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Autosomal Dominant Stargardt-like Macular Dystrophy
Founder Effect and Reassessment of Genetic Heterogeneity
Larry A. Donoso, MD, PhD;
Arcilee T. Frost, MA;
Edwin M. Stone, MD, PhD;
Richard G. Weleber, MD;
Ian M. MacDonald, MD;
Gregory S. Hageman, PhD;
Gerhard W. Cibis, MD;
Robert Ritter III, MS;
Albert O. Edwards, MD, PhD
Arch Ophthalmol. 2001;119:564-570.
Objectives To characterize a disease-associated haplotype in 7 families with autosomal
dominant Stargardt-like macular dystrophy and to determine whether these families
share a common ancestor.
Methods Twenty-five polymorphic DNA markers spanning known dominant Stargardt-like
gene loci were used to determine the haplotype associated with disease. In
addition, an extensive genealogical investigation searching for a common ancestor
shared by all of the 7 families was performed.
Results We clinically evaluated 171 patients and genotyped 145 samples. The
same DNA haplotype on chromosome 6q16 was shared by all evaluated affected
members within the 7 families. In addition, we were able to genealogically
join all of the families into one larger family consisting of 31 branches
and 2314 individuals. Twenty-seven branches have known living descendants,
with 7 branches having affected family members. In addition, we refined the
critical region for the gene to approximately 1000 kilobases (kb) and eliminated
part or all of 9 candidate disease-causing genes.
Conclusions Our study indicates that most reported cases of autosomal dominant Stargardt-like
macular dystrophy in North America are part of a single larger family associated
with a gene locus on chromosome 6q16. Furthermore, the DNA haplotype associated
with disease is useful in excluding individuals with phenotypically similar
retinal conditions.
Clinical Relevance The disease-associated haplotype allows for more accurate genetic counseling
to be given to individuals with a Stargardt-like phenotype inherited in an
autosomal dominant pattern.
From the Henry and Corinne Bower Laboratory, Wills Eye Hospital, Philadelphia,
Pa (Dr Donoso and Ms Frost); Department of Ophthalmology and Visual Sciences,
The Center for Macular Degeneration, University of Iowa, Iowa City (Drs Stone
and Hageman); Casey Eye Institute, Oregon Health Sciences Center, Portland
(Dr Weleber); Department of Ophthalmology, University of Alberta, Edmonton
(Dr MacDonald); Children's Mercy Hospital, Kansas City, Kan (Dr Cibis); and
the Department of Ophthalmology, University of Texas Southwestern Medical
Center, Dallas (Mr Ritter and Dr Edwards). The authors have no financial interest
in any product or company mentioned in this article.
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