TY - JOUR
T1 - 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)
AU - Ghasemi, Mohammad Reza
AU - Fateh, Sahand Tehrani
AU - Ben-Mahmoud, Afif
AU - Gupta, Vijay
AU - Stühn, Lara G.
AU - Lesca, Gaetan
AU - Chatron, Nicolas
AU - Platzer, Konrad
AU - Edery, Patrick
AU - Sadeghi, Hossein
AU - Isidor, Bertrand
AU - Cogné, Benjamin
AU - Schulz, Heidi L.
AU - Krauspe-Stübecke, Ilona
AU - Periyasamy, Radhakrishnan
AU - Nampoothiri, Sheela
AU - Mirfakhraie, Reza
AU - Alijanpour, Sahar
AU - Syrbe, Steffen
AU - Pfeifer, Ulrich
AU - Spranger, Stephanie
AU - Grundmann-Hauser, Kathrin
AU - Haack, Tobias B.
AU - Papadopoulou, Maria T.
AU - da Silva Gonçalves, Tayrine
AU - Panagiotakaki, Eleni
AU - Arzimanoglou, Alexis
AU - Tonekaboni, Seyed Hassan
AU - Rossi, Massimiliano
AU - Korenke, G. Christoph
AU - Lacassie, Yves
AU - Jang, Mi Hyeon
AU - Layman, Lawrence C.
AU - Miryounesi, Mohammad
AU - Kim, Hyung Goo
N1 - Publisher Copyright:
© 2024 The Author(s). American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.
PY - 2024/12/20
Y1 - 2024/12/20
N2 - 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.
AB - 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.
KW - Autism
KW - Cnksr2
KW - Cyth2
KW - Hippocampal atrophy
KW - Intellectual disability
KW - Mrxshg
KW - Pointed fingertips
KW - Psd
KW - Syndactyly
KW - Tapering fingers
UR - http://www.scopus.com/inward/record.url?scp=85212684301&partnerID=8YFLogxK
U2 - 10.1002/ajmg.a.63963
DO - 10.1002/ajmg.a.63963
M3 - Article
AN - SCOPUS:85212684301
SN - 1552-4825
JO - American Journal of Medical Genetics, Part A
JF - American Journal of Medical Genetics, Part A
ER -