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These conditions arise from hemizygous or heterozygous deletions, along with point mutations, affecting <jats:italic>CNKSR2<\/jats:italic>, 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\u2010SCAM, by employing multiple functional domains crucial for synaptic signaling and protein\u2013protein interactions. Predominantly expressed in dendrites, CNKSR2 is vital for dendritic spine morphogenesis in hippocampal neurons. Its loss\u2010of\u2010function 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 <jats:italic>CNKSR2<\/jats:italic>. Each individual displays unique clinical presentations that encompass developmental delay, ID, language\/speech delay, epilepsy, and autism. Genetic analyses revealed 14 distinct variants in <jats:italic>CNKSR2<\/jats:italic>, 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 <jats:italic>CNKSR2<\/jats:italic> 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 <jats:italic>CNKSR2<\/jats:italic> mutations.<\/jats:p>","DOI":"10.1002\/ajmg.a.63963","type":"journal-article","created":{"date-parts":[[2024,12,21]],"date-time":"2024-12-21T05:10:09Z","timestamp":1734757809000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["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\u2010Linked Syndromic Intellectual Development Disorder (<scp>MRXSHG<\/scp>)"],"prefix":"10.1002","volume":"197","author":[{"given":"Mohammad\u2010Reza","family":"Ghasemi","sequence":"first","affiliation":[{"name":"Department of Medical Genetics Faculty of Medicine, Shahid Beheshti University of Medical Sciences  Tehran Iran"},{"name":"Center for Comprehensive 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CHU Nantes  Nantes Cedex 1 France"},{"name":"Universit\u00e9 de Nantes, CNRS, INSERM, l'institut du thorax  Nantes France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin","family":"Cogn\u00e9","sequence":"additional","affiliation":[{"name":"Service de G\u00e9n\u00e9tique M\u00e9dicale, CHU Nantes  Nantes Cedex 1 France"},{"name":"Universit\u00e9 de Nantes, CNRS, INSERM, l'institut du thorax  Nantes France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heidi L.","family":"Schulz","sequence":"additional","affiliation":[{"name":"Zentrum f\u00fcr Humangenetik T\u00fcbingen  T\u00fcbingen Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ilona","family":"Krauspe\u2010St\u00fcbecke","sequence":"additional","affiliation":[{"name":"Bethlehem Health Center Department of Pediatrics and Adolescent Medicine 5  Stolberg 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