cataract

Congenital retinal nonattachment consists of a group of sometimes familial conditions for which no responsible gene has been identified.  In a genomic study of 21 consanguineous NCRNA Pakistani families 3 had mutations in ATOH7 and 10 had mutations in familial exudative vitreoretinopathy genes.  Genotyping did not reveal associated mutations in the remaining 38% of these families. It is likely that multiple entities are represented but until the molecular etiologies are identified, no more specific classification is possible.

Studies in mice document that the Atoh7 gene is important to retinal ganglion cell neurogenesis.  In humans, both autosomal recessive PHPV and congenital nonattachment of the retina are associated with microsatellite linkage and haplotype matching to a region at 10q21 adjacent to the ATOH7 gene but so far no causative mutation has been found in this region.  However, studies in large consanguineous kindreds in which a deleted DNA segment adjacent to ATOH7 segregated with the NCRNA phenotype suggest that a transcription regulator may be at fault in the timing and level of ATOH7 expression.

The disorder known as persistent hyperplastic primary vitreous is generally not considered hereditary since it usually occurs unilaterally and sporadically.  It is sometimes found in association with a number of syndromal conditions as well.  However, it has also been reported in familial patterns consistent with both autosomal recessive and autosomal dominant patterns.  DNA mapping of individuals with bilateral disease found in a consanguineous Pakistani kindred with presumed autosomal recessive disease suggests that a locus at 10q11-q21 may be responsible.

Evidence for autosomal dominant inheritance of persistent hyperplastic primary vitreous comes from rare families with an apparent vertical transmission of the condition.

Congenital nonattachment of the retina is also seen in the osteoporosis-pseudoglioma syndrome (250770).  However, this is a syndromal disorder with neurologic and joint disease in addition to porotic, thin, fragile bones (sometimes called the ocular form of osteogenesis imperfecta) resulting from mutations in LRP5 on chromosome 11.

This is an autosomal recessive disorder resulting from mutations in the VSX2 (formerly CHX10) gene located at 14q24.3.  The gene is expressed in progenitor cells of the developing neuroretina and in inner nuclear cells of the adult retina.   Most parents are consanguineous.

This is an autosomal dominant disorder resulting from mutations in the FTL gene located at 19q33.33.  Phenotypic variability is common as expressed by serum ferritin levels and the characteristics of the lens opacities.

A patient with homozygosity of the FTL mutation has been reported but the phenotype resembled that of heterozygous patients.

Cataracts may also be present among other disorders of iron metabolism.  For example, mutations in the gene HFE (6p21.3) that is responsible for a form of hemachromotosis (235200), can also be associated with lens opacities consisting of both general nuclear sclerosis and discrete opacities.  Epilepsy may be part of the phenotype as well. 

Congenital zonular pulverulent cataracts are inherited in an autosomal dominant pattern resulting from missense mutations in the GJA8 gene (1q21.1) that codes for connexin 50.  These belong to a category of lens opacitites now designated "Cataract 1, Multiple Types" in OMIM (116200). They have been detected in multiple populations and ethnic groups around the world.

Mutations in CZP3 at 13q11-13 coding connexin 46 (601885) result in a similar phenotype (Cataracts, Congenital Zonular Pulverulent 3) suggesting that genetic heterogeneity is present.

This was the first disease locus to be linked on a human autosome, in this case to the Duffy blood group locus on chromosome 1.