Mutation in TMEM98 in a large white kindred with autosomal dominant nanophthalmos linked to 17p12-q12.
OBJECTIVE
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.


METHODS
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.


METHODS
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
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.
Department of Ophthalmology, Flinders University, Flinders Medical Centre, Adelaide, South Australia, Australia.
Mona S
MS
Awadalla
Department of Ophthalmology, Flinders University, Flinders Medical Centre, Adelaide, South Australia, Australia2now also with Menzies Research Institute Tasmania, University of Tasmania, Tasmania, Australia.
Kathryn P
KP
Burdon
Department of Ophthalmology, Flinders University, Flinders Medical Centre, Adelaide, South Australia, Australia.
Emmanuelle
E
Souzeau
Department of Ophthalmology, Flinders University, Flinders Medical Centre, Adelaide, South Australia, Australia.
John
J
Landers
now also with Menzies Research Institute Tasmania, University of Tasmania, Tasmania, Australia3Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, University of Melbourne, Melbourne, Victoria, Australia.
Alex W
AW
Hewitt
Department of Ophthalmology, Flinders University, Flinders Medical Centre, Adelaide, South Australia, Australia.
Shiwani
S
Sharma
Department of Ophthalmology, Flinders University, Flinders Medical Centre, Adelaide, South Australia, Australia.
Jamie E
JE
Craig
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002886:Chromosomes, Human, Pair 17; D059472:Exome; D005260:Female; D008040:Genetic Linkage; D015812:Glaucoma, Angle-Closure / Q000235:genetics*; D006801:Humans; D006956:Hyperopia / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008850:Microphthalmos / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D020641:Polymorphism, Single Nucleotide
D008565:Membrane Proteins; C000592526:TMEM98 protein, human