DNM1-Related Disorders: A Recurrent Splice Variant in an Alternative Transcript Expands the Genetic and Phenotypic Spectrum
Abstract number :
1.349
Submission category :
12. Genetics / 12A. Human Studies
Year :
2021
Submission ID :
1826335
Source :
www.aesnet.org
Presentation date :
12/4/2021 12:00:00 PM
Published date :
Nov 22, 2021, 06:53 AM
Authors :
Sarah Ruggiero, MS, CGC - Children's Hospital of Philadelphia; Laina Lusk, MMSc, CGC - Genetic Counselor, Children's Hospital of Philadelphia; Oliva Wilmarth - Children's Hospital of Philadelphia; Pam Pojomovsky McDonnell, MD - Children's Hospital of Philadelphia; Ingo Helbig, MD - Children's Hospital of Philadelphia
Rationale: Disease-causing variants in DNM1 are a known cause of neurodevelopmental disorders, most often epileptic encephalopathies with infantile spasms evolving to Lennox-Gastaut Syndrome. All previously identified de novo variants cluster within GTPase and middle domains of the DNM1 protein, with a dominant-negative effect presumed to be the disease mechanism. Here we report a recurrent de novo splice site variant in an alternative DNM1 transcript in individuals with developmental and epileptic encephalopathies, suggesting a novel disease mechanism in DNM1-related disorders.
Methods: We recruited individuals through our ongoing clinical cohort and through referrals. Detailed chart review and phenotyping was performed on all individuals, including review of EEG and neuroimaging data.
Results: Three individuals were identified with the de novo DNM1 c. 1197-8G>A variant, a splice variant in an alternative transcript of DNM1, which is not present in the coding region of the primary transcript. All three individuals presented with severe global developmental delays, epileptic encephalopathy with infantile spasms, significant hypotonia, and cortical visual impairment, consistent with the previously reported DNM1 phenotype. Additionally, one individual presented with significant dystonia, also consistent with the typical presentation of DNM1-related disorder.
Conclusions: We report three individuals with a recurrent splice site variant in an alternative transcript of DNM1 with clinical features highly suggestive of a DNM1-related disorder. While it remains unknown how a splice site variant in an alternative transcript replicates the dominant-negative effect of main DNM1 phenotype caused by the previously reported variants, this novel variant expands the understanding of DNM1-related disorders and may provide novel insights into the disease mechanism and treatment options.
Funding: Please list any funding that was received in support of this abstract.: NINDS, The Hartwell Foundation, Children’s Hospital of Philadelphia.
Genetics