eCite Digital Repository

Mutation in TMEM98 in a large white kindred with Autosomal Dominant Nanophthalmos linked to 17p12-q12

Citation

Awadalla, MS and Burdon, KP and Souzeau, E and Landers, J and Hewitt, A and Sharma, S and Craig, JE, Mutation in TMEM98 in a large white kindred with Autosomal Dominant Nanophthalmos linked to 17p12-q12, JAMA Ophthalmology, 132, (8) pp. 970-977. ISSN 2168-6173 (2014) [Refereed Article]


Preview
PDF
475Kb
  

Copyright Statement

Copyright 2014 American Medical Association

DOI: doi:10.1001/jamaophthalmol.2014.946

Abstract

IMPORTANCE Nanophthalmos is a congenital disorder characterized by small eyes, with the main complications being severe hyperopia and angle-closure glaucoma. OBJECTIVE To perform a clinical and genetic investigation of a large white family with autosomal dominant nanophthalmos. DESIGN, SETTING, AND PARTICIPANTS Detailed clinical evaluation and a genome-wide linkage scan was conducted in the family NNO-SA1. Linkage was evaluated with a 10K single-nucleotide polymorphism array, followed by whole exome sequencing, to identify novel segregating coding variants within the linked region. The candidate gene was screened for mutations in additional independent families by direct sequencing of the coding exons and intron/exon boundaries. The expression pattern of the candidate gene in ocular tissues was analyzed by reverse transcriptase-polymerase chain reaction. Participants were recruited through ophthalmology clinics at Flinders Medical Centre, Adelaide, South Australia, Australia. Nanophthalmos was defined as an axial length less than 20.0 mm and/or refractive error greater than +7.00. Of the 35 available individuals from family NNO-SA1, 16 participants (46%) had a diagnosis of nanophthalmos, with mean refraction of +11.8 D and mean axial length of 17.6 mm. Unaffected unrelated individuals serving as controls were screened for the identified mutation. Additional independent families with clinically diagnosed nanophthalmos were also recruited. MAIN OUTCOMES AND MEASURES Nanophthalmos status. RESULTS Significant linkage was detected on chromosome 17 between single-nucleotide polymorphism markers rs2323659 and rs967293, with a maximum location score of 4.1. Exome sequencing identified a single novel segregating missense variant within the linkage region located in exon 8 of the transmembrane-98 (TMEM98) gene c.577G>C (p.Ala193Pro), which was absent in the Exome Variant Server database and among 285 local white individuals serving as controls. The TMEM98 gene was expressed in all ocular tissues tested including sclera and optic nerve head. CONCLUSIONS AND RELEVANCE A novel gene associated with nanophthalmos, TMEM98 most likely represents the cause of the disease in this family. To our knowledge, this represents the first gene identified causing autosomal dominant nanophthalmos.

Item Details

Item Type:Refereed Article
Research Division:Medical and Health Sciences
Research Group:Ophthalmology and Optometry
Research Field:Ophthalmology
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Hearing, Vision, Speech and Their Disorders
Author:Burdon, KP (Associate Professor Kathryn Burdon)
Author:Hewitt, A (Dr Alex Hewitt)
ID Code:92404
Year Published:2014
Web of Science® Times Cited:10
Deposited By:Menzies Institute for Medical Research
Deposited On:2014-06-17
Last Modified:2016-06-27
Downloads:46 View Download Statistics

Repository Staff Only: item control page