Genetic linkage study of high-grade myopia in a Hutterite population from South Dakota.
OBJECTIVE
Myopia is a common, complex disorder, and severe forms have implications for blindness due to increased risk of premature cataracts, glaucoma, retinal detachment, and macular degeneration. Autosomal dominant (AD) non-syndromic high-grade myopia has been mapped to chromosomes 18p11.31, 12q21-23, 17q21-23, 7q36, 2q37.1, 7p15.3, 15q12-13, 3q26, 4q12, 8p23, 4q22-q27, 1p36, and Xq23-q25. Here, we demonstrate evidence of linkage for AD non-syndromic high-grade myopia in a large Hutterite family to a locus on chromosome 10q21.1.


METHODS
After clinical evaluation, genomic DNA was genotyped from 29 members of a Hutterite family from South Dakota (7 affected). The average refractive error of affected individuals was -7.04 diopters. Microsatellite markers were used to exclude linkage to the known AD nonsyndromic high-grade myopia loci as well as to syndromic high-grade myopia loci. A genome screen was then performed using 382 markers with an average inter-marker distance of 10 cM followed by fine-point mapping in all regions of the genome that gave positive LOD scores. SimWalk2 software was used for multipoint linkage based on AD and autosomal recessive (AR) models with a penetrance of 90% and a disease allele frequency of 0.001.


RESULTS
A maximum multipoint LOD score of 3.22 was achieved under an AD model at microsatellite marker D10S1643. Fine point mapping and haplotype analysis defined a critical region of 2.67 cM on chromosome 10q21.1. Haplotype analysis demonstrated two distinct haplotypes segregating with high-grade myopia, indicative of two distinct mutations occurring in the same gene.


CONCLUSIONS
We have identified a presumptive myopia locus for high-grade myopia based on linkage and haplotype analysis.
Nallasamy
Sudha
S
Division of Ophthalmology, Children's Hospital of Philadelphia, Philadelphia, PA, USA. nallasam@mail.med.upenn.edu <nallasam@mail.med.upenn.edu>
Paluru
Prasuna C
PC
Devoto
Marcella
M
Wasserman
Nora F
NF
Zhou
Jie
J
Young
Terri L
TL
D002874:Chromosome Mapping; D005260:Female; D005799:Genes, Dominant; D008040:Genetic Linkage; D023281:Genomics; D006239:Haplotypes; D006801:Humans; D008126:Lod Score; D008297:Male; D018895:Microsatellite Repeats; D009216:Myopia / Q000235:genetics / Q000503:physiopathology*; D010375:Pedigree; D012029:Refraction, Ocular; D012067:Religion; D012720:Severity of Illness Index; D013023:South Dakota