November 2015 | Samhain 2015

Risk for Sudden Cardiac Death Identified

Fri, 6 November 15 09:00

Research into Intellectual Disability Gene Reveals New Condition with Increased QT

UCD researchers and their Norwegian collaborators have highlighted a risk for sudden cardiac death arising from a single gene alteration in a known intellectual disability gene. The X-linked inherited condition, which arises from an alteration in the NAA10 gene, results in varying degrees of intellectual disability with facial dysmorphism, hypotonia, scoliosis and long QT which is associated with risk of sudden adult death. This not only expands the clinical spectrum of NAA10 but also reveals a complex correlation between the mutant enzyme and phenotype severity. 

The novel mutation was identified by whole exome sequencing DNA from members of a single non-consanguineous Irish family who have waited over 24 years for the cause of their various health disorders to be identified. The research, led by Dr Jillian Casey & Dr Sally Ann Lynch (both affiliated to UCD ACoRD and Clinical Genetics at Children’s University Hospital, Dublin), together with colleagues from the Mater Misericordiae University Hospital, Beaumont Hospital and collaborators at the University of Bergen, Norway was published this week in Nature’s Scientific Reports.

The affected family included two brothers who presented with intellectual disability, facial dysmorphism, scoliosis and long QT. As their mother exhibited a milder phenotype, including long QT, X-linked inheritance was immediately suspected. After negative single gene testing, whole exome sequencing identified the responsible mutation in the N-acetly transferase domain of the NAA10 gene. Analysis of both the mother and her siblings showed that this arose as a de novo mutation. Structural and functional analysis of the gene variant demonstrated reduced stability and catalytic activity of the mutant NAA10 enzyme showing that the family’s disorder was caused by impairment of N-terminal acetyltransferase activity.

The two brothers exhibited variable expressivity with one being more intellectually impaired while the other had a more pronounced physical disability. Mutations in the NAA10 gene have previously been associated with Ogden syndrome, Lenz Microphthalmia syndrome (LMS) and non-syndromic development delay. These findings now expand the NAA10 clinical spectrum to include a syndromic development delay disorder with long QT. Previously only Ogden syndrome patients had been described as having cardiac arrhythmias. The authors note that the mutation causing Ogden syndrome and the mutation causing long QT in the reported family are both located within the N-acetyl transferase domain, suggesting a possible interaction or downstream effect on the regulation of an arrhythmia gene.

This research suggests that it is important to consider cardiac screening in both male and female patients who have pathogenic NAA10 mutations as female carriers can have long QT and are at risk of sudden adult death, even if they don’t have the intellectual disability syndrome.

Dr Jillian Casey noted

It is important to heighten awareness of this gene and its associated risk of sudden adult death. In our case, one of the sons had two heart attacks in his teenage years and his mum also had a heart attack. The family have since had pacemakers fitted which can be a life-saving step for people with alterations in this gene.

The study involved collaboration with clinicians across different Dublin hospitals (Children’s University Hospital Temple St, Mater Misericordiae University Hospital, Beaumont Hospital), and scientists from both the UCD Academic Centre on Rare Diseases (ACoRD; Director and co-author Dr Sean Ennis) and the Department of Molecular Biology at the University of Bergen, Norway who proved that the genetic alteration identified caused the clinical presentations.

The research was funded by a Medical Research Charities Group Grant from the Health Research Board and Temple Street Fundraising Office (Children's University Hospital) [MRCG/2013/02].

Article

NAA10 mutation causing a novel intellectual disability syndrome with Long QT due to N-terminal acetyltransferase impairment. Scientific Reports 2015 Nov 2;5:16022.

Jillian P. Casey1,2, Svein I. Støve3, Catherine McGorrian4,5, Joseph Galvin4, Marina Blenski3,Aimee Dunne2, Sean Ennis2, Francesca Brett6, Mary D. King2,7, Thomas Arnesen3,8 & Sally Ann Lynch1,2,9

  1. Clinical Genetics,Temple Street Children’s University Hospital, Temple Street, Dublin 1, Ireland.
  2. UCD Academic Centre on Rare Diseases, School of Medicine, University College Dublin, Dublin 4, Ireland.
  3. Department of Molecular Biology, University of Bergen, Norway.
  4. Department of Cardiology, Mater Misericordiae University Hospital, Eccles Street, Dublin 7, Ireland.
  5. UCD School of Medicine, University College Dublin, Dublin 4, Ireland.
  6. Department of Neuropathology, Beaumont Hospital, Dublin 9, Ireland.
  7. Department of Paediatric Neurology & Clinical Neurophysiology, Temple Street Children’s University Hospital, Dublin 1, Ireland.
  8. Department of Surgery, Haukeland University Hospital, Norway.
  9. Our Lady’s Children’s Hospital, Crumlin, Dublin 12, Ireland.

Related Links

Academic Centre on Rare Diseases (ACoRD)

Children’s University Hospital Temple Street (CUH)

Mater Misericordiae University Hospital (MMUH)

Beaumont Hospital

Dept of Molecular Biology, University of Bergen

Medical Research Charities Group

Health Research Board