Hum Genet (1992) 90 : 177-178
human .. gene cs 9 Springer-Verlag 1992
Autosomal dominant congenital cataract and microphthaimia associated with a familial t(2;16) translocation Yuji Yokoyama, Kouji Narahara, Kazushiro Tsuji, Shinsuke Ninomiya, and Yoshiki Seino Department of Pediatrics, Okayama University Medical School, 2-5-1 Shikata-cho Okayama, 700 Japan Received April 13, 1992
Summary. We describe a family in which autosomal dominant congenital cataract and microphthalmia were segregating together with a reciprocal translocation t(2;16) (p22.3;p13.3) through three generations. This family included four individuals with balanced translocations, three with partial trisomy 2p derived from this translocation, and two with a normal karyotype. All of the subjects with balanced and unbalanced translocations had congenital cataract and microphthalmia, whereas the two individuals with normal karyotypes did not show any ocular anomalies. These observations suggest that the altered function of a gene that lies on the 16p13.3 band and that has an important role in the development of the eye is responsible for this disorder.
Introduction Congenital cataract is one of major ocular anomalies in infancy. Although an etiology is unknown in many cases, the disorder is often hereditary, familial or associated with other ocular anomalies or systemic diseases. Hereditary cataracts are usually inherited as an autosomal dominant trait. The autosomal recessive or X-linked form is rare. At least 13 different types of autosomal dominantly inherited congenital cataract have been documented (McKusick 1990), 4 of which have been mapped to specific human chromosome regions by genetic or cytogenetic studies (Human Gene Mapping 10 1989). We report a family exhibiting the segregation of congenital cataract with microphthalmia, and in which a translocation t(2;16) has occurred.
Case report The proband, a 7-month-old boy, was referred to us for the evaluation of multiple congenital malformations. The infant was born at 37 weeks of gestation to a 39-year-old mother and an unrelated 25year-old father. The pregnancy was complicated by threatened abortion during the first trimester. He was delivered uneventfully by cephalic presentation. The birth weight was 2150 g. He showed poor weight gain, developmental retardation and hypotonia. Physical examination showed a prominent forehead, hypertelorism, Correspondence to: Y. Yokoyama
malformed cars, a flat nasal bridge, downturned corners of the mouth, short fingers, ventricular septal defect and shawl scrotum. Ophthalmologic examination showed cataract and microphthalmia. The anterior chambers were well formed, and the horizontal corneal diameters were 10 ram. The globes were small and the anteroposterior diameters were 16ram as measured by echogram. It was not possible to examine the fundus because of the total opacity of the lens. His clinical features were in accordance with trisomy 2p syndrome, except for the ocular findings (Schinzel 1984).
Results Cytogenetic study of short-term cultures of peripheral blood lymphocytes of the proband showed extra chromosomal material on the short arm of one chromosome 16. His mother, who also had congenital cataract and microphthalmia, was found to have a balanced reciprocal translocation between the short arms of chromosomes 2 and 16. High-resolution banding led to the identification of breakpoints localized at bands 2p22.3 and 16p13.3 (Fig. 1). Pedigree and cytogenetic studies of this family showed the segregation of congenital cataract and microphthalmia and the t(2;16) translocation through 3 generations (Fig. 2). Of 12 family members (8 males and 4 females), 10 had congenital cataract and microphthalmia. The balanced translocation t(2;16)(p22.3;p13.3) was found in 4 subjects (I-l, II-2, II-4 and II-6), and the unbalanced translocation resulting in partial trisomy 2p in 3 subjects (III-2, III-5 and III-6). The 2 patients with partial trisomy 2p (III-2 and III-6) have previously been described by other investigators (Nagano et al. 1980; Mitsudo et al. 1982). However, their karyotypes were erroneously reported to be t(2;16)(p13;pll). All of the subjects with balanced and unbalanced translocations had congenital cataract and microphthalmia, whereas the 2 subjects with normal karyotypes (III-3 and III-4) did not exhibit any ocular abnormalities. The eldest uncle (II-1) and his daughter (III-1) both of whom had congenital cataract refused to be involved in the cytogenetic study. In this family, the disorder was more severe in the male than in the female subjects: all of the males with the balanced translocation were totally blind and worked as masseurs. To define more precisely the localization of the breakpoints in the t(2;16) translocation, we performed molecular analysis in the proband. Dot blot analysis of
178
Fig. 1. Partial GTG-banded karyotypes of the mother (a) and proband (b)
1
2
1
Ill Fig. 2. Pedigree data. An arrow indicates the proband. [ ] ID 2p Trisomy; ~ ) t(2:16)(p22.3;p13.3): ~D@ normal karyotype; [ ] @ not examined: [ ] (]D congenital cataract
the H B A 1 locus with pJW101, which maps to the terminal portion of the short arm of chromosome 16 ( H u m a n Gene Mapping 10.5 1990), showed only a single copy of this locus in the proband (data not shown),
Discussion
The studied family presented with autosomal dominant cataract and microphthalmia and had a t(2;16)(p22.3; p13.3) translocation. The autosomal dominant inheritance was confirmed by the presence of male to male transmission of the disorder, Three inherited diseases associated with cataract and microphthalmia have been reported (McKusick 1990): microphthalmia-cataract (No. 156850); cataract, microphthalmia and nystagmus (No. 212550); and cataract, congenital, with microcornea or
slight microphthalmia (No. 302300). The clinical findings and the m o d e of inheritance in this family makes a diagnosis of microphthalmia-cataract most likely. Specific chromosome abnormalities and linkage studies may localize the gene. Four genes associated with autosomal dominant cataract were listed and m a p p e d in H u m a n G e n e Mapping 10 (1989): C A E (cataract, zonular pulverulent) on lq21-q25, C A P (cataract, anterior polar) on 2p25 or 14q24, C C L (cataract, Coppock-like) on 2q33-q35, and C T M (cataract, Marner type) on 16q22.1. The loci for C A E , C C L and CTM were defined by linkage and hybridization studies, whereas that for C A P was determined by the segregation of an apparently balanced t(2;14) translocation with congenital cataract in a family (Moross et al. 1984). Recently, Weaver et al. (1991) reported a case of isolated bilateral microphthalmia and cataracts associated with a de novo inv(2)(p21q31). However, the patient had other ocular anomalies, such as persistent pupillary m e m b r a n e . The authors suggested that bands 2p21 and 2q31 are possible sites for genes involved in the development of the optic region. Our report is unique in that cataract and microphthalmia segregated with not only balanced but also unbalanced t(2;16)(p22.3:p13.3) translocations. Congenital cataract has never been described in association with trisomy 2p (Schinzel 1984), except for one patient who was reported by Nagano et al. (1980), and who also belonged to the family that we have studied. These findings indicate that the gene(s) responsible for the ocular anomaly in this family are located at one of the breakpoints of the translocation, viz., 16p13.3. Furthermore, molecular analysis has assigned the locus as being proximal to H B A 1 in the 16p13.3 region. We believe that disruption in this region, of a gene concerned with the embryologic development of the eye leads to microphthalmia and cataract. Acknowledgement. We express our gratitude to the Japanese
Cancer Research Resources Bank for providing the DNA probe, pJW 101.
References
Human Gene Mapping 10 (1989) 10th International Workshop on Human Gene Mapping. Cytogenet Cell Genet 51: 1-1148 Human Gene Mapping 10.5 (1990) Update to the 10th International Workshop on Human Gene Mapping. Cytogenet Cell Genet 55 : 1-786 McKusick VA (1990) Mendelian inheritance in man. Catalogs of autosomal dominant, autosomal ressesive, and X-linked phenotypes+ 9th edn. Johns Hopkins University Press, Baltimore Mitsudo K, Tanaka M, Hayashi K, Ukita M, Kajitani T, Kitano H (1982) A case of partial 2p trisomy with thyroxine binding globulin deficiency (in Japanese). Ann Paediatr Jpn 28: 125-134 Moross T, Vaithilingam SS, Styles S, Gardner HA (1984) Autosomal dominant anterior polar cataracts associated with familial 2;14 translocation. J Med Genet 21:52-53 Nagano H, Kano Y, Kobuchi S, Kajitani T (1980) A case of partial 2p trisomy with neuroblastoma. Jpn J Hum Genet 25 : 39-45 Schinzel A (1984) Catalogue of unbalanced chromosomc aberrations in man. de Gruyter, Berlin NewYork, pp 109-11(I Weaver RG, Rao N, Thomas IT, Pettenati MJ (199l) De novo inv(2)(p21q31) associated with isolated bilateral microphthalmia and cataracts. Am J Med Genet 40 : 509-512
human .. gene cs 9 Springer-Verlag 1992
Autosomal dominant congenital cataract and microphthaimia associated with a familial t(2;16) translocation Yuji Yokoyama, Kouji Narahara, Kazushiro Tsuji, Shinsuke Ninomiya, and Yoshiki Seino Department of Pediatrics, Okayama University Medical School, 2-5-1 Shikata-cho Okayama, 700 Japan Received April 13, 1992
Summary. We describe a family in which autosomal dominant congenital cataract and microphthalmia were segregating together with a reciprocal translocation t(2;16) (p22.3;p13.3) through three generations. This family included four individuals with balanced translocations, three with partial trisomy 2p derived from this translocation, and two with a normal karyotype. All of the subjects with balanced and unbalanced translocations had congenital cataract and microphthalmia, whereas the two individuals with normal karyotypes did not show any ocular anomalies. These observations suggest that the altered function of a gene that lies on the 16p13.3 band and that has an important role in the development of the eye is responsible for this disorder.
Introduction Congenital cataract is one of major ocular anomalies in infancy. Although an etiology is unknown in many cases, the disorder is often hereditary, familial or associated with other ocular anomalies or systemic diseases. Hereditary cataracts are usually inherited as an autosomal dominant trait. The autosomal recessive or X-linked form is rare. At least 13 different types of autosomal dominantly inherited congenital cataract have been documented (McKusick 1990), 4 of which have been mapped to specific human chromosome regions by genetic or cytogenetic studies (Human Gene Mapping 10 1989). We report a family exhibiting the segregation of congenital cataract with microphthalmia, and in which a translocation t(2;16) has occurred.
Case report The proband, a 7-month-old boy, was referred to us for the evaluation of multiple congenital malformations. The infant was born at 37 weeks of gestation to a 39-year-old mother and an unrelated 25year-old father. The pregnancy was complicated by threatened abortion during the first trimester. He was delivered uneventfully by cephalic presentation. The birth weight was 2150 g. He showed poor weight gain, developmental retardation and hypotonia. Physical examination showed a prominent forehead, hypertelorism, Correspondence to: Y. Yokoyama
malformed cars, a flat nasal bridge, downturned corners of the mouth, short fingers, ventricular septal defect and shawl scrotum. Ophthalmologic examination showed cataract and microphthalmia. The anterior chambers were well formed, and the horizontal corneal diameters were 10 ram. The globes were small and the anteroposterior diameters were 16ram as measured by echogram. It was not possible to examine the fundus because of the total opacity of the lens. His clinical features were in accordance with trisomy 2p syndrome, except for the ocular findings (Schinzel 1984).
Results Cytogenetic study of short-term cultures of peripheral blood lymphocytes of the proband showed extra chromosomal material on the short arm of one chromosome 16. His mother, who also had congenital cataract and microphthalmia, was found to have a balanced reciprocal translocation between the short arms of chromosomes 2 and 16. High-resolution banding led to the identification of breakpoints localized at bands 2p22.3 and 16p13.3 (Fig. 1). Pedigree and cytogenetic studies of this family showed the segregation of congenital cataract and microphthalmia and the t(2;16) translocation through 3 generations (Fig. 2). Of 12 family members (8 males and 4 females), 10 had congenital cataract and microphthalmia. The balanced translocation t(2;16)(p22.3;p13.3) was found in 4 subjects (I-l, II-2, II-4 and II-6), and the unbalanced translocation resulting in partial trisomy 2p in 3 subjects (III-2, III-5 and III-6). The 2 patients with partial trisomy 2p (III-2 and III-6) have previously been described by other investigators (Nagano et al. 1980; Mitsudo et al. 1982). However, their karyotypes were erroneously reported to be t(2;16)(p13;pll). All of the subjects with balanced and unbalanced translocations had congenital cataract and microphthalmia, whereas the 2 subjects with normal karyotypes (III-3 and III-4) did not exhibit any ocular abnormalities. The eldest uncle (II-1) and his daughter (III-1) both of whom had congenital cataract refused to be involved in the cytogenetic study. In this family, the disorder was more severe in the male than in the female subjects: all of the males with the balanced translocation were totally blind and worked as masseurs. To define more precisely the localization of the breakpoints in the t(2;16) translocation, we performed molecular analysis in the proband. Dot blot analysis of
178
Fig. 1. Partial GTG-banded karyotypes of the mother (a) and proband (b)
1
2
1
Ill Fig. 2. Pedigree data. An arrow indicates the proband. [ ] ID 2p Trisomy; ~ ) t(2:16)(p22.3;p13.3): ~D@ normal karyotype; [ ] @ not examined: [ ] (]D congenital cataract
the H B A 1 locus with pJW101, which maps to the terminal portion of the short arm of chromosome 16 ( H u m a n Gene Mapping 10.5 1990), showed only a single copy of this locus in the proband (data not shown),
Discussion
The studied family presented with autosomal dominant cataract and microphthalmia and had a t(2;16)(p22.3; p13.3) translocation. The autosomal dominant inheritance was confirmed by the presence of male to male transmission of the disorder, Three inherited diseases associated with cataract and microphthalmia have been reported (McKusick 1990): microphthalmia-cataract (No. 156850); cataract, microphthalmia and nystagmus (No. 212550); and cataract, congenital, with microcornea or
slight microphthalmia (No. 302300). The clinical findings and the m o d e of inheritance in this family makes a diagnosis of microphthalmia-cataract most likely. Specific chromosome abnormalities and linkage studies may localize the gene. Four genes associated with autosomal dominant cataract were listed and m a p p e d in H u m a n G e n e Mapping 10 (1989): C A E (cataract, zonular pulverulent) on lq21-q25, C A P (cataract, anterior polar) on 2p25 or 14q24, C C L (cataract, Coppock-like) on 2q33-q35, and C T M (cataract, Marner type) on 16q22.1. The loci for C A E , C C L and CTM were defined by linkage and hybridization studies, whereas that for C A P was determined by the segregation of an apparently balanced t(2;14) translocation with congenital cataract in a family (Moross et al. 1984). Recently, Weaver et al. (1991) reported a case of isolated bilateral microphthalmia and cataracts associated with a de novo inv(2)(p21q31). However, the patient had other ocular anomalies, such as persistent pupillary m e m b r a n e . The authors suggested that bands 2p21 and 2q31 are possible sites for genes involved in the development of the optic region. Our report is unique in that cataract and microphthalmia segregated with not only balanced but also unbalanced t(2;16)(p22.3:p13.3) translocations. Congenital cataract has never been described in association with trisomy 2p (Schinzel 1984), except for one patient who was reported by Nagano et al. (1980), and who also belonged to the family that we have studied. These findings indicate that the gene(s) responsible for the ocular anomaly in this family are located at one of the breakpoints of the translocation, viz., 16p13.3. Furthermore, molecular analysis has assigned the locus as being proximal to H B A 1 in the 16p13.3 region. We believe that disruption in this region, of a gene concerned with the embryologic development of the eye leads to microphthalmia and cataract. Acknowledgement. We express our gratitude to the Japanese
Cancer Research Resources Bank for providing the DNA probe, pJW 101.
References
Human Gene Mapping 10 (1989) 10th International Workshop on Human Gene Mapping. Cytogenet Cell Genet 51: 1-1148 Human Gene Mapping 10.5 (1990) Update to the 10th International Workshop on Human Gene Mapping. Cytogenet Cell Genet 55 : 1-786 McKusick VA (1990) Mendelian inheritance in man. Catalogs of autosomal dominant, autosomal ressesive, and X-linked phenotypes+ 9th edn. Johns Hopkins University Press, Baltimore Mitsudo K, Tanaka M, Hayashi K, Ukita M, Kajitani T, Kitano H (1982) A case of partial 2p trisomy with thyroxine binding globulin deficiency (in Japanese). Ann Paediatr Jpn 28: 125-134 Moross T, Vaithilingam SS, Styles S, Gardner HA (1984) Autosomal dominant anterior polar cataracts associated with familial 2;14 translocation. J Med Genet 21:52-53 Nagano H, Kano Y, Kobuchi S, Kajitani T (1980) A case of partial 2p trisomy with neuroblastoma. Jpn J Hum Genet 25 : 39-45 Schinzel A (1984) Catalogue of unbalanced chromosomc aberrations in man. de Gruyter, Berlin NewYork, pp 109-11(I Weaver RG, Rao N, Thomas IT, Pettenati MJ (199l) De novo inv(2)(p21q31) associated with isolated bilateral microphthalmia and cataracts. Am J Med Genet 40 : 509-512
