Cataract 9, Multiple Types

A number sign (#) is used with this entry because multiple types of cataract (CTRCT9) are caused by heterozygous or homozygous mutation in the CRYAA gene (123580), which encodes alpha-A-crystallin, on chromosome 21q22.

Description

Mutations in the CRYAA gene have been found to cause multiple types of cataract, which have been described as nuclear, zonular central nuclear, laminar, lamellar, anterior polar, posterior polar, cortical, embryonal, anterior subcapsular, fan-shaped, and total. Cataract associated with microcornea, sometimes called the cataract-microcornea syndrome, is also caused by mutation in the CRYAA gene. Both autosomal dominant and autosomal recessive modes of inheritance have been reported. The symbol CATC1 was formerly used for the autosomal recessive form of cataract caused by mutation in the CRYAA gene.

Clinical Features

Litt et al. (1998) studied a 4-generation family with autosomal dominant congenital cataracts that had been described as congenital zonular central nuclear opacities. In 5 of the 13 affected family members, the cataracts were also associated with microphthalmia and microcornea. As adults in their thirties, patients developed cortical and posterior subcapsular cataracts as well. The time of surgery had varied from infancy to late childhood. Visual acuity following surgery had been as good as 20/40 in older adults, but several patients had poor vision in each eye associated with nystagmus. Other sequelae common in this family included amblyopia, strabismus, and glaucoma.

Pras et al. (2000) reported 3 sibs from an inbred Jewish Persian family with autosomal recessive congenital cataract. The patients underwent cataract extraction in the first 3 months of life, and no details of the pathologic findings in the lens were available.

Mackay et al. (2003) described a 4-generation Caucasian family segregating an autosomal dominant form of 'nuclear' cataract presenting at birth or during infancy and confined to the central zone or fetal nucleus of the lens. Haplotype analysis indicated that the disease gene lay in the physical interval between 2 markers flanking the CRYAA gene.

Shafie et al. (2006) examined affected members of 4 Chilean families segregating autosomal dominant cataract and found significant intrafamilial variation with respect to morphology, location within the lens, color, and density. In family 'ADC51,' affected members had cataracts in variable locations within the lens and of different densities; the authors documented interocular asymmetry of density and location and progression. The cataracts included nuclear opacities, posterior subcapsular cataracts, and combinations, and 1 individual had a dense white cataract. Two sisters in family 'ADC52' demonstrated differences in morphology and location of cataract. In family 'ADC53,' there were differences in cataract location, density of similar and disparate opacities, morphology, and color among affected members, but morphology and density were the same in each eye. Cataracts included embryonal cataract of varying densities, pulverulent cortical opacities, posterior star-shaped subcapsular cataract with pulverulent opacities in the cortical or embryonal regions, and dense embryonal cataracts. Some individuals described progression, although this was not documented by the authors. Members of family 'ADC54' exhibited significant variability in the morphology and density of the cataracts; 1 individual had interocular differences in the color of opacities. Shafie et al. (2006) concluded that significant intrafamilial variability in cataract morphology and location within the lens is common in autosomal dominant cataract.

Vanita et al. (2006) examined 10 affected and 9 unaffected members of a large 4-generation family of Indian origin segregating autosomal dominant congenital cataract and microcornea. The bilateral fan-shaped cataracts were visible at birth and consisted of a round, oval, or triangular opacity with irregular margins, approximately 3 mm wide, topped by triangular opacities oriented with the base towards the periphery. In a 6-year-old patient, the base of 1 of the triangular opacities coincided with the edge of the fetal nucleus, whereas the 4 other triangular opacities extended beyond the edge of the fetal nucleus. All affected individuals also had microcornea, with corneas that were less than 10 mm in diameter. There were no other ocular abnormalities detected in this family; in particular, no posterior capsular, polar, or cortical opacities were observed in any of the affected individuals.

Santhiya et al. (2006) described a 24-year-old Indian woman who had decreasing vision beginning at age 17 and who was found to have total opacity on slit-lamp examination, with severe loss of vision. There were no other associated ocular anomalies of the anterior or posterior segment. Her mother had undergone cataract surgery at age 35 years. Her 16-year-old brother denied any vision problems, but slit-lamp examination revealed a peripheral ring-like opacity; he later reported difficulty with distance vision.

Beby et al. (2007) reported 12 affected members of a 4-generation French family with autosomal dominant cataract and iris coloboma. All affected individuals had bilateral early-onset cataract, either present at birth or developing during the first years of life, consisting of a single dense axial opacity of 3 mm confined to the embryonic and fetal nuclei of the lens and associated with bilateral iris coloboma in all patients. Two affected individuals also had congenital microphthalmia. No dysmorphic features, mental retardation, or developmental malformations were observed.

Khan et al. (2007) studied a consanguineous Saudi Arabian family in which 2 sisters and a brother had congenital total white cataract and microcornea, with horizontal corneal diameters of approximately 8 mm at 2 years of age. Two of the 3 affected sibs developed bilateral aphakic glaucoma within a few years of cataract surgery. Their parents and 7 sibs were asymptomatic, but a cousin was reported to have a similar phenotype. None of the 3 affected sibs had any other significant medical history, and all other members of the nuclear family had normal vision and no ocular or systemic disease.

Laurie et al. (2013) described a 3-generation South Australian family with lamellar cataract of variable severity. The proband was diagnosed at 2 years of age with moderate fetal nuclear lamellar cataract with no sutural involvement. His brother was diagnosed at 4.5 years of age with a more severe phenotype, described as dense white nuclear cataract. Their asymptomatic mother, maternal uncle, and maternal grandfather all displayed mild lamellar opacity consisting of fine white dots in a single lamellar shell; the uncle also had a cortical rider. These opacities did not affect visual acuity and were only discovered on examination following the children's diagnosis. The proband's 2 younger sisters had no sign of cataract.

Mapping

In a 4-generation family segregating autosomal dominant congenital cataracts described as congenital zonular central nuclear opacities, Litt et al. (1998) found linkage of the disorder, which they referred to as ADCC-2, to chromosome 21q22.3.

In a 4-generation family of Indian origin segregating autosomal dominant fan-shaped cataract and microcornea, Vanita et al. (2006) performed genomewide linkage analysis and obtained 2-point lod scores of 2.833 with marker D21S1260 and 1.906 with D21S1259 (theta = 0 for both). Further analysis gave a maximum lod score of 3.657 with marker D21S1411, and multipoint analysis also supported linkage in this region of chromosome 21, with a maximum lod score of 3.546 at D21S1411. Haplotype analysis revealed recombination events that narrowed the critical region to an interval on chromosome 21q22.3 that was at least 23.5 cM long.

In a consanguineous Saudi Arabian family with congenital total white cataract and microcornea, Khan et al. (2007) obtained a lod score of 2.5 at chromosome 21q22.3, a region containing the candidate gene CRYAA.

Molecular Genetics

In affected members of a family segregating autosomal dominant congenital cataracts mapping to chromosome 21q22.3, Litt et al. (1998) sequenced the coding region of the CRYAA gene and identified a heterozygous missense mutation (R116C; 123580.0001) that segregated with the disorder.

Pras et al. (2000) identified homozygosity for a nonsense mutation in the CRYAA gene (W9X; 123580.0002) in 3 sibs from an inbred Jewish Persian family with autosomal recessive congenital cataract.

In a 4-generation Caucasian family segregating an autosomal dominant form of 'nuclear' cataract presenting at birth or during infancy and confined to the central zone or fetal nucleus of the lens, Mackay et al. (2003) found by haplotype analysis that the disease locus lay in the physical interval between 2 markers flanking the CRYAA gene. Sequence analysis identified a missense mutation (R49C; 123580.0003) in the CRYAA gene in affected individuals.

In a 4-generation family of Indian origin segregating autosomal dominant fan-shaped cataract and microcornea mapping to chromosome 21q22.3, Vanita et al. (2006) identified heterozygosity for the CRYAA R116C missense mutation (123580.0001), previously found in a North American family with a zonular type of congenital cataract (Litt et al., 1998). Vanita et al. (2006) noted that despite an identical mutation, the ocular phenotype was quite different in the 2 families, with the earlier family exhibiting microphthalmia, amblyopia, strabismus, and glaucoma, as well as development of cortical and posterior subcapsular cataracts in the fourth decade of life.

In a sister and brother and their mother with progressive presenile total cataract, Santhiya et al. (2006) analyzed functional candidate genes and identified heterozygosity for a missense mutation in the CRYAA gene (G98R; 123580.0005). The mutation was not found in their unaffected father or sister, in 30 random DNA samples of Indian origin, or in 96 healthy German controls.

In 12 affected and 4 unaffected members of a 4-generation French family with autosomal dominant cataract and iris coloboma, Beby et al. (2007) analyzed microsatellites for 15 known cataract loci and found suggestive linkage at the CRYAA locus on chromosome 21, as well as a specific haplotype segregating with the disease. Sequence analysis of the CRYAA gene revealed that all affected family members were heterozygous for the R116C mutation; the mutation was not found in unaffected individuals. Two affected individuals also had congenital microphthalmia; the authors noted that Cryaa -/- mice have been found to have both microphthalmia and cataract (Brady et al., 1997).

In 3 affected sibs from a consanguineous Saudi Arabian family with congenital total white cataract and microcornea mapping to 21q22.3, Khan et al. (2007) sequenced the candidate gene CRYAA and identified homozygosity for a missense mutation (R54C; 123580.0006). Their asymptomatic parents and 1 sib were found to be heterozygous for the mutation; on slit-lamp examination, all 3 heterozygotes had similar discernible but clinically insignificant bilateral punctate lenticular opacities that were not present in the other asymptomatic family members.

In 10 Danish families segregating autosomal dominant developmental cataract and microcornea, Hansen et al. (2007) analyzed 9 candidate genes and identified 5 families with heterozygous mutations, 3 of which were in the CRYAA gene (123580.0007-123580.0009), 1 in the GJA8 gene (600897.0008), and 1 in the CRYGD gene (123690.0008). Corneal diameters varied between 8 and 10 mm. Nystagmus was present in some families and absent in others, depending primarily on the degree of visual impairment during the first months of life. Cataract phenotypes varied, but often involved the nuclei, with cortical laminar elements and anterior and posterior polar opacities to a variable extent; most cataracts had a clear peripheral zone. In some patients, cataract progression during the first years of life was noted.

Richter et al. (2008) studied 14 affected and 14 unaffected members of a large 4-generation Chilean family, previously reported by Shafie et al. (2006) as 'family ADC54,' segregating autosomal dominant cataract, microcornea, and/or corneal opacity. Richter et al. (2008) found linkage to chromosome 21 with a maximum lod score of 4.89 at D21S171, and identified a heterozygous missense mutation in the CRYAA gene (R116H; 123580.0004) in affected members of the family. There was significant asymmetry of density, morphology, and color of the cataracts within and between affected individuals; the variable morphology included anterior polar, cortical, embryonal, fan-shaped, and anterior subcapsular cataracts. Richter et al. (2008) stated that, with the exception of iris coloboma, the clinical features of all 6 previously reported families with mutations in the CRYAA gene were found in this Chilean family.

In 4 unrelated South Australian families segregating autosomal dominant cataract, Laurie et al. (2013) analyzed 10 known congenital cataract-associated crystallin genes and identified a heterozygous missense mutation in the CRYAA gene (R21Q; 123580.0010) in all affected individuals from 1 of the families.