Cataract 40

A number sign (#) is used with this entry because of evidence that X-linked cataract-40 is caused by mutation in the NHS gene (300457) on Xp22.

Mutation in the NHS gene also causes Nance-Horan syndrome (302350).

Clinical Features

Walsh and Wegman (1937) reported possible X-linked cataract in a triracial group of southern Maryland. (The authors stated that this group was known locally as 'Weesorts.') The affected males had cataracts, described as lamellar, zonular, or perinuclear, with severe visual impairment and pronounced microcornea. Heterozygous females had posterior suture or posterior stellate cataracts, or a combination of the two, with normal or slight reduction in vision.

Fraccaro et al. (1967) reported possible X-linked inheritance of cataract in a 4-generation family from northern Italy in a pattern similar to that found by Walsh and Wegman (1937). Nine males had congenital total nuclear cataract with severe visual impairment, whereas 8 affected females had normal vision and suture catatract and developed cortical cataract in their forties. One of the affected females was also found to have a posterior polar cataract. One normal-sighted male had bilateral anterior polar cataract, consisting of a single punctiform central opacity. No family member was found to have obvious microphthalmia, but measurements were not taken. All affected males were the offspring of affected females. Only 1 of the affected males married and he had an unaffected son.

Witkop-Oostenrijk (1956) described a family with microphthalmia, microcornea, and congenital cataract in which X-linked dominance (possibly with lethality in the affected hemizygote) might be the genetic mechanism; see also Wettke-Schafer and Kantner (1983).

Capella et al. (1963) observed probable X-linked cataract. Nine men had cataract, 4 also had microcornea in one or both eyes, and 1 had small phthisical eyes.

Fraser and Friedmann (1967) observed a family with possible X-linked cataract.

Krill et al. (1969) described a convincingly X-linked pedigree. Suture cataract was found as an early manifestation in hemizygous males. Goldberg and Hardy (1971) described a family in which isolation of cytomegalovirus from the cataract on one male confused the interpretation (and genetic counseling) until a second affected son was born and suture cataracts were detected in the mother.

Crews and Bundey (1982) stated that cataract pedigrees described as suggestive of X-linked inheritance (e.g., Walsh and Wegman, 1937, Fraccaro et al., 1967, Fraser and Friedmann, 1967, Krill et al., 1969, and Pavone et al., 1981) might well represent autosomal dominant inheritance with greater severity in males.

Francis et al. (2002) examined 23 members of a 4-generation family segregating apparent X-linked congenital cataract. All affected males required cataract extraction in the first few months of life and had a uniformly poor outcome. Affected females had very mild central nuclear opacities, requiring no treatment until typically the sixth decade. Francis et al. (2002) noted that the appearance of the cataract in phakic females was distinct from any autosomal dominant cataract seen previously, involving very slowly progressive, fan-shaped cataracts that were nuclear in distribution. There was no evidence of the features of NHS in any affected males or obligate carriers; however, 4 of the 6 affected males had ventriculoseptal defect and other 'complex' cardiac developmental anomalies. No other family members gave a history of cardiac anomalies. None of the affected males had children, so the absence of male-to-male transmission could not be confirmed. Coccia et al. (2009) restudied this family and stated that the congenital heart defects observed in 4 of 6 affected males included ductus arteriosus, tetralogy of Fallot, ventriculoseptal defect, and stenosis of a major cardiac vessel.

Coccia et al. (2009) studied a 3-generation family with X-linked congenital cataract in which the carrier mother had Y-sutural lens opacities and no other abnormalities. Her father had undergone cataract surgery at 45 years of age. One of her affected sons was diagnosed with dense bilateral nuclear cataracts at 6 weeks of age and underwent lens extraction at 12 weeks, at which time posterior lenticonus of the right eye was found. Both eyes had a normal corneal diameter of 11 mm, axial lengths of 17.9 mm and 18 mm, respectively, and no evidence of glaucoma. He had no dysmorphic features characteristic of NHS, but did have a small pit in the ascending limb of the right ear helix, which might represent a small preauricular sinus. His older brother, who showed no NHS features or preauricular sinus, had mild posterior sutural lens opacities not requiring surgery. Both boys also had laryngomalacia, which presented as inspiratory stridor.

Mapping

By linkage studies in a family segregating possible X-linked inheritance of cataract, Fraccaro et al. (1967) found suggestive evidence that the cataract locus may be within measurable distance of the Xg blood group locus.

Francis et al. (2002) performed linkage analysis in a 4-generation pedigree segregating apparent X-linked congenital cataract and confirmed linkage of the family to a 3-cM interval on chromosome Xp22.13 flanked by markers DXS9902 and DXS999 with a lod score of 3.64 for marker DXS8036 (theta = 0.0). Since the condition appeared to be fully penetrant in heterozygous females, lod scores were also calculated modeling for dominant disease, obtaining a lod score of 4.60 for marker DXS8036 (theta = 0.0).

Brooks et al. (2004) performed haplotype analysis in the 4-generation pedigree with X-linked congenital cataract mapping to Xp22.13 previously studied by Francis et al. (2002) and refined the disease interval to a 3.2-Mb segment flanked by markers DXS9902 and S4. Several candidate genes were screened, including RAI2 (300217), but no mutations were found.

Molecular Genetics

In a 4-generation pedigree with X-linked congenital cataract mapping to Xp22.13, originally described by Francis et al. (2002), Brooks et al. (2004) analyzed the NHS gene (300457) but found no mutations. However, Coccia et al. (2009) restudied this family using array comparative genomic hybridization (CGH) and found a complex rearrangement consisting of triplication of a region encompassing the NHS, SCML1 (300227), and RAI2 genes embedded within a duplicated region (300457.0007). Further analysis revealed that 1 copy of the NHS gene lacked exon 1, another copy had all known exons but was disrupted upstream, and a third copy was intact; the 3 copies of SCML1 and RAI2 appeared to be intact. The rearrangement segregated with disease in the family. Coccia et al. (2009) noted that the additional phenotype of congenital heart defects seen in 4 of the 6 affected males in this family could be due to perturbed NHS gene transcription or to increased dosage of the NHS, SCML1, or RAI2 genes. By array CGH and sequencing analysis in another family segregating X-linked congenital cataract over 3 generations, Coccia et al. (2009) identified an approximately 4.8-kb deletion within the large intron 1 of the NHS gene (300457.0008). This deleted interval contains several highly conserved regions, possibly representing potential promoter sequences. Both mutations were predicted to result in altered transcriptional regulation of the NHS gene.

History

Fraccaro et al. (1967) pointed out that the pedigrees of Stieren (1907) and of Halbertsma (1934), which have been frequently cited as examples of X-linked cataract, are not acceptable. In Stieren's pedigree, 7 of 17 affected males had congenital hydrocephalus and all affected males were born blind and died in convulsions. Thus, they may have suffered from a complex syndrome of which cataract was only one feature. Furthermore, 2 unaffected males had daughters who gave birth to affected sons. In Halbertsma's family, in addition to 10 affected males, 3 females had congenital cataract and one had senile cataract.

Falls (1952) reported a family in which zonular cataract and nystagmus appeared to be X-linked. He pointed out, however, that the family was 'incompletely studied.'