MERTK mutations account for 2% of cases with inherited retinal dystrophy in a large French cohort

Abstract

Purpose : MER tyrosine kinase (MERTK) encodes a surface receptor in the retinal pigment epithelium playing a critical role in photoreceptor outer segment internalization prior to phagocystosis. Mutations in this gene have been associated with severe autosomal recessive retinal dystrophies in the RCS rat model and in humans. The purpose of this study was to report genetic findings and phenotypic characteristics of patients affected with retinal dystrophies due to mutations in MERTK in a large cohort of patients applying state of the art techniques.

Methods : A large French cohort of 1004 patients with inherited retinal diseases underwent a full ophthalmic examination. Informed consent was obtained from each patient and unaffected family member. The study protocol adhered to the tenets of the Declaration of Helsinki and was approved by the local ethics committee. The DNA of patients with a presumed diagnosis of autosomal recessive Rod-Cone Dystrophy and Cone-Rod Dystrophy was assessed. Microarray analysis, targeted Next Generation Sequencing (NGS) and Sanger sequencing were applied to 904 RCD and 100 Cone-Rod Dystrophies. NGS data was also analyzed to detect Copy Number Variation and cases with large deletion were documented applying Multiplex Ligation-dependent Probe Amplification. Familial cosegregation analysis was performed when possible.

Results : A total of 19 patients from 16 unrelated families were found to carry predicted pathogenic mutations in MERTK including 16 cases of RCD and 3 cases of CRD. Sixteen distinct mutations were identified among which 7 are novel. Mutation spectrum in our cohort includes 2 small deletions, 2 small duplications, 1 large exonic deletion, 2 splice-site defects, 6 missense and 3 nonsense changes. The 19 patients carrying these mutations had severe inherited retinal disease with early onset macular involvement.

Conclusions : Our study revealed that mutations in MERTK account for ~2% of inherited retinal dystrophies in France. This new data are useful in the context of current and future therapeutic trials including gene replacement therapy or cell based therapy.

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