September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Complex Multi-Allelic Inherited Retinal Dystrophy: Multiple Genes Contributing Independently and Concurrently in Extended Families
Author Affiliations & Notes
  • Dianna K H Wheaton
    Retina Foundation of the Southwest, Dallas, Texas, United States
    Ophthalmology, Univ Texas Southwestern Medical Center, Dallas, Texas, United States
  • Kaylie D Webb-Jones
    Retina Foundation of the Southwest, Dallas, Texas, United States
  • Sara J Bowne
    Univ Texas Health Science Center, Houston, Texas, United States
  • Lori S Sullivan
    Univ Texas Health Science Center, Houston, Texas, United States
  • Rui Chen
    Baylor College of Medicine, Houston, Texas, United States
  • Stephen P Daiger
    Univ Texas Health Science Center, Houston, Texas, United States
  • David G Birch
    Retina Foundation of the Southwest, Dallas, Texas, United States
    Ophthalmology, Univ Texas Southwestern Medical Center, Dallas, Texas, United States
  • Footnotes
    Commercial Relationships   Dianna Wheaton, None; Kaylie Webb-Jones, None; Sara Bowne, None; Lori Sullivan, None; Rui Chen, None; Stephen Daiger, None; David Birch, None
  • Footnotes
    Support  NIH Grants EY007142, EY09076, R01EY022356, R01EY018571; Foundation Fighting Blindness
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 3135. doi:
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to Subscribers Only
      Sign In or Create an Account ×
    • Get Citation

      Dianna K H Wheaton, Kaylie D Webb-Jones, Sara J Bowne, Lori S Sullivan, Rui Chen, Stephen P Daiger, David G Birch; Complex Multi-Allelic Inherited Retinal Dystrophy: Multiple Genes Contributing Independently and Concurrently in Extended Families. Invest. Ophthalmol. Vis. Sci. 2016;57(12):3135.

      Download citation file:


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

      ×
  • Supplements
Abstract

Purpose : With recent availability of next-generation sequencing (NGS) it is becoming more common to pursue panel testing rather than targeted, sequential gene-by-gene testing. Herein, we describe the identification of multiple, concurrent disease-causing mutations contributing to retinal dystrophy in three relatively small families.

Methods : Family members underwent comprehensive visual function evaluations. An implied genetic inheritance pattern was assigned and updated as additional family members were tested. Family 1 (FAM1) and Family 2 (FAM2) were clinically diagnosed as dominant retinitis pigmentosa (adRP) with suspected non-penetrance (n.p.). Family 3 (FAM3) had an overall adRP pedigree, but the proband was phenotypically cone-rod dystrophy. Genetic analysis was performed by Sanger sequencing, and targeted retinal capture NGS to identify the underlying cause of disease.

Results : Genetic testing of FAM1 (n=4 affected, 1 n.p.) identified a dominant RP1 mutation (c.2029C>T, p.Arg67Ter) that was present for 3 of the 4 affected individuals but absent in the proband and non-penetrant individual. NGS revealed the proband was a compound heterozygote for USH2A mutations (c.1256G>T, p. Cys419Phe / c.2299delG, p.Glu767Serfs*21). FAM2 genetic testing (n=3 affected, 1 n.p.) identified three different retinal dystrophy genes (PRPH2, PRPF8, USH2A) with disease-causing mutations. Affected FAM2 individuals each had a different genotype responsible for their retinal disease. Genetic testing for FAM3 (n=6 affected) identified a PRPH2 mutation (c.647C>T, p.Pro216Leu) tracking with disease in 5 of the 6 affected individuals. Additional testing determined the FAM3 proband harbored compound PRPH2 and CRX dominant mutations with CRX likely accounting for her cone-rod phenotype; her son harbored only the CRX mutation.

Conclusions : Using NGS we are discovering multiple genes contributing to the retinal dystrophy genotypes within a family. Families with noted examples of phenotypic variation or apparent non-penetrant individuals may offer a clue to suspect complex inheritance. Furthermore, this finding underscores that caution should be taken when attributing a single gene disease-causing mutation (or inheritance pattern) to a family as a whole.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

×
×

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.

×