Survival of a male patient harboring CASK Arg27Ter mutation to adolescence
Abstract Background CASK is an X‐linked gene in mammals and its deletion in males is incompatible with life. CASK heterozygous mutations in female patients associate with intellectual disability, microcephaly, pontocerebellar hypoplasia, and optic nerve hypoplasia, whereas CASK hemizygous mutations...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2020-10-01
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| Series: | Molecular Genetics & Genomic Medicine |
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| Online Access: | https://doi.org/10.1002/mgg3.1426 |
| _version_ | 1797300967039827968 |
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| author | Konark Mukherjee Paras A. Patel Deepa S. Rajan Leslie E. W. LaConte Sarika Srivastava |
| author_facet | Konark Mukherjee Paras A. Patel Deepa S. Rajan Leslie E. W. LaConte Sarika Srivastava |
| author_sort | Konark Mukherjee |
| collection | DOAJ |
| description | Abstract Background CASK is an X‐linked gene in mammals and its deletion in males is incompatible with life. CASK heterozygous mutations in female patients associate with intellectual disability, microcephaly, pontocerebellar hypoplasia, and optic nerve hypoplasia, whereas CASK hemizygous mutations in males manifest as early infantile epileptic encephalopathy with a grim prognosis. Here, we report a rare case of survival of a male patient harboring a CASK null mutation to adolescent age. Methods Trio whole exome sequencing analysis was performed from blood genomic DNA. Magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and electroencephalogram (EEG) analyses were performed to determine anomalies in brain development, metabolite concentrations, and electrical activity, respectively. Results Trio‐WES analysis identified a de novo c.79C>T (p.Arginine27Ter) mutation in CASK causing a premature translation termination at the very N‐terminus of the protein. The 17‐years, and 11‐month‐old male patient displayed profound intellectual disability, microcephaly, dysmorphism, ponto‐cerebellar hypoplasia, and intractable epilepsy. His systemic symptoms included overall reduced somatic growth, dysautonomia, ventilator and G tube dependence, and severe osteopenia. Brain MRI revealed a severe cerebellar and brain stem hypoplasia with progressive cerebral atrophy. EEG spectral analysis revealed a global functional defect with generalized background slowing and delta waves dominating even in the awake state. Conclusion This case study is the first to report survival of a male patient carrying a CASK loss‐of‐function mutation to adolescence and highlights that improved palliative care could extend survival. Moreover, the genomic position encoding Arg27 in CASK may possess an increased susceptibility to mutations. |
| first_indexed | 2024-03-07T23:14:40Z |
| format | Article |
| id | doaj.art-0ae629046c964cf9aebb44ab78bff915 |
| institution | Directory Open Access Journal |
| issn | 2324-9269 |
| language | English |
| last_indexed | 2024-03-07T23:14:40Z |
| publishDate | 2020-10-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Genetics & Genomic Medicine |
| spelling | doaj.art-0ae629046c964cf9aebb44ab78bff9152024-02-21T12:03:04ZengWileyMolecular Genetics & Genomic Medicine2324-92692020-10-01810n/an/a10.1002/mgg3.1426Survival of a male patient harboring CASK Arg27Ter mutation to adolescenceKonark Mukherjee0Paras A. Patel1Deepa S. Rajan2Leslie E. W. LaConte3Sarika Srivastava4Fralin Biomedical Research Institute at Virginia Tech Carilion Roanoke VA USAFralin Biomedical Research Institute at Virginia Tech Carilion Roanoke VA USAChildren's Hospital of Pittsburgh of UPMC University of Pittsburgh Pittsburgh PA USAFralin Biomedical Research Institute at Virginia Tech Carilion Roanoke VA USAFralin Biomedical Research Institute at Virginia Tech Carilion Roanoke VA USAAbstract Background CASK is an X‐linked gene in mammals and its deletion in males is incompatible with life. CASK heterozygous mutations in female patients associate with intellectual disability, microcephaly, pontocerebellar hypoplasia, and optic nerve hypoplasia, whereas CASK hemizygous mutations in males manifest as early infantile epileptic encephalopathy with a grim prognosis. Here, we report a rare case of survival of a male patient harboring a CASK null mutation to adolescent age. Methods Trio whole exome sequencing analysis was performed from blood genomic DNA. Magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and electroencephalogram (EEG) analyses were performed to determine anomalies in brain development, metabolite concentrations, and electrical activity, respectively. Results Trio‐WES analysis identified a de novo c.79C>T (p.Arginine27Ter) mutation in CASK causing a premature translation termination at the very N‐terminus of the protein. The 17‐years, and 11‐month‐old male patient displayed profound intellectual disability, microcephaly, dysmorphism, ponto‐cerebellar hypoplasia, and intractable epilepsy. His systemic symptoms included overall reduced somatic growth, dysautonomia, ventilator and G tube dependence, and severe osteopenia. Brain MRI revealed a severe cerebellar and brain stem hypoplasia with progressive cerebral atrophy. EEG spectral analysis revealed a global functional defect with generalized background slowing and delta waves dominating even in the awake state. Conclusion This case study is the first to report survival of a male patient carrying a CASK loss‐of‐function mutation to adolescence and highlights that improved palliative care could extend survival. Moreover, the genomic position encoding Arg27 in CASK may possess an increased susceptibility to mutations.https://doi.org/10.1002/mgg3.1426CASKcerebellar hypoplasiaelectroencephalogramepileptic encephalopathymicrocephaly |
| spellingShingle | Konark Mukherjee Paras A. Patel Deepa S. Rajan Leslie E. W. LaConte Sarika Srivastava Survival of a male patient harboring CASK Arg27Ter mutation to adolescence Molecular Genetics & Genomic Medicine CASK cerebellar hypoplasia electroencephalogram epileptic encephalopathy microcephaly |
| title | Survival of a male patient harboring CASK Arg27Ter mutation to adolescence |
| title_full | Survival of a male patient harboring CASK Arg27Ter mutation to adolescence |
| title_fullStr | Survival of a male patient harboring CASK Arg27Ter mutation to adolescence |
| title_full_unstemmed | Survival of a male patient harboring CASK Arg27Ter mutation to adolescence |
| title_short | Survival of a male patient harboring CASK Arg27Ter mutation to adolescence |
| title_sort | survival of a male patient harboring cask arg27ter mutation to adolescence |
| topic | CASK cerebellar hypoplasia electroencephalogram epileptic encephalopathy microcephaly |
| url | https://doi.org/10.1002/mgg3.1426 |
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