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Conor Patrick Malone, Matthew Carrigan, Karen Collins, Hilary Dempsey, Adrian Dockery, G. Jane Farrar, Paul F Kenna; Intrafamilial Phenotype Variation Associated with BBS1 Met390Arg. Invest. Ophthalmol. Vis. Sci. 2017;58(8):3257.
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© ARVO (1962-2015); The Authors (2016-present)
To report wide phenotype variation in 3 siblings, homozygous for BBS1 Met390Arg, identified by Next Generation Sequencing (NGS)
Over 700 retinopathy patients, including 3 siblings reported here, have been recruited to our ongoing Target 5000 NGS initiative at the Research Foundation, Royal Victoria Eye and Ear Hospital, Dublin. Patients are assessed using best-corrected visual acuity (BCVA), perimetry, colour vision testing, slit-lamp biomicroscopy, electroretinography, fundus photography, and optical coherence tomography. With informed consent, DNA samples undergo exon sequencing of 218 retinopathy-associated genes using target-capture oligo panels.
The proband had nyctalopia at 12 and marked concentric field-loss symptoms at 25. Fundoscopy showed extensive bone-spicule retinal deposits. She was diagnosed with Retinitis Pigmentosa (RP) at 25. BCVA at 45 was Hand Movements in each eye. A sister had reduced day vision and moderate concentric field loss at 18. Fundoscopy showed macular changes. Peripheral pigment deposits have never been observed. She had good night vision until 32. BCVA at 36 was 6/15 in each eye. A brother had nyctalopia and poor day vision at 25. BCVA at 48 was 6/24 in each eye. Peripheral pigment and macular changes supported a diagnosis of RP. Another sibling and both parents were phenotypically normal.NGS revealed all 3 were homozygous for a T > G transversion at nucleotide 1169 in BBS1 resulting in Methionine to Arginine substitution at codon 390. Following clinical diagnosis of RP, but prior to the elucidation of the BBS1 Met390Arg mutation, the proband was diagnosed with renal dysfunction responsive to diet restriction. Her sister with predominantly macular changes was diagnosed with diet-controlled non-insulin dependent diabetes. None of the 3 is significantly obese and none has any evidence of compromised mentation. Following genotyping it emerged that 2 of the 3 had supernumerary toes removed in childhood.
Pleotropism in Bardet Biedl syndrome (BBS) is well documented. Approximately 17 genes are implicated; BBS1 mutations account for almost 25% of cases. Met390Arg accounts for 80% of BBS due to mutations in BBS1. Our study shows that even among siblings BBS may present differently. Identification of a well-known BBS1 mutation in patients in whom clinical findings did not initially point to BBS emphasises the utility of genotyping in refining clinical diagnosis.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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