Autosomal Dominant Stargardt-Like Macular Dystrophy Founder Effect and Reassessment of Genetic Heterogeneity

OPHTHALMIC MOLECULAR GENETICS

SECTION EDITOR: EDWIN M. STONE, MD, PHD 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

Objectives: To characterize a disease-associated hap- dants, with 7 branches having affected family members. lotype in 7 families with autosomal dominant Stargardt- In addition, we refined the critical region for the gene to like macular dystrophy and to determine whether these approximately 1000 kilobases (kb) and eliminated part families share a common ancestor. or all of 9 candidate disease-causing genes.

Methods: Twenty-five polymorphic DNA markers span- Conclusions: Our study indicates that most reported ning known dominant Stargardt-like gene loci were used cases of autosomal dominant Stargardt-like macular dys- to determine the haplotype associated with disease. In trophy in North America are part of a single larger fam- addition, an extensive genealogical investigation search- ily associated with a gene locus on chromosome 6q16. ing for a common ancestor shared by all of the 7 fami- Furthermore, the DNA haplotype associated with dis- lies was performed. ease is useful in excluding individuals with phenotypi- cally similar retinal conditions. Results: We clinically evaluated 171 patients and genotyped 145 samples. The same DNA haplotype on chro- Clinical Relevance: The disease-associated haplo- mosome 6q16 was shared by all evaluated affected mem- type allows for more accurate genetic counseling to be bers within the 7 families. In addition, we were able to given to individuals with a Stargardt-like phenotype in- genealogically join all of the families into one larger fam- herited in an autosomal dominant pattern. ily consisting of 31 branches and 2314 individuals. Twenty-seven branches have known living descen- Arch Ophthalmol. 2001;119:564-570

AMILIES affected by rare he- Autosomal dominant Stargardt-like reditary diseases are often de- macular dystrophy is another rare heredi- scribedindependentlyandare tary retinal disease reported as occurring From the Henry and Corinne 3-13 Bower Laboratory, Wills Eye usually unrelated. However, independently in several families. Clini- Hospital, Philadelphia, Pa molecular genetic studies can cally, the disease usually presents in the (Dr Donoso and Ms Frost); determineF whether such families share a re- teenage years with decreased visual acu- Department of Ophthalmology lated genomic DNA region containing the ity and atrophy of the macular retinal pig- and Visual Sciences, The Center disease locus. Such findings imply that the ment epithelium with or without sur- for Macular Degeneration, disease actually arose in a common ances- rounding subretinal flecks and progresses University of Iowa, Iowa City tor or founder. For example, Fingert and (Drs Stone and Hageman); associates1 found all 27 glaucoma families For editorial comment Casey Eye Institute, Oregon Health Sciences Center, affected with the GLN386STOP mutation see page 573 Portland (Dr Weleber); in the myocilin gene appeared to be related Department of Ophthalmology, through a common ancestor even though rapidly over several years to legal blind- University of Alberta, they were identified in 4 different patient ness. In 1980, Cibis et al8 described one Edmonton (Dr MacDonald); populations. Equally striking is the obser- such large family consisting of 98 at-risk Children’s Mercy Hospital, vation that all 39 families with radial members. Several other families with simi- Kansas City, Kan (Dr Cibis); drusen (malattia leventinese or Doyne hon- lar clinical features were subsequently de- and the Department of eycomb retinal dystrophy) share a single scribed.3,6,7,9 More recently, we described Ophthalmology, University of identical mutation in the EFEMP1 gene the clinical and genetic features of 4 large Texas Southwestern Medical containing the same pattern of DNA se- families living in the United States.10-13 Two Center, Dallas (Mr Ritter and 2 Dr Edwards). The authors have quence variation (haplotype). Thus, the ra- of these families were found to share a no financial interest in any dial drusen mutation appears to have arisen common set of DNA markers (disease- product or company once in an ancestor shared by all 39 fami- associated haplotype) in the disease gene mentioned in this article. lies who lived on 3 different continents. region of chromosome 6 as well as pater-

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/23/2021 PATIENTS AND METHODS federal agencies. Marriage, death, cemetery, census, hospital, and church records were also searched. Although more The patients in this study comprise one single family. There than 3500 family records were obtained, we include only fami- are 31 branches of this family, with 7 branches (Figure 1) lies with direct links to the founder. having affected members. Each of the 7 affected families were Genomic DNA was obtained from peripheral blood and thought to be independent of one another before this study, extracted using standard techniques (QIAmp Blood MIDI kit; andallwerediagnosedashavingautosomaldominantStargardt- Qiagen, Inc, Santa Barbara, Calif). Of the 27 branches with like macular dystrophy. We use the term family to refer to the living descendants, at least 1 sample was obtained from 16 descendants of the top generation of a pedigree known to the branches. One hundred forty-five samples were genotyped. authors at the time they reported the pedigree. When inde- Genotypes at polymorphic short tandem repeat markers span- pendently identified families are found to be related through ning the disease loci on chromosomes 6q16 (13 markers) and genetic analysis or genealogical investigation, we refer to the 13q34 (12 markers) were determined in selected patients as original families as branches of a new larger family. previously described.10-12 Haplotypes were constructed manu- One hundred seventy-one patients at risk for develop- ally and/or by using the algorithm used in the GENEHUNTER ing the disease were examined. Patients were considered af- software package.14 The disease-associated haplotype is that fected if they showed progressive bilateral visual loss of early set of 13 DNA markers on chromosome 6, which segregates onset and if they had atrophic macular lesions as previously in association with dominant Stargardt-like macular dystro- described.10,12 In all cases, the disease status was determined phy. The disease penetrance was estimated from the age of before genotyping and examination. In cases where the pa- disease onset. The penetrances used were as follows: age 0 to tient had died, the disease status was inferred by clinical his- 10 years, 0.62; age 11 to 20 years, 0.90; age 21 years or older, tory or medical and/or governmental records. This study was 0.99; with a disease allele frequency of 0.000001. Two-point approved by the institutional review board at each institution. linkage analysis was performed in selected members (60 fam- Family records were searched at the facilities of the Lat- ily members) of branches 13, 14, and 30 using 3 chromosome ter Day Saints Family History Center in Salt Lake City, Utah. 6 (D6S286, D6S460, and D6S1609) and 3 chromosome 13 Additional information was obtained from interviews with (D13S158, D13S173, and D13S280) markers using the meth- family members and from records from city, state, and ods as previously described.10

III (14) (15)

(…)

(X…) Branch No. 1 2 3 4 5 6789 101112 13 141516171819202122 232425262728293031

Figure 1. Diagram and pedigree depicting founding family and 31 branches. Circle indicates female; square, male; filled circle or square, affected individual; and diagonal line, deceased individual. Thick arrow indicates branch with known macular dystrophy; thin arrow, branch with no known macular dystrophy; and arrowhead, branch with no known descendants. Numbers at bottom correspond to branch of family. Numbers in parentheses indicate an individual family member. For more details concerning branch 5, see Lagali et al;13 branches 13 and 14, see Edwards et al;12 branch 24, see Stone et al;10 and branch 30, see Zhang et al.11 Information on branches 10 and 20 has not been previously published.

nal ancestors, raising the possibility that other families with RESULTS dominant Stargardt-like dystrophies might be related.12 In this study, we show that 7 affected families are part of DESCRIPTION OF APPARENTLY a single, larger family consisting of more than 2000 indi- INDEPENDENT FAMILIES viduals whose affected members share an identical disease-associated haplotype spanning the gene respon- The phenotypic appearance and the disease-associated sible for this condition located on chromosome 6q16. haplotype were determined in these 7 apparently unre-

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Branch Total No. of No.* Descendants Comment 1 40† No known macular dystrophy; simulating eye condition 2 144† No known macular dystrophy; living descendants 3 4 No known macular dystrophy; living descendants 4 145† No known macular dystrophy; living descendants 5 66† Macular dystrophy; living descendants 6 2 No known macular dystrophy; living descendants 7 2 No known macular dystrophy; living descendants 8 2 No known macular dystrophy; living B descendants 9 9 No known macular dystrophy; living descendants 10 25† Macular dystrophy; no known living descendants 11 1 No descendants 12 1 No descendants 13 238† Macular dystrophy; living descendants 14 179† Macular dystrophy; living descendants 15 50† No known macular dystrophy; living descendants 16 33 No known macular dystrophy; living descendants 17 5 No known macular dystrophy; living descendants 18 63† No known macular dystrophy; living descendants 19 30† No known macular dystrophy; living descendants C 20 37† Macular dystrophy; living descendants 21 1 Died at childbirth 22 80† No known macular dystrophy; simulating eye condition 23 1 No descendants 24 457† Macular dystrophy; living descendants 25 45 No known macular dystrophy; living descendants 26 60 No known macular dystrophy; living descendants 27 192† No known macular dystrophy; living descendants 28 46† No known macular dystrophy; simulating eye condition 29 112 No known macular dystrophy; living descendants 30 157† Macular dystrophy; living descendants 31 87 No known macular dystrophy; living descendants Total 2314 D

*Branch number corresponds to the family branch as shown in Figure 1. †A branch from which a blood specimen was obtained and genotyped.

lated families (Table 1). The disease-associated haplotype was useful in combining the families into one larger family, excluding families with this diagnosis from other families, and refining the chromosomal location of the gene responsible for this condition. The results correlated with the genealogical analysis as described herein.

PHENOTYPIC APPEARANCE The clinical course of disease and the phenotypic ap- Figure 2. Representative fundus photographs of patients with autosomal pearance of the fundus were similar in most patients dominant Stargardt-like macular dystrophy showing atrophy of the retinal pigment epithelium centered on the fovea and surrounding subretinal flecks. within the 7 affected families, although some variations A, Branch 30 (see Zhang et al 11); B, branch 14; C, branch 5; and D, branch were observed (Figure 2).10,12 Early disease was char- 24. Note similarity of phenotype with foveal atrophy and flecks.

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II 12 34 III 1234 IV 12 345 V 1 2345678 5 4 11 3 2 7 1 4 6 1 4 3 2 9 1 4 9 2 9 6 5 2 2 4 3 613 VI 1 23 467 5 8 5 VII 4 11 12345 63 2 78 7 1 5 4 6 5 VIII 4 1 4 4 11 3 3 2 3 2 1234 7 9 1 7 1 5 4 4 9 4 6 5 4 1 2 9 1 4 IX 4 3 3 6 5 3 2 3 1 7 9 2 2 9 1 7 4 4 4 3 4 9 4 5 1 2 613 2 9 1 4 3 6 6 5 3 3 9 2 2 2 9 7 4 4 4 3 4 4 2 613 613 2 1 6 6 3 2 2 9 4 4 4 613 2 613 6 2 4 613

Figure 3. Segregation of chromosomal markers. Although a chromosome 13 haplotype (solid blue bar; see Zhang et al11) appears to segregate with the disease locus (V:8, VI:7, and VII:8), the absence of any portion of this haplotype from other members of the family (VIII:1, IX:1, VIII:4, and VII:6) excludes the disease-causing gene from this region. Conversely, all affected patients in all families with disease segregate chromosome 6 markers (solid black bar) with the disease. The markers used for chromosome 6 were D6S430, D6S313, D6S1681, D6S280, D6S286, D6S460, D6S1609, D6S1601, D6S462, D6S275, D6S417, D6S1720, and D6S300. The markers used for chromosome 13 were D13S154, D13S1252, D13S1284, D13S159, D13S1267, D13S1240, D13S158, D13S1256, D13S174, D13S280, D13S1322, and D13S1311. The numbers adjacent to the solid bars correspond to the haplotype associated with chromosome 6 and 13 markers, respectively. The symbols are described in the legend to Figure 1.

acterized by subfoveal atrophy of the retinal pigment epi- It became apparent during our genealogical inves- thelium with or without the presence of flecks. Later in tigation (see the following section) that branch 30 rep- the disease, the foveal lesions were more pronounced, resented a family that was previously described to ex- often with a beaten-metal appearance. At this stage, most hibit linkage between the disease and markers on of the patients demonstrated subretinal flecks. Patients chromosome 13. Records were identified in this study with late-stage disease often show diffuse geographic at- showing ancestors from this branch lived on a farm rophy with or without flecks (Figure 2). adjacent to other family branches (13, 14, and 24) in the early 1800s, confirming the potential for marriage A SINGLE LARGER FAMILY relationships. Maximal 2-point lod scores at a ␪ of 0.0 for the 3 chromosome 6 markers were 7.47, 12.24, and An identical chromosome 6q16 pattern of DNA mark- 7.49. Removing branch 30 reduced the lod scores to 5.77, ers (haplotype) segregated with the disease gene 10.72, and 6.11, respectively. The 2-point lod scores at (Figure 3) in all affected members of all families stud- a ␪ of 0.0/0.1 for the 3 chromosome 13 markers were ied (branches 5, 10, 13, 14, 20, 24, and 30) but not in −27.91/−2.05, −4.88/0.97, and −6.03/0.20, demonstrat- any of the unaffected family members. The probability ing exclusion of the chromosome 13 interval. The lod of 2 individuals sharing this same disease-associated hap- scores without branch 30 were comparable. The chro- lotype by chance is highly unlikely (approximately 1 in mosome 6 disease-associated haplotype was present in 100 trillion).10 This result indicates that these 7 affected all affected family members of this branch studied. families (1237 total members) are genetically related through a common ancestor or founder. Nonaffected fam- REFINEMENT OF CRITICAL REGION ily members or other family members with juvenile- AND SCREENING OF CANDIDATE GENES onset visual loss, including one case of a patient with a childhood intraocular inflammatory disease and one pa- Analysis of the recombinant individuals within our 7 fami- tient with foveal hypoplasia and nystagmus (Table 1; lies with affected individuals enabled us to refine the ge- branches 1 and 22), did not share the haplotype. nomic location of the gene on chromosome 6q16. As il-

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/23/2021 Sex-Average Novel kb 99110 2022 99111 3015 Sanger Distance, cM STR Markers A N/21 N/31 A Sequence Coverage 6q 0 COL12A1 100 COX7A 234P15.C 234P15.3 1.1 234P15.A 234P15.B 200 D6S1596 474L11.A 474L11.B 300 D6S1659 D6S406 351K21.A 400 SSP1 D6S1622 134M13.A q16.1 0.6 134M13.B MYO6 D6S456 472A9.A 500 IMPG1 501M23.A stSG30792 D6S1589 501M23.B 501M23.C 600 HTR1B 0.6 D6S1625 551A13.C D6S284 551A13.A 1007B16.A 700 D6S286 1007B16.B D6S460 411F9.A 411F9.B 800 WI-11442 0.6 D6S1707 424E5.A 136A11.A D6S463 900 D6S1646 q16.2 D6S445 1000 DKFZp564D156 D6S1652 AK000712 D6S1634 1100 1.2 D6S1609 75K24.A TRIP7 D6S1627 1200 stSG28754 75K24.B Critical Region 75K24.1 D6S1601 stSG24780 159G19.A 1300 stSG53542 357D13.A 1400 stSG24900 0.6 357D13.B q16.3 130P1.A 1500 TTK

1600 260P22.A BCKDH E1 0.8 1700

q21 1800

Figure 4. The refined critical region of STG3 is approximately 1000 kilobases (kb). New short tandem repeat polymorphic markers were identified to refine the disease locus of STG3. The centromeric boundary at 551A13.A is defined by a normal recombinant (99111). Another normal recombinant individual (2022), approximately 30-kb telomeric to 551A13.A at 551A13.C, confirms this refinement. These 2 individuals exclude HTR1B and all centromeric genes. The telomeric boundary of the refined critical region is defined by an affected individual (3015) at 260P22.A. This excludes all genes telomeric to and part of BCKDH E1. Twelve unidentified transcripts, probably representing 6 genes, and 4 known genes lie within this region. The Sanger Centre has sequenced a group of overlapping clones spanning the region with 2 gaps as of September 7, 2000.

lustrated in Figure 4, the critical region is estimated to with disease reported herein can be traced to the mar- be approximately 1000 kilobases (kb) using recombi- riage in 1789 between individuals III:14 and III:15 (Fig- nant data from affected and unaffected individuals. The ure 1). This marriage resulted in 31 family branches critical region using only affected individuals is also illus- (Figure 1), giving rise to a total of 2314 descendants trated. Twenty-seven new short tandem repeat markers (Table 1). The total number of family members ranged were developed using genomic sequence from the Sanger from 1 (branches 11, 12, 21, and 23) to 457 (branch Centre (http://www.sanger.ac.uk/hgp/chr6/) to facilitate 24) members per branch (Table 1). Four of the 31 the refinement. branches (11, 12, 21, and 23) did not give rise to any During refinement of the critical region, we screened descendants. Two branches (1 and 22) gave rise to coding sequence in 9 genes. The status of our screening descendants with early-onset visual loss unrelated to using DNA sequencing of gene exons from 1 unaffected macular dystrophy. and 1 affected individual is shown in Table 2. At this Seven branches, designated as 5, 10, 13, 14, 20, 24, time, we have excluded coding sequence variations in the and 30, have descendants with autosomal dominant human kinase gene (TTK), 3 of 4 exons in a novel pro- Stargardt-like macular dystrophy (Table 1 and Figure tein similar to SH3BGR (75K24.1 in the Sanger data- 1). This includes approximately 200 affected individu- base), an unnamed protein (complementary DNA acces- als (approximately 170 known living). Branch 5 has not sion AK000712) except for exon 8, and thyroid receptor been described previously and consists of 66 members. interacting protein (TRIP7). Branches 13 and 14 consist of 238 and 179 members, respectively (Table 1). Branch 20 is composed of 37 GENEALOGICAL ANALYSIS OF members and has not been described previously. APPARENTLY INDEPENDENT FAMILIES Branch 24 is composed of 457 individuals and repre- sents the largest known branch. Branch 30 is composed Having demonstrated that all of the families studied of 157 members. One branch, designated branch 10, herein were genetically related through a common has no known living descendants with the condition. founder, we performed an extensive genealogical inves- Affected members from this branch were previously tigation to identify the relationships between the fami- evaluated (1964) at the University of Iowa Hospitals lies. This investigation revealed that all of the families and Clinics.

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In Critical EST/Gene Accession Exon Sequencing Status Region Sequence Variants COL12A1 NM_004370 66 Partial screen; excluded by meiotic No None observed U73778-precursor recombinant U73379-splice variant COX7A (liver specific) NM_001865 4 Not screened No . . . 234P15.3 Novel protein similar to (predicted) 7 All exons sequenced No Noncoding polymorphism yeast and worm proteins (C/T-Pos 761) SSP1 AF196304 24 Excluded by meiotic recombinant No . . . MYOVI U90236 33 Partial screen; excluded by meiotic No None observed NM_004999-splice variant 31 recombinant IMPG1 AF047492 17 All exons sequenced No None observed stSG30792 Unidentified transcript ...... No . . . HTR1B NM_000712 1 All exons sequenced No Noncoding polymorphisms (G/T Pos 405; A/G Pos 1772) WI-11442 Unidentified transcript ...... Yes . . . DKFZp564D156 Unidentified transcript ...... Yes . . . Unnamed protein AK000712 13 Sequenced 12 of 13 Yes None observed TRIP7 L40357 (partial Cds) Ͼ5 Not screened Yes . . . stSG28754 Unidentified transcript ...... Yes . . . 75K24.1 AL035700 4 All exons sequenced Yes None observed stSG4780 Unidentified transcript ...... Yes . . . stSG53542 Unidentified transcript ...... Yes . . . stSG24900 Unidentified transcript ...... Yes . . . TTK M86699 22 All exons sequenced Yes Noncoding polymorphisms; G/A-Pos 93 G/T Pos 56 G→T Pos 248 G/A Pos 270 BCKDH E1 NM_000056 11 Not screened Yes . . .

*EST indicates expressed sequence tag: Cds, coding sequence; Pos, position; and ellipses, no data or not done.

COMMENT lated to our family, resulting in an even larger family. This is further supported by our genealogical findings in that Our study demonstrates that most families in the United we only traced the descendants from one marriage (Fig- States and Canada with members diagnosed as having au- ure 1; individuals III:14 and III:15). Since individuals III:14 tosomal dominant Stargardt-like macular dystrophy are and III:15 had a total of 16 brothers and sisters, it is likely related and comprise a single larger family. One of the that several additional families (of either the paternal or unifying clinical features we observed independently was maternal line) gave rise to other descendants with this the similar phenotypic appearance and clinical course of condition. A genealogic investigation of these descen- this disorder among the various affected members of the dants is currently in progress. 7 families.10-13 These features included the early onset of All reported linkage studies10,12 on families with au- progressive visual loss associated with bilateral foveal at- tosomal dominant Stargardt-like macular dystrophy, rophy with or without fundus flecks. However, a dark which are available to us, have localized the disease gene choroid on fluorescein angiography was not a feature of to chromosome 6. Zhang and associates11 previously re- this family as has been observed in a substantial fraction ported linkage to chromosome 13 in branch 30. Our re- of patients with recessive Stargardt macular dystrophy. sults, based on genealogical and molecular genetic find- These relationships among independently described fami- ings, indicate that this branch also is part of the family lies were further demonstrated by a combination of mo- described herein. Ultimately, the genetic defect in this lecular genetic and genealogical approaches. disorder will rely on the identification of the actual disease- A prominent molecular genetic feature of all 7 fami- causing gene and will help clarify this discrepancy. lies was that they shared an identical DNA haplotype on Although the genetic defect has not been identified to chromosome 6. This result indicated that all 7 families date in this disorder, our results have narrowed the genetic descended from a common ancestor or founder. The interval for the disease-causing gene on chromosome 6 to chance of 2 individuals having this same disease- approximately 1000 kb. Several candidate genes (Table 2) associated haplotype is extremely small. A family from inthisinterval,includingCol12A1(collagen-associatedgene), which all of these families arose was subsequently iden- SSP1 (protein kinase gene), MYO6 (myosin 6 gene), TTK tified genealogically. (human kinase gene), and TRIP7 (thyroid receptor inter- Although the size of the family reported herein is acting protein), were screened, and no mutations were iden- large, we are aware of other families9,15,16 that have been tified that correlated with disease status. reported to link to chromosome 6. Based on our results, Although the current population of the United States it is likely that some of these families may also be re- is relatively diverse, the early settlement of the country

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/23/2021 occurred in well-defined movements. One such move- sequence data were produced by the human chromosome 6 ment, the Great Scottish-Irish Movement, occurred in the sequencing group at the Sanger Centre, Wellcome Trust Ge- mid-1700s primarily through Pennsylvania before set- nomic Centre, Hinxton, Cambridge, England. tling in stages to the west and south.17 All of the families Corresponding author and reprints: Albert O. Ed- identified in our study, including individuals III:14 and wards, MD, PhD, Department of Ophthalmology, Univer- III:15 (Figure 1), appear to have originated from this Scot- sity of Texas Southwestern Medical Center, 5323 Harry Hines tish-Irish movement. Furthermore, the 31 branches of Blvd, Dallas, TX 75390-9057 (e-mail: Albert.Edwards this family appear to have settled in a relatively narrow @UTSouthwestern.edu). region in the United States, with most of the known families living within the same or adjacent states. REFERENCES In one branch (10), there were no living descen- 1. Fingert JH, Heon E, Liebman JM, et al. Analysis of myocilin mutations in 1703 dants with macular dystrophy to study. This finding in- glaucoma patients from five different populations. Hum Mol Genet. 1999;8:899- dicates other additional families with this condition may 905. have existed or have not been uncovered to date. Fur- 2. Stone EM, Lotry AJ, Munier FL, et al. A single EFEMP1 mutation is associated thermore, it is not always possible to determine the dis- with both malattia leventinese and Doyne honeycomb retinal dystrophy. Nat Genet. 1999;22:199-202. ease status of early ancestors. This is true in our study as 3. Aaberg TM. Stargardt’s disease and fundus flavimaculatus: evaluation of mor- well. However, in some cases, it is possible to infer it from phologic progression and intrafamilial co-existence. Trans Am Ophthalmol Soc. vital records. For example, 2 individuals were mustered 1986;84:453-487. out of the US Army during the Civil War and received 4. Vail D, Shoch D. Hereditary degeneration of the macula. Trans Am Ophthalmol pensions at ages 17 and 18 years because of blindness, Soc. 1958;56:58-68. 5. Vail D, Shoch D. Hereditary degeneration of the macula, II: follow-up report and implying they inherited the disease genotype. histopathologic study. Trans Am Ophthalmol Soc. 1965;63:51-63. The identification and characterization of this large 6. Bither PP, Berns LA. Stargardt’s disease: a review of the literature. J Am Optom family will be useful both clinically and in studies di- Assoc. 1988;59:106-111. rected toward identifying the gene responsible for this 7. Bither PP, Berns LA. Dominant inheritance of Stargardt’s disease. J Am Optom Assoc. 1988;59:112-117. disorder. The finding that many of these patients are re- 8. Cibis GW, Morey M, Harris DJ. Dominantly inherited macular dystrophy with flecks lated and share an identical disease-associated haplo- (Stargardt). Arch Ophthalmol. 1980;98:1785-1789. type will also be useful in counseling families carrying 9. Zhang K, Kniazeva M, Hutchinson A, Han M, Dean M, Allikmets R. The ABCR the gene for this condition. gene in recessive and dominant Stargardt diseases: a genetic pathway in macular degeneration. Genomics. 1999;60:234-237. 10. Stone EM, Nichols BE, Kimura AE, Weingeist TA, Drack A, Sheffield VC. Clinical Accepted for publication December 14, 2000. features of a Stargardt-like dominant progressive macular dystrophy with ge- This study was supported in part by the Henry and netic linkage to chromosome 6. Arch Ophthalmol. 1994;112:765-772. Corinne Bower Laboratory for Macular Degeneration, Phila- 11. Zhang K, Bither PP, Park R, Donoso LA, Seidman JG, Seidman CE. A dominant delphia, Pa; the Elizabeth C. King Trust, the estates of Mar- Stargardt’s macular dystrophy locus maps to chromosome 13q34. Arch Oph- thalmol. 1994;112:759-764. garet Mercer, Harry B. Wright, Reuben and Mollie Gordon 12. Edwards AO, Miedziak A, Vrabec T, et al. Autosomal dominant Stargardt-like macu- Foundation, and Martha W. S. Rogers, and Research to Pre- lar dystrophy, I: clinical characterization, longitudinal follow-up and evidence for vent Blindness Inc (RPB) (University of Texas Southwest- a common ancestry in families linked to chromosome 6q14. Am J Ophthalmol. ern Medical Center, the University of Iowa, and Wills Eye 1999;127:426-435. Hospital); a career development award from RPB and the 13. Lagali PS, Griesinger IB, Chambers ML, et al. Genetic analysis of a putative Star- gardt’s-like disease gene in a five-generation Canadian family. Invest Ophthal- Foundation Fighting Blindness (Dr Edwards); the Associa- mol Vis Sci. 1999;40(suppl):S602. tion for Macular Diseases, Macular Degeneration Interna- 14. Kruglyak L, Daly MJ, Reeve-Daly MP, Lander ES. Parametric and nonparametric tional, the Kyle Curran Memorial Fund for Juvenile Macu- linkage analysis: a unified multipoint approach. Am J Hum Genet. 1996;58:1347- lar Degeneration (Dr Weleber); Foundation Fighting 1363. 15. Gehrig A, Felbor U, Kelsell RE, Hunt DM, Maumenee IH, Weber BH. Assessment Blindness; and National Institutes of Health grants EY11515 of the interphotoreceptor matrix proteoglycan-1 (IMPG1) gene localized to 6q13- (Dr Hageman), EY10539 (Dr Stone), and EY12699 (Drs q15 in autosomal dominant Stargardt-like disease (ADSTGD), progressive bifo- Edwards and Donoso). Dr Donoso is the Thomas D. Duane cal chorioretinal atrophy (PBCRA), and North Carolina macular dystrophy (MCDR1). Professor of Ophthalmology, Wills Eye Hospital and Jeffer- J Med Genet. 1998;35:641-645. son Medical College, Thomas Jefferson University. 16. Felbor U, Gehrig A, Sauer CG, et al. Genomic organization and chromosomal lo- calization of the interphotoreceptor matrix proteoglycan-1 (IMPG1) gene: a can- Wallace McMeel, MD, provided helpful discussions and didate for 6q linked retinopathies. Cytogenet Cell Genet. 1998;81:12-17. Kang Zhang, MD, provided a fundus photograph. Dale Drake 17. Leyburn JG. The Scotch-Irish: A Social History. Chapel Hill: University of North and Robert Andrew provided genealogical assistance. The Carolina Press; 1962.

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