April 2014
Volume 55, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2014
Exome Sequencing of Familial and Sporadic Cases with Pseudoexfoliation Syndrome (XFS)
Author Affiliations & Notes
  • Mansoor Sarfarazi
    Molecular Ophthal Genetics Lab, Univ of Connecticut Health Ctr, Farmington, CT
  • Roshanak Sharafieh
    Molecular Ophthal Genetics Lab, Univ of Connecticut Health Ctr, Farmington, CT
  • Robert Ritch
    Einhorn Clinical Research Center, New York Eye and Ear Infirmary, New York, NY
  • Jeffrey M Liebmann
    Einhorn Clinical Research Center, New York Eye and Ear Infirmary, New York, NY
  • Ahti Tarkkanen
    Ophthalmology, Helsinki University Central Hospital, Helsinki, Finland
  • Francesc Lopez-Giraldez
    Yale Center for Genome Analysis (YCGA), Yale University School of Medicine, New Haven, CT
  • Kaya Bilguvar
    Yale Center for Genome Analysis (YCGA), Yale University School of Medicine, New Haven, CT
  • Richard P Lifton
    Yale Center for Genome Analysis (YCGA), Yale University School of Medicine, New Haven, CT
  • Shrikant Mane
    Yale Center for Genome Analysis (YCGA), Yale University School of Medicine, New Haven, CT
  • Anne H Child
    Cardiovascular Genetics, St George's, University of London, London, United Kingdom
Investigative Ophthalmology & Visual Science April 2014, Vol.55, 3815. doi:
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to authenticated users only.
      Sign In or Create an Account ×
    • Get Citation

      Mansoor Sarfarazi, Roshanak Sharafieh, Robert Ritch, Jeffrey M Liebmann, Ahti Tarkkanen, Francesc Lopez-Giraldez, Kaya Bilguvar, Richard P Lifton, Shrikant Mane, Anne H Child; Exome Sequencing of Familial and Sporadic Cases with Pseudoexfoliation Syndrome (XFS). Invest. Ophthalmol. Vis. Sci. 2014;55(13):3815.

      Download citation file:


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

      ×
  • Supplements
Abstract

Purpose: To identify new causative genes in a group of XFS subjects by next-generation exome sequencing (NGES) method.

Methods: The cohort consisted of 72 affected XFS individuals, including 28 members of 13 unrelated families (Sibs, Parent-Child, Niece-Uncle, 1st to 3rd degree cousins) and 44 sporadic cases (28 with and 16 without Glaucoma). Exome capture was performed using the NimbleGen SeqCap EZ V2 followed by sequencing on the Illumina HiSeq 2000. Reads were mapped to the human genome (hg19) with ELAND aligner and variants were called with SAMtools.

Results: Exome sequencing revealed 2,539,812 variants in 72 XFS subjects, of which 90% had a Quality Score of ≥60 and 94% of bases were covered at least 8-times. Removal of duplicates and common alterations revealed 470,441 variants in 17,989 unique genes. Subsequent filtrations against 1,000 Genome, NHLBI Exomes, dbSNP, Simple Repeats and Genome Segmental Duplications identified 291,022 novel variants, of which 37,501 (8,347 Missense; 1,631 Nonsense; 7,022 Synonymous; 20,501 Non-Coding) were present in 2 or more affected XFS subjects. Overall, 113 genes showed novel amino acid alterations in at least 10% of our XFS cases. However, when familial co-segregation of these novel coding variants was considered, only 12 genes segregated in one or more of our XFS families. Bioinformatic analysis and direct-Sanger sequencing are currently being utilized to evaluate the causative nature of these candidate genes in our original exome-sequenced subjects and their immediate respective family members. Additionally, we have observed another 24,281 insertions or deletions (InDels) in our 72 XFS subjects, of which 52 novel variants were identified in 2 or more affected cases. However, only 22 of these InDels were observed in both familial and sporadic cases. The exact contribution of these InDels and their roles in the etiology of XFS phenotype is currently being evaluated.

Conclusions: This is the first study to use NGES in a group of 72 familial and sporadic XFS cases. The NGES identified 12 genes with single novel amino acid alterations and 22 other genes with InDels predicting to instigate premature termination of their encoded normal proteins. The exact nature of these DNA alterations and their potential XFS-causing roles are currently under investigation. Note: Other contributing authors are M.E. Turacli, C. O’Brien, F. Mercieca and A. Spiteri

Keywords: 539 genetics • 440 candidate gene analysis • 413 aging  
×
×

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.

×