Discovery of a neuromuscular syndrome caused by biallelic variants in ASCC3
Summary: 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 congen...
Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Elsevier
2021-04-01
|
Series: | HGG Advances |
Subjects: | |
Online Access: | http://www.sciencedirect.com/science/article/pii/S2666247721000051 |
id |
doaj-cb443ab29c294cd38ee393efc5038a34 |
---|---|
record_format |
Article |
spelling |
doaj-cb443ab29c294cd38ee393efc5038a342021-05-04T07:33:08ZengElsevierHGG Advances2666-24772021-04-0122100024Discovery of a neuromuscular syndrome caused by biallelic variants in ASCC3Divya Nair0Dong Li1Hannah Erdogan2Andrew Yoon3Margaret H. Harr4Gaber Bergant5Borut Peterlin6Maruša Škrjanec Pušenjak7Parul Jayakar8Rolph Pfundt9Sandra Jansen10Kirsty McWalter11Alpa Sidhu12Sheila Saliganan13Emanuele Agolini14Arthur Jacob15Jennifer Pasquier16Rafii Arash17Kimia Kahrizi18Hossein Najmabadi19Hans-Hilger Ropers20Elizabeth J. Bhoj21Children’s Hospital of Philadelphia, Philadephia, PA, USAChildren’s Hospital of Philadelphia, Philadephia, PA, USAChildren’s Hospital of Philadelphia, Philadephia, PA, USAChildren’s Hospital of Philadelphia, Philadephia, PA, USAChildren’s Hospital of Philadelphia, Philadephia, PA, USAClinical Institute of Genomic Medicine, University Medical Centre Ljubljana, Ljubljana, SloveniaClinical Institute of Genomic Medicine, University Medical Centre Ljubljana, Ljubljana, SloveniaClinical Institute of Genomic Medicine, University Medical Centre Ljubljana, Ljubljana, SloveniaNicklaus Children’s Hospital, Miami, FL, USADepartment of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboudumc, the NetherlandsDepartment of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboudumc, the NetherlandsGeneDx, Gaithersburg, MD, USAUniversity of Iowa, Iowa City, IA, USAAmbry Genetics, Aliso Viejo, CA, USATranslational Cytogenomics Research Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, ItalyDepartment of Genetic Medicine, Genetic Intelligence Laboratory, Weill Cornell Medicine in Qatar, Education City, Al Luqta St, Ar-Rayyan, QatarDepartment of Genetic Medicine, Genetic Intelligence Laboratory, Weill Cornell Medicine in Qatar, Education City, Al Luqta St, Ar-Rayyan, QatarDepartment of Genetic Medicine, Genetic Intelligence Laboratory, Weill Cornell Medicine in Qatar, Education City, Al Luqta St, Ar-Rayyan, QatarGenetics Research Center University of Social Welfare and Rehabilitation Sciences, Tehran, IranGenetics Research Center University of Social Welfare and Rehabilitation Sciences, Tehran, IranMax Planck Institute for Molecular GeneticsIhnestr. 63-73, Berlin, GermanyChildren’s Hospital of Philadelphia, Philadephia, PA, USA; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2666247721000051Activating Signal Cointegrator 1 ComplexSubunit 3ASCC3neurogeneticsneuromuscular |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Divya Nair Dong Li Hannah Erdogan Andrew Yoon Margaret H. Harr Gaber Bergant Borut Peterlin Maruša Škrjanec Pušenjak Parul Jayakar Rolph Pfundt Sandra Jansen Kirsty McWalter Alpa Sidhu Sheila Saliganan Emanuele Agolini Arthur Jacob Jennifer Pasquier Rafii Arash Kimia Kahrizi Hossein Najmabadi Hans-Hilger Ropers Elizabeth J. Bhoj |
spellingShingle |
Divya Nair Dong Li Hannah Erdogan Andrew Yoon Margaret H. Harr Gaber Bergant Borut Peterlin Maruša Škrjanec Pušenjak Parul Jayakar Rolph Pfundt Sandra Jansen Kirsty McWalter Alpa Sidhu Sheila Saliganan Emanuele Agolini Arthur Jacob Jennifer Pasquier Rafii Arash Kimia Kahrizi Hossein Najmabadi Hans-Hilger Ropers Elizabeth J. Bhoj Discovery of a neuromuscular syndrome caused by biallelic variants in ASCC3 HGG Advances Activating Signal Cointegrator 1 Complex Subunit 3 ASCC3 neurogenetics neuromuscular |
author_facet |
Divya Nair Dong Li Hannah Erdogan Andrew Yoon Margaret H. Harr Gaber Bergant Borut Peterlin Maruša Škrjanec Pušenjak Parul Jayakar Rolph Pfundt Sandra Jansen Kirsty McWalter Alpa Sidhu Sheila Saliganan Emanuele Agolini Arthur Jacob Jennifer Pasquier Rafii Arash Kimia Kahrizi Hossein Najmabadi Hans-Hilger Ropers Elizabeth J. Bhoj |
author_sort |
Divya Nair |
title |
Discovery of a neuromuscular syndrome caused by biallelic variants in ASCC3 |
title_short |
Discovery of a neuromuscular syndrome caused by biallelic variants in ASCC3 |
title_full |
Discovery of a neuromuscular syndrome caused by biallelic variants in ASCC3 |
title_fullStr |
Discovery of a neuromuscular syndrome caused by biallelic variants in ASCC3 |
title_full_unstemmed |
Discovery of a neuromuscular syndrome caused by biallelic variants in ASCC3 |
title_sort |
discovery of a neuromuscular syndrome caused by biallelic variants in ascc3 |
publisher |
Elsevier |
series |
HGG Advances |
issn |
2666-2477 |
publishDate |
2021-04-01 |
description |
Summary: 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. |
topic |
Activating Signal Cointegrator 1 Complex Subunit 3 ASCC3 neurogenetics neuromuscular |
url |
http://www.sciencedirect.com/science/article/pii/S2666247721000051 |
work_keys_str_mv |
AT divyanair discoveryofaneuromuscularsyndromecausedbybiallelicvariantsinascc3 AT dongli discoveryofaneuromuscularsyndromecausedbybiallelicvariantsinascc3 AT hannaherdogan discoveryofaneuromuscularsyndromecausedbybiallelicvariantsinascc3 AT andrewyoon discoveryofaneuromuscularsyndromecausedbybiallelicvariantsinascc3 AT margarethharr discoveryofaneuromuscularsyndromecausedbybiallelicvariantsinascc3 AT gaberbergant discoveryofaneuromuscularsyndromecausedbybiallelicvariantsinascc3 AT borutpeterlin discoveryofaneuromuscularsyndromecausedbybiallelicvariantsinascc3 AT marusaskrjanecpusenjak discoveryofaneuromuscularsyndromecausedbybiallelicvariantsinascc3 AT paruljayakar discoveryofaneuromuscularsyndromecausedbybiallelicvariantsinascc3 AT rolphpfundt discoveryofaneuromuscularsyndromecausedbybiallelicvariantsinascc3 AT sandrajansen discoveryofaneuromuscularsyndromecausedbybiallelicvariantsinascc3 AT kirstymcwalter discoveryofaneuromuscularsyndromecausedbybiallelicvariantsinascc3 AT alpasidhu discoveryofaneuromuscularsyndromecausedbybiallelicvariantsinascc3 AT sheilasaliganan discoveryofaneuromuscularsyndromecausedbybiallelicvariantsinascc3 AT emanueleagolini discoveryofaneuromuscularsyndromecausedbybiallelicvariantsinascc3 AT arthurjacob discoveryofaneuromuscularsyndromecausedbybiallelicvariantsinascc3 AT jenniferpasquier discoveryofaneuromuscularsyndromecausedbybiallelicvariantsinascc3 AT rafiiarash discoveryofaneuromuscularsyndromecausedbybiallelicvariantsinascc3 AT kimiakahrizi discoveryofaneuromuscularsyndromecausedbybiallelicvariantsinascc3 AT hosseinnajmabadi discoveryofaneuromuscularsyndromecausedbybiallelicvariantsinascc3 AT hanshilgerropers discoveryofaneuromuscularsyndromecausedbybiallelicvariantsinascc3 AT elizabethjbhoj discoveryofaneuromuscularsyndromecausedbybiallelicvariantsinascc3 |
_version_ |
1721479863414554624 |