Autosomal Dominant Congenital Cataracts via the MIP Gene

Cataracts are described as opacification of the crystalline lens of the eye that result in abnormal refraction index and light scattering. Congenital cataracts are a leading cause of reversible blindness in childhood. They account for one-tenth of the cases of childhood blindness (Francis and Moore. 2004. PubMed ID: 14743013). Estimated prevalence rate is 1.2 - 6.0 per 10,000 live births. Early diagnosis and surgery and optical correction have resulted in an improved outcome for infants with either unilateral or bilateral cataracts (Lambert and Drack. 1996. PubMed ID: 8724637).

Only 10–25% of congenital cataracts are hereditary. Cataracts are most often inherited as an autosomal dominant trait. Cataracts also exhibit autosomal recessive or X-linked inheritance (Hejtmancik. 2008. PubMed ID: 18035564). X-linked cataract is seen in Nance-Horan syndrome (NHS), which is an especially rare disorder. NHS has cataracts along with prominent dental findings, dysmorphic features, and intellectual disability (Toutain et al. 1997. PubMed ID: 9048931; Stambolian et al. 1990. PubMed ID: 1971992). Currently, isolated or primary cataracts have been mapped to about 39 genetic loci, and over 25 of those are connected to pathogenic variants in specific genes. However, this number is constantly increasing (Hejtmancik. 2008. PubMed ID: 18035564).

Pathogenic variants in MIP are causative for autosomal dominant and recessive congenital cataracts, with recessive being the rare form (Gu et al. 2007. PubMed ID: 17893667; Bateman et al. 1986. PubMed ID: 3456204; Bateman et al. 2000. PubMed ID: 10937580). To date, ~25 pathogenic variants have been reported. The majority of the pathogenic variants that cause dominant congenital cataracts are missense variants, although all types of variants have been reported in both the dominant and recessive forms (Yu et al. 2014. PubMed ID: 24405844; Human Gene Mutation Database). There is no specific correlation regarding the genotype and specific forms of cataracts.

MIP encodes lens water channel protein AQP0 (major intrinsic protein), which is an abundant junctional membane protein that controlls the water content for the lens and also as a cell-to-cell adhesion molecule. AQP0 is expressed only in terminally differentiated fiber cells, which are the major cell type of the crystalline lens (Gu et al. 2007. PubMed ID: 17893667; Kumari et al. 2013. PubMed ID: 24120416). Pathogenic missense variants have been reported to impair cell-to-cell adhesion, which plays a vital role in maintaining lens transparency and homeostasis (Kumari et al. 2013. PubMed ID: 24120416).

In one study, whole exome sequencing identified causative variants in 39% of families affected by cataracts. The genes studied were CRYAA, CRYBB1, CRYBB3, CRYGC, CRYGD, GJA8, and MIP. The MIP gene accounted for only one family (Reis et al. 2013. PubMed ID: 23508780).

This test provides full coverage of all coding exons of the MIP gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).