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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

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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