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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) Publisher Pubmed



Ghasemi MR1, 2 ; Fateh ST2, 3 ; Benmahmoud A4 ; Gupta V4 ; Stuhn LG5 ; Lesca G6, 7 ; Chatron N6, 7 ; Platzer K8 ; Edery P6, 9 ; Sadeghi H10 ; Isidor B11, 12 ; Cogne B11, 12 ; Schulz HL13 ; Krauspestubecke I14 Show All Authors
Authors
  1. Ghasemi MR1, 2
  2. Fateh ST2, 3
  3. Benmahmoud A4
  4. Gupta V4
  5. Stuhn LG5
  6. Lesca G6, 7
  7. Chatron N6, 7
  8. Platzer K8
  9. Edery P6, 9
  10. Sadeghi H10
  11. Isidor B11, 12
  12. Cogne B11, 12
  13. Schulz HL13
  14. Krauspestubecke I14
  15. Periyasamy R15
  16. Nampoothiri S16
  17. Mirfakhraie R1
  18. Alijanpour S1
  19. Syrbe S17
  20. Pfeifer U18
  21. Spranger S19
  22. Grundmannhauser K5, 20
  23. Haack TB5, 20
  24. Papadopoulou MT21
  25. Da Silva Goncalves T21
  26. Panagiotakaki E21
  27. Arzimanoglou A21, 22
  28. Tonekaboni SH23
  29. Rossi M9, 24
  30. Korenke GC25
  31. Lacassie Y26
  32. Jang MH27
  33. Layman LC28, 29
  34. Miryounesi M1, 2
  35. Kim HG4, 27
Show Affiliations
Authors Affiliations
  1. 1. Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  2. 2. Center for Comprehensive Genetic Services, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  3. 3. Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
  4. 4. Neurological Disorders Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Doha, Qatar
  5. 5. Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany
  6. 6. Department of Medical Genetics, Member of the ERN EpiCARE, University Hospitals of Lyon (HCL), Lyon, France, Lyon, France
  7. 7. University Claude Bernard Lyon 1, Lyon, France
  8. 8. Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany
  9. 9. GENDEV Team, INSERM U1028, CNRS UMR5292, Lyon Neuroscience Research Centre, Lyon, France
  10. 10. Genomic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  11. 11. Service de Genetique Medicale, CHU Nantes, Nantes Cedex 1, France
  12. 12. Universite de Nantes, CNRS, INSERM, l'institut du thorax, Nantes, France
  13. 13. Zentrum fur Humangenetik Tubingen, Tubingen, Germany
  14. 14. Bethlehem Health Center Department of Pediatrics and Adolescent Medicine 5, Stolberg, Germany
  15. 15. Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
  16. 16. Department of Pediatric Genetics, Amrita Institute of Medical Sciences & Research Centre, Cochin, India
  17. 17. Division for Pediatric Epileptology, Heidelberg University Hospital, Heidelberg, Germany
  18. 18. Division of Child Neurology and Metabolic Medicine, Center for Child and Adolescent Medicine, Heidelberg University Hospital, Heidelberg, Germany
  19. 19. Praxis fuer Humangenetik, Klinikum Bremen-Mitte, Bremen, Germany
  20. 20. Centre for Rare Diseases, University of Tuebingen, Tuebingen, Germany
  21. 21. Department of Paediatric Clinical Epileptology, Sleep Disorders and Functional Neurology, University Hospitals of Lyon (HCL), Member of the European Reference Network (ERN) EpiCARE, France
  22. 22. Sant Joan De Deu Children's Hospital, Member of the ERN EpiCARE, University of Barcelona, Institut de Recerca Sant Joan de Deu, Spain
  23. 23. Pediatric Neurology Excellence Center, Pediatric Neurology Department, Mofid Children Hospital, Faculty of Medicine, Shahid Beheshti University of Medical Sciences (SBMU), Tehran, Iran
  24. 24. Department of Genetics, Lyon University Hospitals, Lyon, France
  25. 25. Department of Neuropediatrics, University Children's Hospital, Klinikum Oldenburg, Oldenburg, Germany
  26. 26. Division of Genetics, Department of Pediatrics, Louisiana State University Health Science Center and Children's Hospital, New Orleans, LA, United States
  27. 27. Department of Neurosurgery, Robert Wood Johnson Medical School, Rutgers University, the State University of New Jersey, Piscataway, NJ, United States
  28. 28. Section of Reproductive Endocrinology, Infertility & Genetics, Department of Obstetrics & Gynecology, Augusta University, Augusta, GA, United States
  29. 29. Department of Neuroscience and Regenerative Medicine, Augusta University, Augusta, GA, United States

Source: American Journal of Medical Genetics, Part A Published:2025


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. © 2024 The Author(s). American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.
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