Incomplete penetrance and variable phenotypes of a novel NPRL2 frameshift variant: from familial focal epilepsy with variable foci 2 to neurodevelopmental disorders
Abstract Background Familial focal epilepsy with variable foci 2 (FFEVF2), an autosomal dominant disorder caused by pathogenic heterozygous variants in the NPRL2 gene, is characterized by focal epilepsy originating in different cortical regions of the temporal, frontal, parietal, and occipital lobes...
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2025-08-01
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| author | Hui Zhu Qiyan Wang Wenxin Deng Shuyao Zhu Lan Zeng Ai Chen Ying Pang Fu Xiong |
| author_facet | Hui Zhu Qiyan Wang Wenxin Deng Shuyao Zhu Lan Zeng Ai Chen Ying Pang Fu Xiong |
| author_sort | Hui Zhu |
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| description | Abstract Background Familial focal epilepsy with variable foci 2 (FFEVF2), an autosomal dominant disorder caused by pathogenic heterozygous variants in the NPRL2 gene, is characterized by focal epilepsy originating in different cortical regions of the temporal, frontal, parietal, and occipital lobes of the brain. Methods The study included a Chinese family in which proband had epilepsy, and her brother had autism, attention deficit hyperactivity disorder (ADHD), and mild intellectual disability (ID). Blood samples of the two children and their parents were collected for whole exome sequencing (WES). Results Proband was a 1-month-and-7-day-old baby girl with epilepsy manifesting as focal to bilateral tonic-clonic seizures and cranial magnetic resonance imaging showing focal cortical dysplasia or subcortical grey matter ectopia in the left anterior and posterior central gyrus. WES revealed a heterozygous variant of the NPRL2 gene [c.907delC (p. Gln303Serfs*11)]. Sanger sequencing confirmed that the variant was inherited from her unaffected mother. According to the ACMG, the variant was classified as likely pathogenic. Finally, she was diagnosed with FFEVF2. Her epilepsy type was only reported in one patient with FFEVF2 with multiple seizure types. Follow-up revealed that she had a global developmental delay and absent language, and despite numerous antiseizure medications, her seizures were uncontrolled. Her brother carried the same mutated gene, which manifested primarily as autism, ADHD, speech deficit, and mild ID. So far, he has had no seizures and a negative electroencephalogram. But he could have seizures in the future, and it’s worth following up. Conclusion This study describes a family with a new NPRL2 variant, where affected members exhibited various neurological disorders including FFEVF2, autism, and ADHD, demonstrating incomplete penetrance. |
| format | Article |
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| institution | Kabale University |
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| language | English |
| publishDate | 2025-08-01 |
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| spelling | doaj-art-1fada024570d422ca06af6d3bb6775642025-08-20T03:45:52ZengBMCBMC Neurology1471-23772025-08-0125111310.1186/s12883-025-04339-6Incomplete penetrance and variable phenotypes of a novel NPRL2 frameshift variant: from familial focal epilepsy with variable foci 2 to neurodevelopmental disordersHui Zhu0Qiyan Wang1Wenxin Deng2Shuyao Zhu3Lan Zeng4Ai Chen5Ying Pang6Fu Xiong7Department of Pediatrics, Sichuan Provincial Women’s and Children’s Hospital, The Affiliated Women’s and Children’s Hospital of Chengdu Medical CollegeChildren’s Hospital of Chengdu Medical CollegeDepartment of Neonatology, Sichuan Provincial Women’s and Children’s Hospital, The Affiliated Women’s and Children’s Hospital of Chengdu Medical CollegeDepartment of Pediatrics, Sichuan Provincial Women’s and Children’s Hospital, The Affiliated Women’s and Children’s Hospital of Chengdu Medical CollegeDepartment of Medical Genetics and Prenatal Diagnosis, Sichuan Provincial Women’s and Children’s Hospital, The Affiliated Women’s and Children’s Hospital of Chengdu Medical CollegeDepartment of Pediatrics, Sichuan Provincial Women’s and Children’s Hospital, The Affiliated Women’s and Children’s Hospital of Chengdu Medical CollegeDepartment of Pediatrics, Sichuan Provincial Women’s and Children’s Hospital, The Affiliated Women’s and Children’s Hospital of Chengdu Medical CollegeDepartment of Pediatrics, Sichuan Provincial Women’s and Children’s Hospital, The Affiliated Women’s and Children’s Hospital of Chengdu Medical CollegeAbstract Background Familial focal epilepsy with variable foci 2 (FFEVF2), an autosomal dominant disorder caused by pathogenic heterozygous variants in the NPRL2 gene, is characterized by focal epilepsy originating in different cortical regions of the temporal, frontal, parietal, and occipital lobes of the brain. Methods The study included a Chinese family in which proband had epilepsy, and her brother had autism, attention deficit hyperactivity disorder (ADHD), and mild intellectual disability (ID). Blood samples of the two children and their parents were collected for whole exome sequencing (WES). Results Proband was a 1-month-and-7-day-old baby girl with epilepsy manifesting as focal to bilateral tonic-clonic seizures and cranial magnetic resonance imaging showing focal cortical dysplasia or subcortical grey matter ectopia in the left anterior and posterior central gyrus. WES revealed a heterozygous variant of the NPRL2 gene [c.907delC (p. Gln303Serfs*11)]. Sanger sequencing confirmed that the variant was inherited from her unaffected mother. According to the ACMG, the variant was classified as likely pathogenic. Finally, she was diagnosed with FFEVF2. Her epilepsy type was only reported in one patient with FFEVF2 with multiple seizure types. Follow-up revealed that she had a global developmental delay and absent language, and despite numerous antiseizure medications, her seizures were uncontrolled. Her brother carried the same mutated gene, which manifested primarily as autism, ADHD, speech deficit, and mild ID. So far, he has had no seizures and a negative electroencephalogram. But he could have seizures in the future, and it’s worth following up. Conclusion This study describes a family with a new NPRL2 variant, where affected members exhibited various neurological disorders including FFEVF2, autism, and ADHD, demonstrating incomplete penetrance.https://doi.org/10.1186/s12883-025-04339-6NPRL2NPRL2-associated epilepsyFamilial focal epilepsy with variable foci 2Focal epilepsy |
| spellingShingle | Hui Zhu Qiyan Wang Wenxin Deng Shuyao Zhu Lan Zeng Ai Chen Ying Pang Fu Xiong Incomplete penetrance and variable phenotypes of a novel NPRL2 frameshift variant: from familial focal epilepsy with variable foci 2 to neurodevelopmental disorders BMC Neurology NPRL2 NPRL2-associated epilepsy Familial focal epilepsy with variable foci 2 Focal epilepsy |
| title | Incomplete penetrance and variable phenotypes of a novel NPRL2 frameshift variant: from familial focal epilepsy with variable foci 2 to neurodevelopmental disorders |
| title_full | Incomplete penetrance and variable phenotypes of a novel NPRL2 frameshift variant: from familial focal epilepsy with variable foci 2 to neurodevelopmental disorders |
| title_fullStr | Incomplete penetrance and variable phenotypes of a novel NPRL2 frameshift variant: from familial focal epilepsy with variable foci 2 to neurodevelopmental disorders |
| title_full_unstemmed | Incomplete penetrance and variable phenotypes of a novel NPRL2 frameshift variant: from familial focal epilepsy with variable foci 2 to neurodevelopmental disorders |
| title_short | Incomplete penetrance and variable phenotypes of a novel NPRL2 frameshift variant: from familial focal epilepsy with variable foci 2 to neurodevelopmental disorders |
| title_sort | incomplete penetrance and variable phenotypes of a novel nprl2 frameshift variant from familial focal epilepsy with variable foci 2 to neurodevelopmental disorders |
| topic | NPRL2 NPRL2-associated epilepsy Familial focal epilepsy with variable foci 2 Focal epilepsy |
| url | https://doi.org/10.1186/s12883-025-04339-6 |
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