Journal article
Discovery of a neuromuscular syndrome caused by biallelic variants in ASCC3
HGG advances, Vol.2(2), pp.100024-100024
04/08/2021
DOI: 10.1016/j.xhgg.2021.100024
PMCID: PMC8756546
PMID: 35047834
Abstract
Activating Signal Cointegrator 1 Complex, Subunit 3 (ASCC3) is part of the four-part ASC-1 transcriptional cointegrator complex. This complex includes ASCC1 (associated with spinal muscular atrophy with congenital bone fractures 2), TRIP4 (associated with spinal muscular atrophy with congenital bone fractures 1), and ASCC2 (not yet associated with human disease.) ASCC3 encodes a DNA helicase responsible for generating single-stranded DNA as part of the DNA damage response. Interestingly, ASCC3 expresses coding and non-coding isoforms, which act in opposition to balance the recovery of gene transcription after UV-induced DNA damage. Here we report the discovery of ASCC3 as the cause of a neuromuscular syndrome in seven unreported individuals from six unrelated families and updates on the one previously reported family. All the individuals share a neurologic phenotype that ranges from severe developmental delay to muscle fatigue. There appears to be genotype-phenotype correlation, as the most mildly affected individual is homozygous for a rare missense variant, while the more severely affected individuals are compound heterozygotes for a missense and a presumed loss-of-function (LOF) variant. There are no individuals with biallelic presumed LOF variants in our cohort or in gnomAD, as this genotype may not be compatible with life. In summary we report a syndrome in these eleven individuals from seven families with biallelic variants in ASCC3.
Although other members of the ASC-1 transcriptional cointegrator complex are associated with severe neuromuscular syndromes, the phenotype of Activating Signal Cointegrator 1 Complex, Subunit 3 (ASCC3) has not previously been delineated. Here we describe 11 individuals with a variable pediatric-onset neuromuscular syndrome caused by biallelic variants in ASCC3.
Details
- Title: Subtitle
- Discovery of a neuromuscular syndrome caused by biallelic variants in ASCC3
- Creators
- Divya Nair - Children's Hospital of PhiladelphiaDong Li - Children's Hospital of PhiladelphiaHannah Erdogan - Children's Hospital of PhiladelphiaAndrew Yoon - Children's Hospital of PhiladelphiaMargaret H. Harr - Children's Hospital of PhiladelphiaGaber Bergant - Ljubljana University Medical CentreBorut Peterlin - Ljubljana University Medical CentreMaruša Škrjanec Pušenjak - Ljubljana University Medical CentreParul Jayakar - Miami Children's HospitalRolph Pfundt - Nijmegen Institute for Cognition and InformationSandra Jansen - Nijmegen Institute for Cognition and InformationKirsty McWalter - GeneDxAlpa Sidhu - University of IowaSheila Saliganan - Ambry Genetics (United States)Emanuele Agolini - Bambino Gesù Children's HospitalArthur Jacob - Weill Cornell MedicineJennifer Pasquier - Weill Cornell MedicineRafii Arash - Weill Cornell MedicineKimia Kahrizi - University of Social Welfare and Rehabilitation SciencesHossein Najmabadi - University of Social Welfare and Rehabilitation SciencesHans-Hilger Ropers - Max Planck Institute for Molecular GeneticsElizabeth J. Bhoj - Children's Hospital of Philadelphia
- Resource Type
- Journal article
- Publication Details
- HGG advances, Vol.2(2), pp.100024-100024
- DOI
- 10.1016/j.xhgg.2021.100024
- PMID
- 35047834
- PMCID
- PMC8756546
- NLM abbreviation
- HGG Adv
- ISSN
- 2666-2477
- eISSN
- 2666-2477
- Publisher
- Elsevier Inc
- Language
- English
- Date published
- 04/08/2021
- Academic Unit
- Stead Family Department of Pediatrics; Medical Genetics and Genomics
- Record Identifier
- 9984354035902771
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