Cytogenet. Cell Genet. 22: 295-297 (1978)
Confirmation of genetic heterogeneity in autosomal dominant forms of congenital cataracts from linkage studies P.M . C onneally ,1 A.F. W ilson ,1 A.D. M erritt ,1 E.M . H elveston ,2 C.G. P almer ,1 and L.Y. W ang 1 Departments of 'Medical Genetics and SOphthalmology, Indiana University School of Medicine, Indianapolis, Ind.
Publication No. 77-64 from the Department of Medical Genetics; this work was supported in part by the Indiana University Human Genetics Center, USPHS grant P50 GM 21054, and USPHS training grant T01 GM 1056.
Downloaded by: Univ. of Michigan, Taubman Med.Lib. 141.211.4.224 - 5/12/2018 11:45:37 AM
The first assignment of a disease locus to an autosome was described by R enwick. and L awler .1 They studied a large English pedigree with total nuclear cataract (zonular pulverulent), first described by N ettlesh ip and O g ilv ie ,2 and found linkage with the Duffy (Fy) locus. No definite recombinants were found, and the final probability of linkage, after combination with an a priori probability against linkage, was assessed as 0.977. They also reinvestigated a large Danish pedigree:! which gave no evidence for linkage with the Fy locus, suggesting that at least two separate cataract loci were involved. Later, H ammerstein and Sch o lz 1 studied a six-generation family with hereditary central cataract and found no evidence for linkage with 11 markers, including Fy. Recently, H u n izin g er et al.5 studied a family with autosomal dominant total nuclear cataract. Forty-four members of the family were examined for linkage between the cataract locus and 21 informative marker loci. They found no significant evidence favoring linkage between the cataract locus and any of the informative marker systems which included the Fy locus. In summary, only one cataract family has been shown to be linked to a polymorphic marker (Fy), and all others gave negative scores. This study was initiated to determine whether other families with dominant forms of congenital cataract show linkage with chromosome 1 or other polymorphic markers and thus test for linkage heterogeneity.
Conneallv et al.
296
Gene assignments using family studies
Seven families with dominant congenital bilateral cataract were tested for linkage with a total of 19 marker loci: A BO, Se, MNSs, K, Fy, Ik, P, aHp, PGMj, A M Y ¡, AMY.,, PGD, ACP j, Rh, the parotid saliva markers (Db, Pb, Pa, Pr), and lqh. Linkage analysis was performed using LIPED.G a computer program that analyzes whole families. The diagnosis on all affected family members was confirmed by an ophthalmologist, usually one of us (E.M.H.), and in cases of doubt, a slit-lamp examination was performed.
Table I gives the results for three chromosome 1 markers located near the original cataract locus, Fy, lqh, and AMY, (A M Y / was not informaTable /. Lod scores at various recombination fractions (0) for cataract and Fy, lqh, and A M Y , for seven families. Family No.
Ind. No.
1 2 3 4 5 6 7
18 79 25 12 35 12 7
1 2 3 4 5 6 7
18 79 25 12 35 12 7
1 2 3 4 5 6 7
18 79 25 12 35 12 7
Recombination fraction (0) 0.0
0.05
0.10
0.20
0.30
0.40
-0.17 -2.50 -2.31 -0.42 0.28 0.28 -
0.0 -1.49 -1.48 -0.20 0.42 0.26 -
0.05 -0.71 -0.72 -0.05 0.40 0.20 -
0.0 -0.40 -0.34 -0.01 0.25 0.15 -
-0.03 -0.19 -0.12 0.00 0.08 0.08 -
2.45 -1.85 -0.52 0.69 -0.38 -1.00 NT
2.20 -1.26 -0.29 0.61 -0.17 -0.70 NT
1.66 -0.69 -0.12 0.43 -0.03 -0.40 NT
1.10 -0.39 -0.05 0.25 -0.01 -0.22 NT
0.53 -0.17 -0.01 0.09 0.00 -0.10 NT
-1.72 -0.42 0.01
-1.14 -0.17 0.01
-0.59 0.02 0.01
-0.30 0.07 0.00 -
-0.11 0.06 0.00
Fy — oo — CO — oo — oo
-2.27 0.30 —a lq h
2.70 — OO
-3.74 0.78 -3.22 — OO
NTb A M Y 2 — oc — oo
0.02 -
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
0.17
0.14
0.12
0.07
0.03
0.01
Downloaded by: Univ. of Michigan, Taubman Med.Lib. 141.211.4.224 - 5/12/2018 11:45:37 AM
» Not informative. I»Not tested.
Conneally et al.
Gene assignments using family studies
297
tive). Only family 1 showed definite evidence for linkage, in this case with lqh. The maximum lod score was 2.70 at a recombination fraction of 0.0. This represents odds of 500:1 in favor of linkage. However, the results for Fy are inconclusive. Inspection of the pedigree showed that all Fy-informative matings were intercrosses; thus the amount of information relative to linkage was minimal. Other than family 4, which gave slightly positive scores with lqh but negative scores with Fy, and family 7, which had very little information, close linkage of cataract with Fy, lqh, and AMY, could be effectively ruled out. Furthermore, no evidence for linkage in these families to the other loci could be demonstrated. Family 1 is the first confirmation of linkage of the cataract locus to chromosome 1 since the original assignment 15 years ago. The cataract in this family is clinically identical to that in the original N ettlesh ip and O g ii .vie family. The clinical description of this cataract in the two affected sons of the proband was as follows: the lenticular opacities present were located in the fetal nucleus with scattered, fine, diffuse cortical opacities and incomplete cortical riders similar to those described by N ettlesh ip and O g ilv ie .123456 These results further substantiate the hypothesis of genetic hetero geneity, i.e., that two or more loci are involved in the etiology of dominant congenital cataract.
1 R enwick, J.H. and L awler, S.D.: Probable linkage between a congenital cataract locus and the Duffy blood group locus. Ann. hum. Genet. 27: 67-84 (1963). 2 N ettleship, E. and Ogilvie , F.M.: A peculiar form of hereditary congenital cataract. Trans. Ophthal. Soc. U.K. 26: 191-206 (1906). 3 M ohr, J.: Estimation of linkage between the Lutheran and the Lewis blood groups. Acta path, microbiol. scand. 29: 339-344 (1951). 4 H ammerstein, W. and Scholz, W.: Familiäre Form einer “Cataracta centralis”: klinisch-genetische Studie mit Koppelungsdaten. Arch. Klin. exp. Ophthal. 189: 9-19 (1974). 5 H untzinger, R.S.; W eitkamp, L.R., and Roca, P.D.: Linkage relationship of a locus for congenital total nuclear cataract. J. med. Genet. 75: 113-115 (1977). 6 O tt, J.: Estimation of the recombination fraction in human pedigrees: efficient computation of the likelihood for human linkage studies. Am. J. hum. Genet. 26: 588-597 (1974).
Downloaded by: Univ. of Michigan, Taubman Med.Lib. 141.211.4.224 - 5/12/2018 11:45:37 AM
The technical assistance of M.J. Dobbs and the field studies of M. F ox-T aggart and N. W ilkinson are gratefully acknowledged. We wish to express our appreciation for the assistance provided by the computing facilities of the Indiana University computing network.
Confirmation of genetic heterogeneity in autosomal dominant forms of congenital cataracts from linkage studies P.M . C onneally ,1 A.F. W ilson ,1 A.D. M erritt ,1 E.M . H elveston ,2 C.G. P almer ,1 and L.Y. W ang 1 Departments of 'Medical Genetics and SOphthalmology, Indiana University School of Medicine, Indianapolis, Ind.
Publication No. 77-64 from the Department of Medical Genetics; this work was supported in part by the Indiana University Human Genetics Center, USPHS grant P50 GM 21054, and USPHS training grant T01 GM 1056.
Downloaded by: Univ. of Michigan, Taubman Med.Lib. 141.211.4.224 - 5/12/2018 11:45:37 AM
The first assignment of a disease locus to an autosome was described by R enwick. and L awler .1 They studied a large English pedigree with total nuclear cataract (zonular pulverulent), first described by N ettlesh ip and O g ilv ie ,2 and found linkage with the Duffy (Fy) locus. No definite recombinants were found, and the final probability of linkage, after combination with an a priori probability against linkage, was assessed as 0.977. They also reinvestigated a large Danish pedigree:! which gave no evidence for linkage with the Fy locus, suggesting that at least two separate cataract loci were involved. Later, H ammerstein and Sch o lz 1 studied a six-generation family with hereditary central cataract and found no evidence for linkage with 11 markers, including Fy. Recently, H u n izin g er et al.5 studied a family with autosomal dominant total nuclear cataract. Forty-four members of the family were examined for linkage between the cataract locus and 21 informative marker loci. They found no significant evidence favoring linkage between the cataract locus and any of the informative marker systems which included the Fy locus. In summary, only one cataract family has been shown to be linked to a polymorphic marker (Fy), and all others gave negative scores. This study was initiated to determine whether other families with dominant forms of congenital cataract show linkage with chromosome 1 or other polymorphic markers and thus test for linkage heterogeneity.
Conneallv et al.
296
Gene assignments using family studies
Seven families with dominant congenital bilateral cataract were tested for linkage with a total of 19 marker loci: A BO, Se, MNSs, K, Fy, Ik, P, aHp, PGMj, A M Y ¡, AMY.,, PGD, ACP j, Rh, the parotid saliva markers (Db, Pb, Pa, Pr), and lqh. Linkage analysis was performed using LIPED.G a computer program that analyzes whole families. The diagnosis on all affected family members was confirmed by an ophthalmologist, usually one of us (E.M.H.), and in cases of doubt, a slit-lamp examination was performed.
Table I gives the results for three chromosome 1 markers located near the original cataract locus, Fy, lqh, and AMY, (A M Y / was not informaTable /. Lod scores at various recombination fractions (0) for cataract and Fy, lqh, and A M Y , for seven families. Family No.
Ind. No.
1 2 3 4 5 6 7
18 79 25 12 35 12 7
1 2 3 4 5 6 7
18 79 25 12 35 12 7
1 2 3 4 5 6 7
18 79 25 12 35 12 7
Recombination fraction (0) 0.0
0.05
0.10
0.20
0.30
0.40
-0.17 -2.50 -2.31 -0.42 0.28 0.28 -
0.0 -1.49 -1.48 -0.20 0.42 0.26 -
0.05 -0.71 -0.72 -0.05 0.40 0.20 -
0.0 -0.40 -0.34 -0.01 0.25 0.15 -
-0.03 -0.19 -0.12 0.00 0.08 0.08 -
2.45 -1.85 -0.52 0.69 -0.38 -1.00 NT
2.20 -1.26 -0.29 0.61 -0.17 -0.70 NT
1.66 -0.69 -0.12 0.43 -0.03 -0.40 NT
1.10 -0.39 -0.05 0.25 -0.01 -0.22 NT
0.53 -0.17 -0.01 0.09 0.00 -0.10 NT
-1.72 -0.42 0.01
-1.14 -0.17 0.01
-0.59 0.02 0.01
-0.30 0.07 0.00 -
-0.11 0.06 0.00
Fy — oo — CO — oo — oo
-2.27 0.30 —a lq h
2.70 — OO
-3.74 0.78 -3.22 — OO
NTb A M Y 2 — oc — oo
0.02 -
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
0.17
0.14
0.12
0.07
0.03
0.01
Downloaded by: Univ. of Michigan, Taubman Med.Lib. 141.211.4.224 - 5/12/2018 11:45:37 AM
» Not informative. I»Not tested.
Conneally et al.
Gene assignments using family studies
297
tive). Only family 1 showed definite evidence for linkage, in this case with lqh. The maximum lod score was 2.70 at a recombination fraction of 0.0. This represents odds of 500:1 in favor of linkage. However, the results for Fy are inconclusive. Inspection of the pedigree showed that all Fy-informative matings were intercrosses; thus the amount of information relative to linkage was minimal. Other than family 4, which gave slightly positive scores with lqh but negative scores with Fy, and family 7, which had very little information, close linkage of cataract with Fy, lqh, and AMY, could be effectively ruled out. Furthermore, no evidence for linkage in these families to the other loci could be demonstrated. Family 1 is the first confirmation of linkage of the cataract locus to chromosome 1 since the original assignment 15 years ago. The cataract in this family is clinically identical to that in the original N ettlesh ip and O g ii .vie family. The clinical description of this cataract in the two affected sons of the proband was as follows: the lenticular opacities present were located in the fetal nucleus with scattered, fine, diffuse cortical opacities and incomplete cortical riders similar to those described by N ettlesh ip and O g ilv ie .123456 These results further substantiate the hypothesis of genetic hetero geneity, i.e., that two or more loci are involved in the etiology of dominant congenital cataract.
1 R enwick, J.H. and L awler, S.D.: Probable linkage between a congenital cataract locus and the Duffy blood group locus. Ann. hum. Genet. 27: 67-84 (1963). 2 N ettleship, E. and Ogilvie , F.M.: A peculiar form of hereditary congenital cataract. Trans. Ophthal. Soc. U.K. 26: 191-206 (1906). 3 M ohr, J.: Estimation of linkage between the Lutheran and the Lewis blood groups. Acta path, microbiol. scand. 29: 339-344 (1951). 4 H ammerstein, W. and Scholz, W.: Familiäre Form einer “Cataracta centralis”: klinisch-genetische Studie mit Koppelungsdaten. Arch. Klin. exp. Ophthal. 189: 9-19 (1974). 5 H untzinger, R.S.; W eitkamp, L.R., and Roca, P.D.: Linkage relationship of a locus for congenital total nuclear cataract. J. med. Genet. 75: 113-115 (1977). 6 O tt, J.: Estimation of the recombination fraction in human pedigrees: efficient computation of the likelihood for human linkage studies. Am. J. hum. Genet. 26: 588-597 (1974).
Downloaded by: Univ. of Michigan, Taubman Med.Lib. 141.211.4.224 - 5/12/2018 11:45:37 AM
The technical assistance of M.J. Dobbs and the field studies of M. F ox-T aggart and N. W ilkinson are gratefully acknowledged. We wish to express our appreciation for the assistance provided by the computing facilities of the Indiana University computing network.
