Whole genome sequencing reveals novel mutations causing autosomal dominant inherited macular degeneration

ABSTRACT

Background: Age-related macular degeneration (AMD) is a common sight threatening condition. However, there are a number of monogenic macular dystrophies that are clinically similar to AMD, which can potentially provide pathogenetic insights.

Methods: Three siblings from a non-consanguineous Greek-Cypriot family reported central visual disturbance and nyctalopia. The patients had full ophthalmic examinations and color fundus photography, spectral-domain ocular coherence tomography and scanning laser ophthalmoscopy. Targeted polymerase chain reaction (PCR) was performed as a first step to attempt to identify suspected mutations in C1QTNF5 and TIMP3 followed by whole genome sequencing.

Results: The three patients were noted to have symptoms of nyctalopia, early paracentral visual field loss and, in older patients, central vision loss. Imaging identified pseudodrusen, retinal atrophy and RPE-Bruch’s membrane separation. Whole genome sequencing of the proband revealed two novel heterozygous variants in C1QTNF5, c.556C>T, and c.569C>G. The mutation segregated with disease in this family, occurred in cis, and resulted in missense amino acid changes P186S and S190W in C1QTNF5. In silico modeling of the variants revealed that the S190W mutations was likely to have the greatest pathologic effect and that the combination of the mutations was likely to have an additive effect.

Conclusions: The novel mutations in C1QTNF5 identified here expand the genotypic spectrum of mutations causing late-onset retinal dystrophy.

KEYWORDS:

• Macular dystrophy
• nyctalopia
• whole genome sequencing
• C1QTNF5

Acknowledgments

We thank Dr. David Goodsell, Scripps research institute for advice regarding protein modeling.

Disclosure statement

All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

Additional information

Funding

This work was supported by The National Institute for Health Research England (NIHR) for the NIHR BioResource – Rare Diseases project (grant number RG65966); The work was also supported by the Moorfields Eye Hospital, UCL Institute of Ophthalmology NIHR Biomedical Research Centre; Shyamanga Borooah was supported by a Fulbright-Fight for Sight scholarship and a Foundation Fighting Blindness Career Development Award; Joe Marsh was supported by a MRC Career Development Award (MR/M02122X/1); Gavin Arno was sponsored by a Fight for Sight senior research fellowship; Medical Research Council [MR/M02122X/1]; Programme Grants for Applied Research [RG65966].