Meesmann Corneal Dystrophy (MCD) via the KRT12 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 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; Klintworth 2009). 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; Munier et al. 2002). CDs are typically evident in first or second decades of life, and manifestations are restricted to the cornea (Zenteno et al. 2006; Klintworth 2009).

Meesmann corneal dystrophy (MCD) is characterized by fragile corneal epithelium and intraepithelial microcyst formation. MCD is generally mild and affected individuals are often asymptomatic while some suffer from recurrent erosions leading to lacrimation, photophobia, and deterioration in visual acuity (Szaflik et al. 2008).

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 and ZEB1 genes (Poulaki and Colby 2008; Klintworth 2009; Riazuddin et al. 2010; Riazuddin et al. 2013; Bredrup et al. 2005). CHST6 and TACSTD2 pathogenic variants cause autosomal recessive CDs.

Dominant-negative variants in KRIT3 and KRT12 cause dominant Meesmann corneal dystrophy (MCD) (Allen et al. 2016). KRT12 encoded Keratin 12 is an intermediate-filament protein expressed specifically in corneal epithelium (Nishida et al. 1997). Nishida et al. showed that the pathogenic variants found in their cohort were either in the highly conserved alpha-helix-initiation motif of rod domain 1A or in the alpha-helix-termination motif of rod domain 2B, which are essential for keratin filament assembly (Nishida et al. 1997). To date, over 20 causative variants have been reported (Human Gene Mutation Database). Nearly all of these are missense; no pathogenic premature termination variants have been reported to date.

Due to genetic heterogeneity of corneal dystrophy (CD), estimating the clinical sensitivity for some genes is difficult. A mutation spectrum analysis identified TGFBI pathogenic variants in 80% (50/61) of corneal dystrophy patients (Munier et al. 2002). 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). These studies indicate that pathogenic variants in KRT12 are not a common cause of CDs.

This test provides full coverage of all coding exons of the KRT12 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).