Corneal Dystrophies Panel

Corneal dystrophies (CDs) are rare inherited disorders. Clinically, CDs are characterized as loss of corneal transparency and impaired refraction, which may be caused by a progressive accumulation of deposits (which can be amyloid, hyaline or a combination) on different layers of the cornea. With disease progression, visual acuity gradually decreases and can lead to visual impairment (Correa-Gomez et al. 2007. PubMed ID: 17893671; Klintworth 2009. PubMed ID: 19236704). CDs are non-inflammatory corneal diseases that are classified into three groups based on the sole or predominant anatomical location of the deposits. The three groups are anterior CDs, stromal CDs and posterior CDs. Most CDs exhibit autosomal dominant inheritance with a high degree of penetration. However, CDs present marked inter-and intra-familial variation in clinical expressivity (Klintworth 2009. PubMed ID: 19236704; Munier et al. 2002. PubMed ID: 11923233). CDs are typically evident in first or second decades of life, and manifestations are restricted to the cornea (Zenteno et al. 2006. PubMed ID: 16636649; Klintworth 2009. PubMed ID: 19236704).

Corneal dystrophies (CDs) are genetically heterogeneous. Autosomal dominant and autosomal recessive Mendelian modes of inheritance have been reported. Different types of corneal dystrophies are caused by pathogenic variants in the AGBL1, CHST6, COL8A2, KRIT3, DCN, KRT12, PIKFYVE, SLC4A11, TACSTD2, TGFBI, UBIAD1, VSX1, CHRDL1, CYP4V2, FOXE3, GJA8, GSN, KERA, LOXHD1, MAF, OVOL2, PRDM5, TCF4, ZNF469, PITX2 and ZEB1 genes (Poulaki and Colby 2008. PubMed ID: 18214787; Klintworth 2009. PubMed ID: 19236704; Riazuddin et al. 2010. PubMed ID: 20036349; Riazuddin et al. 2013. PubMed ID: 24094747; Bredrup et al. 2005. PubMed ID 15671264). CHST6, CYP4V2, KERA, LOXHD1, PRDM5, ZNF469 and TACSTD2 pathogenic variants cause autosomal recessive CDs. The remaining genes are all associated with autosomal dominant CDs. All types of pathogenic variants (missense, nonsense, splicing, small insertions/duplications, large deletions and duplications) have been reported in AGBL1 (~2), CHST6 (~150), COL8A2 (~5), ZEB1 (~2), DCN, KRT12 (~20), PIKFYVE (~10), SLC4A11 (~90), TACSTD2 (~25), TGFBI (~65), UBIAD1 (~25), VSX1 (~10) CHRDL1 (~20), CYP4V2 (~80), FOXE3 (~3), GJA8 (~3) GSN (~2), KERA (~10), LOXHD1 (~15), MAF (~2), OVOL2 (~4), PRDM5 (~10), TCF4 (~2), ZNF469 (~30), PITX2 (~1), and ZEB1 (~40) that are causative for CDs (Human Gene Mutation Database).

See individual gene test descriptions for information on molecular biology of gene products and mutation spectra.

Due to genetic heterogeneity, determining the clinical sensitivity is difficult. A mutation spectrum analysis identified TGFBI pathogenic variants in 80% (50/61) of corneal dystrophy patients (Munier et al. 2002. PubMed ID: 11923233). A mutation screening in 26 affected members of 20 Japanese Gelatinous drop-like corneal dystrophy families identified TACSTD2 pathogenic variants in all 26 individuals. A founder mutation c.352C>T(p.Gln118*) was found in 33 out of 40 (82.5%) disease alleles (Tsujikawa et al. 1999. PubMed ID: 10192395).

So far, only in AGBL1, CHST6, CHRDL1, COL8A2, CYP4V2, KRT12, KRT3, LOXHD1, PIP5K3, PITX2, PRDM5, SLC4A11, TACSTD2, TCF4 and UBIAD1 have large deletions and duplications been reported (Human Gene Mutation Database).

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

This panel typically provides 99.3% coverage of all coding exons of the genes 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 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).