CCDC82 and neurodevelopment: a novel genetic variant linked to infantile spasms and hypotonia
Abstract Background Neurodevelopmental disorders (NDDs) are a heterogeneous group of conditions characterized by impairments in motor, cognitive, and behavioral functions. Despite advances in genomic sequencing, the genetic basis of many NDDs remains unexplored. CCDC82 encodes a coiled-coil domain-c...
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BMC
2025-08-01
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| Series: | BMC Medical Genomics |
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| Online Access: | https://doi.org/10.1186/s12920-025-02201-9 |
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| author | Zahra Safarian Shiva Mehrabi Arghavan Rakhshani Nejad Sajad Alavimanesh Pegah Kavousinia Mohammad Hossein Shushizadeh Seyedeh Faezeh Hassani Latifeh Onagh Abdolazim Sarli Nahid Rezaie |
| author_facet | Zahra Safarian Shiva Mehrabi Arghavan Rakhshani Nejad Sajad Alavimanesh Pegah Kavousinia Mohammad Hossein Shushizadeh Seyedeh Faezeh Hassani Latifeh Onagh Abdolazim Sarli Nahid Rezaie |
| author_sort | Zahra Safarian |
| collection | DOAJ |
| description | Abstract Background Neurodevelopmental disorders (NDDs) are a heterogeneous group of conditions characterized by impairments in motor, cognitive, and behavioral functions. Despite advances in genomic sequencing, the genetic basis of many NDDs remains unexplored. CCDC82 encodes a coiled-coil domain-containing protein with an unknown function in the nervous system. This study aims to further delineate the clinical spectrum of CCDC82-related disorders by identifying a novel homozygous nonsense variant in an Iranian family with early-onset hypotonia, infantile spasms, and developmental delay. Methods An 8-month-old male proband of Turkmen descent, born to consanguineous parents, presented with severe hypotonia, spasticity, infantile spasms, and developmental delay. Electroencephalography (EEG) revealed a hypsarrhythmic pattern, and brain MRI showed no significant structural abnormalities. Whole-exome sequencing (WES) was performed on the proband, followed by in silico pathogenicity analysis and segregation studies in the family. Sanger sequencing confirmed the variant, and bioinformatics tools assessed its potential impact. Results WES identified a novel homozygous nonsense variant in CCDC82 (NM_024725.4: c.709 C > T, p.Arg237Ter), which was classified as pathogenic according to ACMG guidelines. This variant is predicted to result in nonsense-mediated decay. This variant was absent in population databases and segregated with the disease phenotype in the family. In silico analyses supported its deleterious effect, and evolutionary conservation studies indicated a conserved role of CCDC82 in neuronal function. Conclusion This study reports a novel pathogenic variant in CCDC82 associated with a severe neurodevelopmental disorder. These findings expand the known phenotypic spectrum associated with biallelic CCDC82 variants, reinforcing its role in early-onset hypotonia and infantile spasms. Further investigations are necessary to confirm its functional role and establish CCDC82 as a novel disease-associated gene. |
| format | Article |
| id | doaj-art-b60a2c74a2854efba044b33b267ff7b3 |
| institution | Kabale University |
| issn | 1755-8794 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | BMC |
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| series | BMC Medical Genomics |
| spelling | doaj-art-b60a2c74a2854efba044b33b267ff7b32025-08-24T11:56:19ZengBMCBMC Medical Genomics1755-87942025-08-011811710.1186/s12920-025-02201-9CCDC82 and neurodevelopment: a novel genetic variant linked to infantile spasms and hypotoniaZahra Safarian0Shiva Mehrabi1Arghavan Rakhshani Nejad2Sajad Alavimanesh3Pegah Kavousinia4Mohammad Hossein Shushizadeh5Seyedeh Faezeh Hassani6Latifeh Onagh7Abdolazim Sarli8Nahid Rezaie9Faculty of Medicine, Shahid Beheshti University of Medical SciencesDepartment of Genetics, Faculty of New Sciences and Technologies, Tehran Medical Sciences Branch, Islamic Azad UniversityDepartment of Biology, Kavian Institute of Higher EducationStudent Research Committee, Shahrekord University of Medical SciencesDepartment of Medical Biotechnology, Faculty of Medicine, Birjand University of Medical SciencesDepartment of Biochemistry, Shushizadeh Medical LaboratoryDepartment of Molecular medicine, Pasteur Institute of IranDepartment of obstetrics and gynecology, school of medicine, Golestan University of Medical SciencesGorgan Congenital Malformations Research Center, Golestan University of Medical SciencesStudent Research Committee, Faculty of Medicine, Mashhad University of Medical SciencesAbstract Background Neurodevelopmental disorders (NDDs) are a heterogeneous group of conditions characterized by impairments in motor, cognitive, and behavioral functions. Despite advances in genomic sequencing, the genetic basis of many NDDs remains unexplored. CCDC82 encodes a coiled-coil domain-containing protein with an unknown function in the nervous system. This study aims to further delineate the clinical spectrum of CCDC82-related disorders by identifying a novel homozygous nonsense variant in an Iranian family with early-onset hypotonia, infantile spasms, and developmental delay. Methods An 8-month-old male proband of Turkmen descent, born to consanguineous parents, presented with severe hypotonia, spasticity, infantile spasms, and developmental delay. Electroencephalography (EEG) revealed a hypsarrhythmic pattern, and brain MRI showed no significant structural abnormalities. Whole-exome sequencing (WES) was performed on the proband, followed by in silico pathogenicity analysis and segregation studies in the family. Sanger sequencing confirmed the variant, and bioinformatics tools assessed its potential impact. Results WES identified a novel homozygous nonsense variant in CCDC82 (NM_024725.4: c.709 C > T, p.Arg237Ter), which was classified as pathogenic according to ACMG guidelines. This variant is predicted to result in nonsense-mediated decay. This variant was absent in population databases and segregated with the disease phenotype in the family. In silico analyses supported its deleterious effect, and evolutionary conservation studies indicated a conserved role of CCDC82 in neuronal function. Conclusion This study reports a novel pathogenic variant in CCDC82 associated with a severe neurodevelopmental disorder. These findings expand the known phenotypic spectrum associated with biallelic CCDC82 variants, reinforcing its role in early-onset hypotonia and infantile spasms. Further investigations are necessary to confirm its functional role and establish CCDC82 as a novel disease-associated gene.https://doi.org/10.1186/s12920-025-02201-9CCDC82Neurodevelopmental disorderHypotoniaEpilepsyWhole-exome sequencingGenetic variant |
| spellingShingle | Zahra Safarian Shiva Mehrabi Arghavan Rakhshani Nejad Sajad Alavimanesh Pegah Kavousinia Mohammad Hossein Shushizadeh Seyedeh Faezeh Hassani Latifeh Onagh Abdolazim Sarli Nahid Rezaie CCDC82 and neurodevelopment: a novel genetic variant linked to infantile spasms and hypotonia BMC Medical Genomics CCDC82 Neurodevelopmental disorder Hypotonia Epilepsy Whole-exome sequencing Genetic variant |
| title | CCDC82 and neurodevelopment: a novel genetic variant linked to infantile spasms and hypotonia |
| title_full | CCDC82 and neurodevelopment: a novel genetic variant linked to infantile spasms and hypotonia |
| title_fullStr | CCDC82 and neurodevelopment: a novel genetic variant linked to infantile spasms and hypotonia |
| title_full_unstemmed | CCDC82 and neurodevelopment: a novel genetic variant linked to infantile spasms and hypotonia |
| title_short | CCDC82 and neurodevelopment: a novel genetic variant linked to infantile spasms and hypotonia |
| title_sort | ccdc82 and neurodevelopment a novel genetic variant linked to infantile spasms and hypotonia |
| topic | CCDC82 Neurodevelopmental disorder Hypotonia Epilepsy Whole-exome sequencing Genetic variant |
| url | https://doi.org/10.1186/s12920-025-02201-9 |
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