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Zou, Xuan, MD, PhD*; Fu, Qing, MD; Fang, Sha, PhD; Li, Hui, MD*; Ge, Zhongqi, PhD§,¶; Yang, Lizhu, MD*; Xu, Mingchu, PhD§,¶; Sun, Zixi, MD*; Li, Huajin, MD, PhD*; Li, Yumei, PhD†,§; Dong, Fangtian, MD*; Chen, Rui, PhD§,¶,**,††; Sui, Ruifang, MD, PhD*

doi: 10.1097/IAE.0000000000002242
Original Study: PDF Only

Purpose: To characterize the phenotypic variability and report the genetic defects in a cohort of Chinese patients with biallelic variants of the retinol dehydrogenase 12 (RDH12) gene.

Methods: The study included 38 patients from 38 unrelated families with biallelic pathogenic RDH12 variants. Systematic next-generation sequencing data analysis, Sanger sequencing validation, and segregation analysis were used to identify the pathogenic mutations. Detailed ophthalmic examinations, including electroretinogram, fundus photography, fundus autofluorescence and optical coherence tomography, and statistical analysis were performed to evaluate phenotype variability.

Results: Twenty-five different mutations of RDH12 were identified in the 38 families. Six of these variants were novel. Val146Asp was observed at the highest frequency (23.7%), and it was followed by Arg62Ter (14.5%) and Thr49Met (9.2%). Twenty-three probands were diagnosed with early-onset severe retinal dystrophy, 6 with Leber congenital amaurosis, 7 with autosomal recessive retinitis pigmentosa, and 2 with cone-rod dystrophy. Self-reported nyctalopia occurred in about a half of patients (55.3%) and was significantly more common among older patients (P < 0.01). Nyctalopia was not significantly associated with best-corrected visual acuity (P = 0.72), but older patients had significantly greater best-corrected visual acuity loss (P < 0.01). Only 15.8% of the patients had nystagmus, which was significantly more likely to occur among 36.8% of the patients with hyperopia >3D (P < 0.01) and/or in cases of reduced best-corrected visual acuity (P = 0.01), but was not associated with age (P = 0.87).

Conclusion: Several high-frequency RDH12 variants were identified in patients with inherited retinal dystrophies, most of which were missense mutations. Variable but characteristic phenotypes of a progressive nature was observed. Overall, the findings indicated that biallelic RDH12 mutations are a common cause of early-onset retinal dystrophy and a rare cause of cone-rod dystrophy.

This study describes the phenotypic variability and genetic defects observed in a cohort of 38 Chinese patients with biallelic variants of the RDH12 gene. To the best of our knowledge, our study represents the largest collection of RDH12 patients worldwide to date.

*Department of Ophthalmology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China;

Department of Ophthalmology, Huashan Hospital, Fudan University, Shanghai, China;

School of Statistics, Capital University of Economics and Business, Beijing, China;

§Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas;

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas;

**Structural and Computational Biology and Molecular Biophysics Program, Baylor College of Medicine, Houston, Texas; and

††Program in Developmental Biology, Baylor College of Medicine, Houston, Texas.

Reprint requests: Ruifang Sui, MD, PhD, Department of Ophthalmology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China; e-mail:

The Foundation Fighting Blindness, USA, CD-CL-0808-0470-PUMCH and CD-CL-0214-0637-PUMCH; National Natural Science Foundation of China, China, 81470669; Beijing Natural Science Foundation, China, 7152116; The Chinese Ministry of Science and Technology, China, 2010DFB33430; CAMS Innovation Fund for Medical Sciences, China, CIFMS 2016-12M-1-002; National Eye Institute, USA, R01EY022356, R01EY018571, vision core grant P30EY002520; The Retina Research Foundation, the Foundation Fighting Blindness, USA, BR-GE-0613-0618-BCM.

None of the authors has any financial/conflicting interests to disclose.

© 2019 by Ophthalmic Communications Society, Inc.