Case Report: A Novel KMT2E Splice Site Variant as a Cause of O'Donnell-Luria-Rodan Syndrome in a Male Patient
BackgroundO'Donnell-Luria-Rodan (ODLURO) syndrome is an autosomal dominant systemic disorder characterized by global developmental delay caused by mutations in the KMT2E gene. The aim of this study was to investigate the role of KMT2E mutations as a cause of ODLURO syndrome in a Chinese boy.Met...
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Frontiers Media S.A.
2022-02-01
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| Series: | Frontiers in Pediatrics |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fped.2022.822096/full |
| _version_ | 1818324423797637120 |
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| author | Zixuan Cao Chunli Wang Jing Chen Hu Guo Chunfeng Wu Gang Zhang Le Ding |
| author_facet | Zixuan Cao Chunli Wang Jing Chen Hu Guo Chunfeng Wu Gang Zhang Le Ding |
| author_sort | Zixuan Cao |
| collection | DOAJ |
| description | BackgroundO'Donnell-Luria-Rodan (ODLURO) syndrome is an autosomal dominant systemic disorder characterized by global developmental delay caused by mutations in the KMT2E gene. The aim of this study was to investigate the role of KMT2E mutations as a cause of ODLURO syndrome in a Chinese boy.MethodsWe reported the clinical course of a Chinese boy who was diagnosed with ODLURO syndrome by the whole exome sequencing. We extracted genomic DNA of the proband and parents, gene variations were screened using whole-exome sequencing, followed by validation using direct Sanger sequencing. The effect of mRNA splicing variants were analyzed through a minigene splice assay and in vitro reverse transcription PCR (RT-PCR).ResultsThe proband presented with recurrent seizures and developmental delay. Using genetic analysis, we identified that the proband carried a de novo heterozygous splicing variant (c.1248+1G>T) in the KMT2E gene. In vivo transcript analysis showed that the proband did not carry any KMT2E mRNA transcript, while a specific exon11-exon13 (440 bp) transcript was detected in the unaffected parents. The in vitro minigene splice assay conducted in HEK293 cells confirmed that the c.1248+1G>T variant resulted in exon 12 skipping, which in turn caused an alteration in KMT2E mRNA splicing. The mutant transcript created a premature stop codon at the 378 amino acid position that could have been caused nonsense-mediated mRNA decay (NMD).ConclusionWe verified the pathogenic effect of the KMT2E c.1248+1G>T splicing variant, which disturbed normal mRNA splicing and caused mRNA decay. Our findings suggest that splice variants play an important role in the molecular basis of ODLURO, and that careful molecular profiling of these patients could play an essential role in tailoring of personalized treatment options soon. |
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| language | English |
| last_indexed | 2024-12-13T11:28:21Z |
| publishDate | 2022-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pediatrics |
| spelling | doaj.art-a231d2063c5b45ce9345153b7b45aa862022-12-21T23:48:03ZengFrontiers Media S.A.Frontiers in Pediatrics2296-23602022-02-011010.3389/fped.2022.822096822096Case Report: A Novel KMT2E Splice Site Variant as a Cause of O'Donnell-Luria-Rodan Syndrome in a Male PatientZixuan Cao0Chunli Wang1Jing Chen2Hu Guo3Chunfeng Wu4Gang Zhang5Le Ding6Department of Neurology, Children's Hospital of Nanjing Medical University, Nanjing, ChinaNanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, ChinaDepartment of Neurology, Children's Hospital of Nanjing Medical University, Nanjing, ChinaDepartment of Neurology, Children's Hospital of Nanjing Medical University, Nanjing, ChinaDepartment of Neurology, Children's Hospital of Nanjing Medical University, Nanjing, ChinaDepartment of Neurology, Children's Hospital of Nanjing Medical University, Nanjing, ChinaDepartment of Neurology, Children's Hospital of Nanjing Medical University, Nanjing, ChinaBackgroundO'Donnell-Luria-Rodan (ODLURO) syndrome is an autosomal dominant systemic disorder characterized by global developmental delay caused by mutations in the KMT2E gene. The aim of this study was to investigate the role of KMT2E mutations as a cause of ODLURO syndrome in a Chinese boy.MethodsWe reported the clinical course of a Chinese boy who was diagnosed with ODLURO syndrome by the whole exome sequencing. We extracted genomic DNA of the proband and parents, gene variations were screened using whole-exome sequencing, followed by validation using direct Sanger sequencing. The effect of mRNA splicing variants were analyzed through a minigene splice assay and in vitro reverse transcription PCR (RT-PCR).ResultsThe proband presented with recurrent seizures and developmental delay. Using genetic analysis, we identified that the proband carried a de novo heterozygous splicing variant (c.1248+1G>T) in the KMT2E gene. In vivo transcript analysis showed that the proband did not carry any KMT2E mRNA transcript, while a specific exon11-exon13 (440 bp) transcript was detected in the unaffected parents. The in vitro minigene splice assay conducted in HEK293 cells confirmed that the c.1248+1G>T variant resulted in exon 12 skipping, which in turn caused an alteration in KMT2E mRNA splicing. The mutant transcript created a premature stop codon at the 378 amino acid position that could have been caused nonsense-mediated mRNA decay (NMD).ConclusionWe verified the pathogenic effect of the KMT2E c.1248+1G>T splicing variant, which disturbed normal mRNA splicing and caused mRNA decay. Our findings suggest that splice variants play an important role in the molecular basis of ODLURO, and that careful molecular profiling of these patients could play an essential role in tailoring of personalized treatment options soon.https://www.frontiersin.org/articles/10.3389/fped.2022.822096/fullO'Donnell-Luria-Rodan's syndromeKMT2Eepilepsysplice variantabnormal mRNA splicing |
| spellingShingle | Zixuan Cao Chunli Wang Jing Chen Hu Guo Chunfeng Wu Gang Zhang Le Ding Case Report: A Novel KMT2E Splice Site Variant as a Cause of O'Donnell-Luria-Rodan Syndrome in a Male Patient Frontiers in Pediatrics O'Donnell-Luria-Rodan's syndrome KMT2E epilepsy splice variant abnormal mRNA splicing |
| title | Case Report: A Novel KMT2E Splice Site Variant as a Cause of O'Donnell-Luria-Rodan Syndrome in a Male Patient |
| title_full | Case Report: A Novel KMT2E Splice Site Variant as a Cause of O'Donnell-Luria-Rodan Syndrome in a Male Patient |
| title_fullStr | Case Report: A Novel KMT2E Splice Site Variant as a Cause of O'Donnell-Luria-Rodan Syndrome in a Male Patient |
| title_full_unstemmed | Case Report: A Novel KMT2E Splice Site Variant as a Cause of O'Donnell-Luria-Rodan Syndrome in a Male Patient |
| title_short | Case Report: A Novel KMT2E Splice Site Variant as a Cause of O'Donnell-Luria-Rodan Syndrome in a Male Patient |
| title_sort | case report a novel kmt2e splice site variant as a cause of o donnell luria rodan syndrome in a male patient |
| topic | O'Donnell-Luria-Rodan's syndrome KMT2E epilepsy splice variant abnormal mRNA splicing |
| url | https://www.frontiersin.org/articles/10.3389/fped.2022.822096/full |
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