Next-generation sequencing revealed a novel mutation in the gene encoding the beta subunit of rod phosphodiesterase.
OBJECTIVE
To report the phenotypes caused by a novel mutation in the PDE6B gene in a family with two affected siblings and one affected cousin with a 2-year follow-up.


METHODS
Three patients from a family with a history of retinitis pigmentosa underwent clinical evaluations. The affected patients' DNA was analyzed using next-generation sequencing and segregation analyses were performed for the family.


METHODS
Edward S. Harkness Eye Institute, New York Presbyterian Hospital.


METHODS
Two siblings, one cousin, and five unaffected family members.


METHODS
Macular appearance assessed by funduscopy, autofluorescence imaging, spectral-domain optical coherence tomography and visual function assessed by electroretinography.


RESULTS
The proband, brother, and cousin had rod-cone degeneration with cystoid macular edema. Fundus autofluorescence showed hyperautofluorescent ring constriction over time. Spectral-domain optical coherence tomography revealed retinal pigment epithelium atrophy, loss of external limiting membrane, retinal layer thinning, and reduction in ellipsoid zone length over time. Next-generation whole exome sequencing revealed a homozygous c.1923_1969ins6del47 nonsense PDE6B mutation, which has not been previously described, that segregated with the disease in the family.


CONCLUSIONS
The homozygous PDE6B mutation causes retinitis pigmentosa. Acetazolamide treatment improved visual acuity but rod degeneration continued. Despite having the same mutation and living in the same environment, the proband's brother progressed at a faster rate starting at a younger age, suggesting that gene modifiers may influence the expressivity of the phenotype. Next-generation sequencing, used to discover this mutation, is a practical new technology that can detect novel disease-causing alleles, where previous arrayed primer extension (APEX) technology could not.
College of Physicians & Surgeons, Columbia University , New York, NY , USA .
Sherry
S
Shen
Tharikarn
T
Sujirakul
Stephen H
SH
Tsang
D000293:Adolescent; D002257:Carbonic Anhydrase Inhibitors / Q000627:therapeutic use; D018389:Codon, Nonsense; D003241:Consanguinity; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6 / Q000235:genetics*; D004252:DNA Mutational Analysis; D004596:Electroretinography; D059472:Exome / Q000235:genetics; D005451:Fluorescein Angiography; D056726:Genetic Association Studies; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008704:Methazolamide / Q000627:therapeutic use; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D012160:Retina / Q000502:physiology; D012174:Retinitis Pigmentosa / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D041623:Tomography, Optical Coherence; D014792:Visual Acuity; D055815:Young Adult
D002257:Carbonic Anhydrase Inhibitors; D018389:Codon, Nonsense; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; C517431:PDE6B protein, human; D008704:Methazolamide
Fundus autofluorescence; PDE6; next-generation sequencing; optical coherence tomography; retinitis pigmentosa; rod phosphodiesterase; whole exome sequencing