Anterior Segment Dysgenesis via the CPAMD8 Gene

Anterior segment dysgenesis (ASD) disorders are rare developmental disorders in which the anterior segment of the eye including the iris, cornea, lens and trabecular meshwork are affected and result in a spectrum of anomalies such as aniridia, cataracts and glaucoma that lead to visual disability in childhood (Ito and Walter. 2014. PubMed ID: 24433355; Brémond-Gignac et al. 2010. PubMed ID: 20806047; Semina et al. 2001. PubMed ID: 11159941).

ASD can be an isolated or a syndromic disorder with systemic defects. Onset varies from congenital, juvenile and later depending on type of disorder (Reis and Semina. 2011. PubMed ID: 21730847). The most common syndromic ASD disorders are Axenfeld–Rieger syndrome (ARS), Peters’ anomaly, and systemic anomalies including Alagille syndrome, SHORT syndrome and Pierson syndrome (Doucette et al. 2011. PubMed ID: 21150893). ASD is associated with a ~50% risk for glaucoma (Alward. 2000. PubMed ID: 11004268).

All the CPAMD8-associated ASD affected individuals show distinct ocular manifestations that include bilateral iris hypoplasia, ectopia lentis, corectopia, ectropion uveae, and cataracts (Cheong et al. 2016. PubMed ID: 27839872).

With the advent of gene therapy and other types of treatments, the identification of causative genes and variants is becoming increasingly important.

Anterior segment dysgenesis (ASD) demonstrates both autosomal dominant and recessive patterns of inheritance, often with incomplete penetrance and variable expressivity (Alward. 2000. PubMed ID: 11004268; Cheong et al. 2016. PubMed ID: 27839872; Hollmann et al. 2017. PubMed ID: 28683140).

CPAMD8 is associated with a rare unique form of autosomal recessive Anterior segment dysgenesis. CPAMD8 encodes C3 and PZP-like alpha-2-macroglobulin domain-containing protein 8, which has been shown to have spatiotemoporal expression (Cheong et al. 2016. PubMed ID: 27839872). RT-PCR and in situ hybridization revealed CPAMD8 is expressed in the iris, cornea, and embryonic neural retina, including strong expression in the distal tips of the retinal neuroepithelium that form the iris and ciliary body and weak expression in lens. These results were consistent with the CPAMD8 expression in the affected tissues. Impaired CPAMD8 function possibly disrupts the normal development of the lens and iris structures (Cheong et al. 2016. PubMed ID: 27839872). CPAMD8 has been cited as a nonessential gene for growth of human tissue culture cells (Online Gene Essentiality, ogee.medgenius.info).

CPAMD8 is associated with Morgagnian cataract in cattle, which suggests a role in lens development (Hollmann et al. 2017. PubMed ID: 28683140; Braun et al. 2019. PubMed ID: 31877171

So far, about 5 causative variants (missense, splicing, small frameshift deletions and insertions) have been reported in CPAMD8. No de novo variants have been documented to date (Human Gene Mutation Database).

Predicting clinical sensitivity for the CPAMD8 gene is challenging due to genetic heterogeneity and the limited number of reported cases. All the documented causative variants are detectable by this NGS technology.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the CPAMD8 gene plus 10 bases flanking noncoding DNA in all available transcripts in addition to 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).