Novel Digital Anomalies, Hippocampal Atrophy, and Mutations Expand the Genotypic and Phenotypic Spectra of <scp><i>CNKSR2</i></scp> in the Houge Type of X‐Linked Syndromic Intellectual Development Disorder (<scp>MRXSHG</scp>)

The Houge type of X-linked syndromic intellectual developmental disorder (MRXSHG) encompasses a spectrum of neurodevelopmental disorders characterized by intellectual disability (ID), language/speech delay, attention issues, and epilepsy. These conditions arise from hemizygous or heterozygous deletions, along with point mutations, affecting CNKSR2, a gene located at Xp22.12. CNKSR2, also known as CNK2 or MAGUIN, functions as a synaptic scaffolding molecule within the neuronal postsynaptic density (PSD) of the central nervous system. It acts as a link connecting postsynaptic structural proteins, such as PSD95 and S-SCAM, by employing multiple functional domains crucial for synaptic signaling and protein-protein interactions. Predominantly expressed in dendrites, CNKSR2 is vital for dendritic spine morphogenesis in hippocampal neurons. Its loss-of-function variants result in reduced PSD size and impaired hippocampal development, affecting processes including neuronal proliferation, migration, and synaptogenesis. We present 15 patients including three from the MENA (Middle East and North Africa), a region with no documented mutations in CNKSR2. Each individual displays unique clinical presentations that encompass developmental delay, ID, language/speech delay, epilepsy, and autism. Genetic analyses revealed 14 distinct variants in CNKSR2, comprising five nonsense, three frameshift, two splice, and four missense variants, of which 13 are novel. The ACMG guidelines unanimously interpreted these 14 variants in 15 individuals as pathogenic, highlighting the detrimental impact of these CNKSR2 genetic alterations and confirming the molecular diagnosis of MRXSHG. Importantly, variants Ser767Phe and Ala827Pro may lead to proteasomal degradation or reduced PSD size, contributing to the neurodevelopmental phenotype. Furthermore, these two amino acids, along with another two affected by four missense variants, exhibit complete conservation in nine vertebrate species, illuminating their crucial role in the gene's functionality. Our study revealed unique new digital and brain phenotype, including pointed fingertips (fetal pads of fingertips), syndactyly, tapering fingers, and hippocampal atrophy. These novel clinical features in MRXSHG, combined with 13 novel variants, expand the phenotypic and genotypic spectra of MRXSHG associated with CNKSR2 mutations.

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American Journal of Medical Genetics Part A
Published
2024-12-20
DOI
https://doi.org/10.1002/ajmg.a.63963
Primary Topic
Genetics and Neurodevelopmental Disorders
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article
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article

Novel Digital Anomalies, Hippocampal Atrophy, and Mutations Expand the Genotypic and Phenotypic Spectra of CNKSR2 in the Houge Type of X‐Linked Syndromic Intellectual Development Disorder (MRXSHG)

Konrad Platzer, Maria T. Papadopoulou, Afif Ben‐Mahmoud, Periyasamy Radhakrishnan et al.
American Journal of Medical Genetics Part A
Genetics and Neurodevelopmental Disorders
article

Novel Digital Anomalies, Hippocampal Atrophy, and Mutations Expand the Genotypic and Phenotypic Spectra of CNKSR2 in the Houge Type of X‐Linked Syndromic Intellectual Development Disorder (MRXSHG)

Konrad Platzer, Maria T. Papadopoulou, Afif Ben‐Mahmoud, Periyasamy Radhakrishnan, Sheela Nampoothiri, Alexis A. Arzimanoglou, Massimiliano Rossi, Seyed Hassan Tonekaboni, Teresa Gonçalves, Stephanie Spranger, Gaëtan Lesca, Kathrin Grundmann‐Hauser, Eleni Panagiotakaki, Hossein Sadeghi, Ulrich Pfeifer, Hyung‐Goo Kim, Sahand Tehrani Fateh, Yves Lacassie, Reza Mirfakhraie, Mi‐Hyeon Jang, Mohammad‐Reza Ghasemi, Lawrence C. Layman, Vijay Gupta, Patrick Edery, Lara G. Stühn, Sahar Alijanpour, Nicolas Chatron, Heidi L. Schulz, Bertrand Isidor, Benjamin Cogné, Tobias B. Haack, Georg Christoph Korenke, Mohammad Miryounesi, Steffen Syrbe, Ilona Krauspe‐Stübecke
article en

Abstract

The Houge type of X-linked syndromic intellectual developmental disorder (MRXSHG) encompasses a spectrum of neurodevelopmental disorders characterized by intellectual disability (ID), language/speech delay, attention issues, and epilepsy. These conditions arise from hemizygous or heterozygous deletions, along with point mutations, affecting CNKSR2, a gene located at Xp22.12. CNKSR2, also known as CNK2 or MAGUIN, functions as a synaptic scaffolding molecule within the neuronal postsynaptic density (PSD) of the central nervous system. It acts as a link connecting postsynaptic structural proteins, such as PSD95 and S-SCAM, by employing multiple functional domains crucial for synaptic signaling and protein-protein interactions. Predominantly expressed in dendrites, CNKSR2 is vital for dendritic spine morphogenesis in hippocampal neurons. Its loss-of-function variants result in reduced PSD size and impaired hippocampal development, affecting processes including neuronal proliferation, migration, and synaptogenesis. We present 15 patients including three from the MENA (Middle East and North Africa), a region with no documented mutations in CNKSR2. Each individual displays unique clinical presentations that encompass developmental delay, ID, language/speech delay, epilepsy, and autism. Genetic analyses revealed 14 distinct variants in CNKSR2, comprising five nonsense, three frameshift, two splice, and four missense variants, of which 13 are novel. The ACMG guidelines unanimously interpreted these 14 variants in 15 individuals as pathogenic, highlighting the detrimental impact of these CNKSR2 genetic alterations and confirming the molecular diagnosis of MRXSHG. Importantly, variants Ser767Phe and Ala827Pro may lead to proteasomal degradation or reduced PSD size, contributing to the neurodevelopmental phenotype. Furthermore, these two amino acids, along with another two affected by four missense variants, exhibit complete conservation in nine vertebrate species, illuminating their crucial role in the gene's functionality. Our study revealed unique new digital and brain phenotype, including pointed fingertips (fetal pads of fingertips), syndactyly, tapering fingers, and hippocampal atrophy. These novel clinical features in MRXSHG, combined with 13 novel variants, expand the phenotypic and genotypic spectra of MRXSHG associated with CNKSR2 mutations.

American Journal of Medical Genetics Part AVol. 197(5)
Université Claude Bernard Lyon 1 (FR), Rutgers, The State University of New Jersey (US), Louisiana State University (US), Amrita Institute of Medical Sciences and Research Centre (IN), Centre National de la Recherche Scientifique (FR), Hospital Sant Joan de Déu Barcelona (ES), Inserm (FR), Manipal Academy of Higher Education (IN), Université de Lyon (FR), Heidelberg University (DE), Augusta University (US), University Hospital Heidelberg (DE), Centre de Recherche en Neurosciences de Lyon (FR), Hospices Civils de Lyon (FR), Klinikum Oldenburg (DE), Praxis für Humangenetik Tübingen (DE), Institut du Thorax (FR), Hamad bin Khalifa University (QA), European Clinical Research Infrastructure Network (FR), Klinikum Bremen-Mitte (DE), Génétique Médicale & Génomique Fonctionelle (FR), Bethlehem Gesundheitszentrum Stolberg (DE), ERN EpiCARE (FR), Institut de Recerca Sant Joan de Déu, Shahid Beheshti University of Medical Sciences (IR), Tehran University of Medical Sciences (IR), Universitat de Barcelona (ES), Louisiana State University Health Sciences Center New Orleans (US), Kasturba Medical College, Manipal (IN), University of Tübingen (DE), Leipzig University (DE), Nantes Université (FR)
Louisiana State University, Kasturba Medical College, Manipal, Hamad Bin Khalifa University, Institut National de la Santé et de la Recherche Médicale, Khalifa University of Science, Technology and Research, Tehran University of Medical Sciences and Health Services, Centre National de la Recherche Scientifique, Universitat de Barcelona, Shahid Beheshti University of Medical Sciences, Université de Nantes, Universitätsklinikum Heidelberg, School of Medicine, Shahid Beheshti University of Medical Sciences, Qatar Biomedical Research Institute, Hamad Bin Khalifa University
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