Congenital Cataracts via the CHMP4B Gene

Cataracts are described as opacification of the crystalline lens of the eye that result in abnormal refraction index and light scattering. Congenital cataracts (CC) 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. CC 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 CHMP4B are causative for autosomal dominant and recessive congenital cataracts (Yamada et al. 2000. PubMed ID: 10909854; Shiels et al. 2007. PubMed ID: 17701905). To date, two missense variants in this gene have been documented causative (Human Gene Mutation Database). Linkage analysis followed by mutation analysis in a large 6-generation White family with autosomal dominant “progressive childhood posterior subcapsular” cataracts identified a heterozygous missense variant (c.386A>T) that segregated with the disease in this large pedigree (Shiels et al. 2007. PubMed ID: 17701905). CHMP4B encoded charged multivesicular body protein is major binding partner of the ALG-2-interacting protein Alix and is involved in multivesicular body sorting (Katoh et al. 2003. PubMed ID: 12860994).

Predicting clinical sensitivity for the CHMP4B gene is challenging due to genetic heterogeneity of cataracts and also due to the limited number of CHMP4B-associated cataract cases.

This test provides full coverage of all coding exons of the CHMP4B 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).