A case of congenital heart defects and familial exudative vitreoretinopathy caused by activation of a cryptic splice donor in NOTCH1
Abstract Background NOTCH1 is associated with two disorders of vascular development, Adams-Oliver Syndrome 5 (AOS5) and aortic valve disease 1 (AOVD1). Here we report a disease-causing variant in NOTCH1 that has a previously undemonstrated effect on splicing. Additionally, we found that the proband...
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BMC
2025-05-01
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| Series: | BMC Medical Genomics |
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| Online Access: | https://doi.org/10.1186/s12920-025-02160-1 |
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| author | Joseph Farris Camila Dergam-Larson Madeline Lopour Kahlen Darr Lisa A. Schimmenti Brittni A. Scruggs Laura J. Lambert Eric W. Klee |
| author_facet | Joseph Farris Camila Dergam-Larson Madeline Lopour Kahlen Darr Lisa A. Schimmenti Brittni A. Scruggs Laura J. Lambert Eric W. Klee |
| author_sort | Joseph Farris |
| collection | DOAJ |
| description | Abstract Background NOTCH1 is associated with two disorders of vascular development, Adams-Oliver Syndrome 5 (AOS5) and aortic valve disease 1 (AOVD1). Here we report a disease-causing variant in NOTCH1 that has a previously undemonstrated effect on splicing. Additionally, we found that the proband has the optic phenotype of familial exudative vitreoretinopathy (FEVR) which has been reported for probands with pathogenic variants in genes in the notch signaling pathway, but never for NOTCH1. Case presentation The proband presented with a ventricular septal defect, pulmonic stenosis, and ocular findings consistent with familial exudative vitreoretinopathy (FEVR), which NOTCH1 has not been associated with to date. Trio exome sequencing identified a paternally inherited variant of uncertain significance in NOTCH1:c.2153 A > G. We assessed the variant’s effect using RT-PCR, finding an increased use of a cryptic donor compared to the control. On this basis, we were able to re-classify this variant as pathogenic. Conclusions We expand the phenotypic spectrum of NOTCH1 and contribute to the building evidence that variants in NOTCH1 cause a spectrum of disorders of vascular development. |
| format | Article |
| id | doaj-art-c404eb41d2e0478da74f732efe4495b9 |
| institution | OA Journals |
| issn | 1755-8794 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
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| series | BMC Medical Genomics |
| spelling | doaj-art-c404eb41d2e0478da74f732efe4495b92025-08-20T02:00:02ZengBMCBMC Medical Genomics1755-87942025-05-011811710.1186/s12920-025-02160-1A case of congenital heart defects and familial exudative vitreoretinopathy caused by activation of a cryptic splice donor in NOTCH1Joseph Farris0Camila Dergam-Larson1Madeline Lopour2Kahlen Darr3Lisa A. Schimmenti4Brittni A. Scruggs5Laura J. Lambert6Eric W. Klee7Center for Individualized Medicine, Mayo ClinicCenter for Individualized Medicine, Mayo ClinicDepartment of Clinical Genomics, Mayo ClinicDepartment of Clinical Genomics, Mayo ClinicDepartment of Clinical Genomics, Mayo ClinicDepartment of Ophthalmology, Mayo ClinicCenter for Individualized Medicine, Mayo ClinicCenter for Individualized Medicine, Mayo ClinicAbstract Background NOTCH1 is associated with two disorders of vascular development, Adams-Oliver Syndrome 5 (AOS5) and aortic valve disease 1 (AOVD1). Here we report a disease-causing variant in NOTCH1 that has a previously undemonstrated effect on splicing. Additionally, we found that the proband has the optic phenotype of familial exudative vitreoretinopathy (FEVR) which has been reported for probands with pathogenic variants in genes in the notch signaling pathway, but never for NOTCH1. Case presentation The proband presented with a ventricular septal defect, pulmonic stenosis, and ocular findings consistent with familial exudative vitreoretinopathy (FEVR), which NOTCH1 has not been associated with to date. Trio exome sequencing identified a paternally inherited variant of uncertain significance in NOTCH1:c.2153 A > G. We assessed the variant’s effect using RT-PCR, finding an increased use of a cryptic donor compared to the control. On this basis, we were able to re-classify this variant as pathogenic. Conclusions We expand the phenotypic spectrum of NOTCH1 and contribute to the building evidence that variants in NOTCH1 cause a spectrum of disorders of vascular development.https://doi.org/10.1186/s12920-025-02160-1NOTCH1Adams-oliver syndromeFamilial exudative vitreoretinopathyRare diseaseSplice variant |
| spellingShingle | Joseph Farris Camila Dergam-Larson Madeline Lopour Kahlen Darr Lisa A. Schimmenti Brittni A. Scruggs Laura J. Lambert Eric W. Klee A case of congenital heart defects and familial exudative vitreoretinopathy caused by activation of a cryptic splice donor in NOTCH1 BMC Medical Genomics NOTCH1 Adams-oliver syndrome Familial exudative vitreoretinopathy Rare disease Splice variant |
| title | A case of congenital heart defects and familial exudative vitreoretinopathy caused by activation of a cryptic splice donor in NOTCH1 |
| title_full | A case of congenital heart defects and familial exudative vitreoretinopathy caused by activation of a cryptic splice donor in NOTCH1 |
| title_fullStr | A case of congenital heart defects and familial exudative vitreoretinopathy caused by activation of a cryptic splice donor in NOTCH1 |
| title_full_unstemmed | A case of congenital heart defects and familial exudative vitreoretinopathy caused by activation of a cryptic splice donor in NOTCH1 |
| title_short | A case of congenital heart defects and familial exudative vitreoretinopathy caused by activation of a cryptic splice donor in NOTCH1 |
| title_sort | case of congenital heart defects and familial exudative vitreoretinopathy caused by activation of a cryptic splice donor in notch1 |
| topic | NOTCH1 Adams-oliver syndrome Familial exudative vitreoretinopathy Rare disease Splice variant |
| url | https://doi.org/10.1186/s12920-025-02160-1 |
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