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To the Editor We read with interest the article titled “Mutation in TMEM98 in a Large White Kindred With Autosomal Dominant Nanophthalmos Linked to 17p12-q12” by Awadalla et al.1 The authors described a novel variant (c.577G>C, p.A193P) in TMEM98 that is associated with autosomal dominant nanophthalmos in a large family.
Based on exome sequencing of approximately 1200 samples from Chinese individuals with various forms of genetic eye diseases in our laboratory (in a study approved by the institutional review board of the Zhongshan Ophthalmic Center, Guangzhou, China), 4 novel heterozygous variations in TMEM98 were detected and then confirmed using Sanger sequencing, including c.2T>C (p.M1?), c.56C>T (p.S19L), c.149T>C (p.I50T), and c.398A>C (p.K133T) (Figure and Table 1). The first 3 variants were identified in patients with high myopia, and the last was found in a patient with cone-rod dystrophy. None of these patients had signs of nanophthalmos. None of these 4 variations was detected in 576 alleles from 288 unrelated healthy individuals.
Pedigrees are shown to the left (+ indicates wild-type allele; M, mutant allele; arrows, probands; squares, males; circles, females; and blackened symbols, affected individuals), sequences with variations are shown in the middle, and sequences from healthy controls are shown to the right. The variations are described under each sequence.
Segregation analysis of the 4 variants in a limited number of available family members is shown in the Figure. The c.2T>C (p.M1?) variation failed to cosegregate with high myopia in family HM851. The clinical data of the patients are shown in Table 2.
High myopia, cone-rod dystrophy, and nanophthalmos are distinct entities. The association of multiple mutations in the same gene with these completely distinct phenotypes would be unusual. In another gene associated with nanophthalmos, MFRP,2 no mutations were identified in 407 families with high myopia (Q.Z., unpublished data, August 17, 2014). In addition, TMEM98 encodes a transmembrane protein that is widely expressed throughout human tissues and could play a role in chemoresistance of hepatocellular carcinoma.3 Therefore, additional studies seem warranted to validate the association between TMEM98 mutations and nanophthalmos.
Corresponding Author: Qingjiong Zhang, MD, PhD, State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 54 Xianlie Rd, Guangzhou 510060, China (firstname.lastname@example.org).
Published Online: November 27, 2014. doi:10.1001/jamaophthalmol.2014.4915.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
Funding/Support: This work was supported by grants U1201221 from the National Natural Science Foundation of China, S2013030012978 from the Natural Science Foundation of Guangdong, and 2011A080300002 from Guangdong Department of Science and Technology Translational Medicine Center and by fundamental research funds of the State Key Laboratory of Ophthalmology (Dr Zhang).
Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Additional Contributions: We thank the patients and their family members for their participation.
Sun W, Zhang Q. Does the Association Between TMEM98 and Nanophthalmos Require Further Confirmation? JAMA Ophthalmol. 2015;133(3):358–359. doi:10.1001/jamaophthalmol.2014.4915
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