June 2021
Volume 62, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2021
A novel gelsolin variant associated with Familial Amyloidosis of the Finnish type in an Australian family
Author Affiliations & Notes
  • Sean Mullany
    Flinders Centre for Ophthalmology, Eye and Vision Research, Flinders University, Adelaide, South Australia, Australia
  • Emmanuelle Souzeau
    Flinders Centre for Ophthalmology, Eye and Vision Research, Flinders University, Adelaide, South Australia, Australia
  • Sonja Klebe
    College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia
  • Tiger Zhou
    Flinders Centre for Ophthalmology, Eye and Vision Research, Flinders University, Adelaide, South Australia, Australia
  • Lachlan Knight
    Flinders Centre for Ophthalmology, Eye and Vision Research, Flinders University, Adelaide, South Australia, Australia
  • Ayub Qassim
    Flinders Centre for Ophthalmology, Eye and Vision Research, Flinders University, Adelaide, South Australia, Australia
  • Ella Berry
    Flinders Centre for Ophthalmology, Eye and Vision Research, Flinders University, Adelaide, South Australia, Australia
  • Henry Marshall
    Flinders Centre for Ophthalmology, Eye and Vision Research, Flinders University, Adelaide, South Australia, Australia
  • Matthew Hussey
    Department of Pathology, Flinders Medical Centre, Bedford Park, South Australia, Australia
  • Andrew Dubowsky
    Department of Pathology, Flinders Medical Centre, Bedford Park, South Australia, Australia
  • James Breen
    Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, South Australia, Australia
  • Mark Hassall
    Flinders Centre for Ophthalmology, Eye and Vision Research, Flinders University, Adelaide, South Australia, Australia
  • Richard A Mills
    Flinders Centre for Ophthalmology, Eye and Vision Research, Flinders University, Adelaide, South Australia, Australia
  • Jamie E Craig
    Flinders Centre for Ophthalmology, Eye and Vision Research, Flinders University, Adelaide, South Australia, Australia
  • Owen M Siggs
    Flinders Centre for Ophthalmology, Eye and Vision Research, Flinders University, Adelaide, South Australia, Australia
  • Footnotes
    Commercial Relationships   Sean Mullany, None; Emmanuelle Souzeau, None; Sonja Klebe, None; Tiger Zhou, None; Lachlan Knight, None; Ayub Qassim, None; Ella Berry, None; Henry Marshall, None; Matthew Hussey, None; Andrew Dubowsky, None; James Breen, None; Mark Hassall, None; Richard Mills, None; Jamie Craig, None; Owen Siggs, None
  • Footnotes
    Support  NHMRC Program grants APP1550144 and APP1157571
Investigative Ophthalmology & Visual Science June 2021, Vol.62, 1499. doi:
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to authenticated users only.
      Sign In or Create an Account ×
    • Get Citation

      Sean Mullany, Emmanuelle Souzeau, Sonja Klebe, Tiger Zhou, Lachlan Knight, Ayub Qassim, Ella Berry, Henry Marshall, Matthew Hussey, Andrew Dubowsky, James Breen, Mark Hassall, Richard A Mills, Jamie E Craig, Owen M Siggs; A novel gelsolin variant associated with Familial Amyloidosis of the Finnish type in an Australian family. Invest. Ophthalmol. Vis. Sci. 2021;62(8):1499.

      Download citation file:


      © ARVO (1962-2015); The Authors (2016-present)

      ×
  • Supplements
Abstract

Purpose : This study identified and sought to validate the association between a novel gelsolin (GSN) variant and the phenotype of Familial Amyloidosis of the Finnish type (FAF) in three first degree relatives harbouring a previously undocumented variant, and manifesting multiple clinical and ophthalmic features consistent with systemic gelsolin (GSN) amyloidosis.

Methods : Three first degree relatives presenting to a single tertiary ophthalmic outpatient clinic exhibiting clinical features consistent with FAF including cutis laxa and vision-affecting corneal stromal changes were enrolled in a genetic study of corneal disease. DNA extracted from whole blood samples collected from two individuals was subjected to exome sequencing. Genes associated with corneal disease were assessed for rare and potentially deleterious variants. Histopathological and immunohistochemical studies of proband corneal tissue collected at the time of corneal graft surgery were performed to investigate for the presence of GSN within corneal deposits.

Results : A previously undocumented GSN:c.1477T>C variant resulting in a predicted p.(Trp493Arg) missense variant was identified in the two individuals who underwent exome sequencing. This variant was subsequently confirmed in all three affected individuals through Sanger sequencing. This rare variant which was absent from the Genome Aggregation Database (gnomAD), a large population-based database of 125,748 exomes and 15,708 genomes, was predicted to be damaging by in silico tools (Phred scaled CADD score: 20.8). Histopathological studies performed on the proband cornea demonstrated irregular stromal inclusions which manifested classic amyloid features when subjected to Congo red staining, and intense GSN labelling in immunohistochemical studies.

Conclusions : This study is the first to describe an association between the GSN:c.1477T>C,p.(Trp493Arg) variant and FAF. This novel variant which affects a GSN region distant from the classic p.Asp214Asn variant and the gelsolin 2 (G2) domain, may lead to insights into the amyloidogenic mechanisms of FAF-associated GSN variants.

This is a 2021 ARVO Annual Meeting abstract.

×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×