains to behaviour
Vernes, S. (PI)
UK Research and Innovation
1/11/20 → 31/10/25
Project: Fellowship

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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., ... 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

@article{bb6444e3795249d382f09687a60343aa,

title = "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.",

author = "Gianluca D'Onofrio and Andrea Accogli and Mariasavina Severino and Haluk Caliskan and Tomislav Kokotovi{\'c} and Antonela Blazekovic and Jercic, {Kristina Gotovac} and Silvana Markovic and Tamara Zigman and Krnjak Goran and Nina Bari{\v s}i{\'c} and Vlasta Duranovic and Ana Ban and Fran Borovecki and Ramad{\v z}a, {Danijela Petkovi{\'c}} and Ivo Bari{\'c} and Walid Fazeli and Peter Herkenrath and Carla Marini and Roberta Vittorini and Vykuntaraju Gowda and Arjan Bouman and Clarissa Rocca and Alkhawaja, {Issam Azmi} and Murtaza, {Bibi Nazia} and Rehman, {Malik Mujaddad Ur} and {Al Alam}, Chadi and Gisele Nader and Mancardi, {Maria Margherita} and Thea Giacomini and Siddharth Srivastava and Alvi, {Javeria Raza} and Hoda Tomoum and Sara Matricardi and Michele Iacomino and Antonella Riva and Marcello Scala and Francesca Madia and Angela Pistorio and Vincenzo Salpietro and Carlo Minetti and Jean-Baptiste Rivi{\`e}re and Myriam Srour and Stephanie Efthymiou and Reza Maroofian and Henry Houlden and Vernes, {Sonja Catherine} and Federico Zara and Pasquale Striano and Vanja Nagy",

note = "Funding: Open access funding provided by Universit{\`a} 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.",

year = "2023",

month = may,

day = "14",

doi = "10.1007/s00439-023-02552-2",

language = "English",

journal = "Human Genetics",

issn = "0340-6717",

publisher = "Springer-Verlag",

}

D'Onofrio, G, Accogli, A, Severino, M, Caliskan, H, Kokotović, T, Blazekovic, A, Jercic, KG, Markovic, S, Zigman, T, Goran, K, Barišić, N, Duranovic, V, Ban, A, Borovecki, F, Ramadža, DP, Barić, I, Fazeli, W, Herkenrath, P, Marini, C, Vittorini, R, Gowda, V, Bouman, A, Rocca, C, Alkhawaja, IA, Murtaza, BN, Rehman, MMU, Al Alam, C, Nader, G, Mancardi, MM, Giacomini, T, Srivastava, S, Alvi, JR, 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, SC, 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

TY - JOUR

T1 - Genotype-phenotype correlation in contactin-associated protein-like 2 (CNTNAP-2) developmental disorder

AU - D'Onofrio, Gianluca

AU - Accogli, Andrea

AU - Severino, Mariasavina

AU - Caliskan, Haluk

AU - Kokotović, Tomislav

AU - Blazekovic, Antonela

AU - Jercic, Kristina Gotovac

AU - Markovic, Silvana

AU - Zigman, Tamara

AU - Goran, Krnjak

AU - Barišić, Nina

AU - Duranovic, Vlasta

AU - Ban, Ana

AU - Borovecki, Fran

AU - Ramadža, Danijela Petković

AU - Barić, Ivo

AU - Fazeli, Walid

AU - Herkenrath, Peter

AU - Marini, Carla

AU - Vittorini, Roberta

AU - Gowda, Vykuntaraju

AU - Bouman, Arjan

AU - Rocca, Clarissa

AU - Alkhawaja, Issam Azmi

AU - Murtaza, Bibi Nazia

AU - Rehman, Malik Mujaddad Ur

AU - Al Alam, Chadi

AU - Nader, Gisele

AU - Mancardi, Maria Margherita

AU - Giacomini, Thea

AU - Srivastava, Siddharth

AU - Alvi, Javeria Raza

AU - Tomoum, Hoda

AU - Matricardi, Sara

AU - Iacomino, Michele

AU - Riva, Antonella

AU - Scala, Marcello

AU - Madia, Francesca

AU - Pistorio, Angela

AU - Salpietro, Vincenzo

AU - Minetti, Carlo

AU - Rivière, Jean-Baptiste

AU - Srour, Myriam

AU - Efthymiou, Stephanie

AU - Maroofian, Reza

AU - Houlden, Henry

AU - Vernes, Sonja Catherine

AU - Zara, Federico

AU - Striano, Pasquale

AU - Nagy, Vanja

N1 - 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.

PY - 2023/5/14

Y1 - 2023/5/14

N2 - 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.

AB - 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.

U2 - 10.1007/s00439-023-02552-2

DO - 10.1007/s00439-023-02552-2

M3 - Article

C2 - 37183190

SN - 0340-6717

JO - Human Genetics

JF - Human Genetics

ER -

Genotype-phenotype correlation in contactin-associated protein-like 2 (CNTNAP-2) developmental disorder

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Sonja Vernes UKRI Future Leaders: Mammalian vocal communication as a model for human language; from genes and brains to behaviour

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