ZEB1-Associated Corneal Dystrophies via the ZEB1 Gene

Corneal dystrophies (CDs) are rare inherited disorders. Clinically, CDs are characterized as loss of corneal transparency and impaired refraction, which may be caused by 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).

CDs are genetically heterogeneous (Poulaki and Colby. 2008. PubMed ID: 18214787). 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).

Pathogenic variants in ZEB1 are associated with autosomal dominant posterior polymorphous corneal dystrophy (PPCD3) and Fuchs’ endothelial corneal dystrophy (FECD6). To date, ~50 pathogenic variants (missense, nonsense, splicing, small frameshift and large deletions and small frameshift duplications have been reported (Human Gene Mutation Database). Variants that result in Loss of function have been reported in PPCD3, and missense variants that result in reduced protein function have been reported in patients with FECD6 (Lechner et al. 2013. PubMed ID: 23599324; HGMD).

ZEB1 encodes zinc finger E box-binding homeobox 1 (which also is known as transcription factor 8) that may play an important role in maintaining endothelial cell function and corneal clarity. ZEB1 contains two zinc finger domain clusters, located at amino acids 240 to 277 and 918 to 971, which may work in concert in DNA binding (Chung et al. 2014. PubMed ID: 25190660).

The prevalence of ZEB1 pathogenic variants in patients with posterior polymorphous corneal dystrophy (PPCD) varied from 9 to 45% with the majority of pathogenic variants reported in exon 7 (Lechner et al. 2013. PubMed ID: 23599324). Only 2% of the Fuchs’ endothelial corneal dystrophy cases are due to pathogenic variants in ZEB1 (Lechner et al. 2013. PubMed ID: 23599324).

This test provides full coverage of all coding exons of the ZEB1 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).