The effect of a single SMARCA4 exon deletion on RNA splicing: Implications for variant classification
Abstract Background Exon deletions are generally considered pathogenic, particularly when they are located out of frame. Here, we describe a pediatric, female patient presenting with hypercalcemia and a small cell carcinoma of the ovary, hypercalcemic type, and carrying a germline de novo SMARCA4 ex...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-10-01
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| Series: | Molecular Genetics & Genomic Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/mgg3.2232 |
| _version_ | 1827795053012058112 |
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| author | Anna Byrjalsen Ulrik Stoltze Mana Mehrjouy Jane Hübertz Frederiksen Mads Bak Ulf Birkedal Henrik Hasle Anne‐Marie Gerdes Kjeld Schmiegelow Karin Wadt Thomas van Overeem Hansen |
| author_facet | Anna Byrjalsen Ulrik Stoltze Mana Mehrjouy Jane Hübertz Frederiksen Mads Bak Ulf Birkedal Henrik Hasle Anne‐Marie Gerdes Kjeld Schmiegelow Karin Wadt Thomas van Overeem Hansen |
| author_sort | Anna Byrjalsen |
| collection | DOAJ |
| description | Abstract Background Exon deletions are generally considered pathogenic, particularly when they are located out of frame. Here, we describe a pediatric, female patient presenting with hypercalcemia and a small cell carcinoma of the ovary, hypercalcemic type, and carrying a germline de novo SMARCA4 exon 14 deletion. Methods The SMARCA4 deletion was identified by whole genome sequencing, and the effect on the RNA level was examined by gel‐ and capillary electrophoresis and nanopore sequencing. Results The deletion was in silico predicted to be truncating, but RNA analysis revealed two major transcripts with deletion of exon 14 alone or exon 14 through 15, where the latter was located in‐frame. Because the patient's phenotype matched that of other patients with pathogenic germline variants in SMARCA4, the deletion was classified as likely pathogenic. Conclusion We propose to include RNA analysis in classification of single‐exon deletions, especially if located outside of known functional domains, as this can identify any disparate effects on the RNA and DNA level, which may have implications for variant classification using the American College of Medical Genetics and Genomics guidelines. |
| first_indexed | 2024-03-11T18:42:43Z |
| format | Article |
| id | doaj.art-6879caf35ea64e219f83a8cc94719a3d |
| institution | Directory Open Access Journal |
| issn | 2324-9269 |
| language | English |
| last_indexed | 2024-03-11T18:42:43Z |
| publishDate | 2023-10-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Genetics & Genomic Medicine |
| spelling | doaj.art-6879caf35ea64e219f83a8cc94719a3d2023-10-12T08:38:42ZengWileyMolecular Genetics & Genomic Medicine2324-92692023-10-011110n/an/a10.1002/mgg3.2232The effect of a single SMARCA4 exon deletion on RNA splicing: Implications for variant classificationAnna Byrjalsen0Ulrik Stoltze1Mana Mehrjouy2Jane Hübertz Frederiksen3Mads Bak4Ulf Birkedal5Henrik Hasle6Anne‐Marie Gerdes7Kjeld Schmiegelow8Karin Wadt9Thomas van Overeem Hansen10Department of Clinical Genetics, Rigshospitalet Copenhagen University Hospital Copenhagen DenmarkDepartment of Pediatrics and Adolescent Medicine, Rigshospitalet Copenhagen University Hospital Copenhagen DenmarkDepartment of Pediatrics and Adolescent Medicine, Rigshospitalet Copenhagen University Hospital Copenhagen DenmarkDepartment of Clinical Genetics, Rigshospitalet Copenhagen University Hospital Copenhagen DenmarkDepartment of Clinical Genetics, Rigshospitalet Copenhagen University Hospital Copenhagen DenmarkDepartment of Clinical Genetics, Rigshospitalet Copenhagen University Hospital Copenhagen DenmarkDepartment of Pediatrics Aarhus University Hospital Aarhus N DenmarkDepartment of Clinical Genetics, Rigshospitalet Copenhagen University Hospital Copenhagen DenmarkDepartment of Pediatrics and Adolescent Medicine, Rigshospitalet Copenhagen University Hospital Copenhagen DenmarkDepartment of Clinical Genetics, Rigshospitalet Copenhagen University Hospital Copenhagen DenmarkDepartment of Clinical Genetics, Rigshospitalet Copenhagen University Hospital Copenhagen DenmarkAbstract Background Exon deletions are generally considered pathogenic, particularly when they are located out of frame. Here, we describe a pediatric, female patient presenting with hypercalcemia and a small cell carcinoma of the ovary, hypercalcemic type, and carrying a germline de novo SMARCA4 exon 14 deletion. Methods The SMARCA4 deletion was identified by whole genome sequencing, and the effect on the RNA level was examined by gel‐ and capillary electrophoresis and nanopore sequencing. Results The deletion was in silico predicted to be truncating, but RNA analysis revealed two major transcripts with deletion of exon 14 alone or exon 14 through 15, where the latter was located in‐frame. Because the patient's phenotype matched that of other patients with pathogenic germline variants in SMARCA4, the deletion was classified as likely pathogenic. Conclusion We propose to include RNA analysis in classification of single‐exon deletions, especially if located outside of known functional domains, as this can identify any disparate effects on the RNA and DNA level, which may have implications for variant classification using the American College of Medical Genetics and Genomics guidelines.https://doi.org/10.1002/mgg3.2232de novosingle‐exon deletionsmall cell carcinoma of the ovarySMARCA4splicingvariant classification |
| spellingShingle | Anna Byrjalsen Ulrik Stoltze Mana Mehrjouy Jane Hübertz Frederiksen Mads Bak Ulf Birkedal Henrik Hasle Anne‐Marie Gerdes Kjeld Schmiegelow Karin Wadt Thomas van Overeem Hansen The effect of a single SMARCA4 exon deletion on RNA splicing: Implications for variant classification Molecular Genetics & Genomic Medicine de novo single‐exon deletion small cell carcinoma of the ovary SMARCA4 splicing variant classification |
| title | The effect of a single SMARCA4 exon deletion on RNA splicing: Implications for variant classification |
| title_full | The effect of a single SMARCA4 exon deletion on RNA splicing: Implications for variant classification |
| title_fullStr | The effect of a single SMARCA4 exon deletion on RNA splicing: Implications for variant classification |
| title_full_unstemmed | The effect of a single SMARCA4 exon deletion on RNA splicing: Implications for variant classification |
| title_short | The effect of a single SMARCA4 exon deletion on RNA splicing: Implications for variant classification |
| title_sort | effect of a single smarca4 exon deletion on rna splicing implications for variant classification |
| topic | de novo single‐exon deletion small cell carcinoma of the ovary SMARCA4 splicing variant classification |
| url | https://doi.org/10.1002/mgg3.2232 |
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