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Review
. 2023 Jul;142(7):909-925.
doi: 10.1007/s00439-023-02552-2. Epub 2023 May 14.

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

Gianluca D'Onofrio #  1 , Andrea Accogli #  2   3 , Mariasavina Severino  4 , Haluk Caliskan  5 , Tomislav Kokotović  5   6 , Antonela Blazekovic  7 , Kristina Gotovac Jercic  7   8 , Silvana Markovic  9 , Tamara Zigman  10 , Krnjak Goran  11 , Nina Barišić  10 , Vlasta Duranovic  12 , Ana Ban  12 , Fran Borovecki  7   8 , Danijela Petković Ramadža  10 , Ivo Barić  10 , Walid Fazeli  13 , Peter Herkenrath  13 , Carla Marini  14 , Roberta Vittorini  15 , Vykuntaraju Gowda  16 , Arjan Bouman  17 , Clarissa Rocca  18 , Issam Azmi Alkhawaja  19 , Bibi Nazia Murtaza  20 , Malik Mujaddad Ur Rehman  21 , Chadi Al Alam  22 , Gisele Nader  22 , Maria Margherita Mancardi  23 , Thea Giacomini  23 , Siddharth Srivastava  24 , Javeria Raza Alvi  25 , Hoda Tomoum  26 , Sara Matricardi  27 , Michele Iacomino  28 , Antonella Riva  1 , Marcello Scala  1 , Francesca Madia  28 , Angela Pistorio  29 , Vincenzo Salpietro  17 , Carlo Minetti  1 , Jean-Baptiste Rivière  30   31 , Myriam Srour  32   33 , Stephanie Efthymiou  17 , Reza Maroofian  17 , Henry Houlden  17 , Sonja Catherine Vernes  34   35 , Federico Zara  1   27 , Pasquale Striano  36   37 , Vanja Nagy  38   39
Affiliations
Review

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

Gianluca D'Onofrio et al. Hum Genet. 2023 Jul.

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.

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Conflict of interest statement

The authors have no relevant financial or non-financial interests to disclose.

Figures

Fig. 1
Fig. 1
a Ind- 5, -6, -7, -8, -12, -14, -15, -16 and -17 iconography is shown (from left to right). Common facial dysmorphisms are shown including prominent ears (Ind-6 and Ind-7) and hypertelorism (Ind-6, Ind-12). Ind-7 shows mild ptosis of the left eyelid. Ind-14 presents with lips thickness, prognathism, and prominent philtrum. A lean, elongated face with mild lax skin is observed in Ind-15. Ind-17 has sparse hair. No noticeable dysmorphisms are appreciable in Ind-5, Ind-8, Ind-16 and Ind-17. b Brain MRI findings of the patients and a control; sagittal T1-weighted (first) and coronal and/or axial T2-weighted (middle and/or last) images. Inferior cerebellar vermis hypoplasia is noted in all the cases included in the figure (thin arrows) associated with mild superior cerebellar vermis atrophy in Ind-3, Ind-8, Ind-12, and Ind-17 (empty arrowheads). A thin corpus callosum is present in Ind-2, Ind-13 and Ind-16, while a thick posterior corpus callosum is noted in Ind-3 and Ind-8 (empty arrows). Mild white matter volume reduction with consequent ventricular enlargement is noted in Ind-3, Ind-13 and Ind-16 (asterisks). Cerebellar dentate nuclei T2 hyperintensity is visible in Ind-6 and Ind-12 (arrowheads). In Ind-2, Ind-8 and Ind-12 there are additional uni- or bilateral T2 hyperintensities at the level of the anterior temporal lobes (thick arrows) in keeping with focal cortical dysplasias
Fig. 2
Fig. 2
EEG features. a. Ind-1, 10 years old. Sleep recording. High voltage bilateral anterior delta waves and focal spikes over the frontal regions of both hemispheres. b Ind-2, 2 years 9 months. Awake recording. Synchronous and asynchronous spikes on bilateral frontal–temporal regions. c Ind-10, 3 years old. Awake recording. Right central-temporal medium voltage sharp waves. d Ind-10, 3 years old. Sleep recording. Nearly sub-continuous trend of right central-temporal sharp waves in the N2 phase, with a tendency to spread
Fig. 3
Fig. 3
Summary of the key clinical features of patients carrying mono- or bi-allelic pathogenic CNTNAP2 variants in our cohort and the literature. ID intellectual disability, NPsy neuropsychiatric findings. Statistical significance refers to patients with biallelic versus monoallelic variants
Fig. 4
Fig. 4
CNTNAP2 variants position in our cohort (in bold, # individual) and previously published patients. The arrow indicates a deletion, and the line a duplication
See this image and copyright information in PMC

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