Achromatopsia (ACHM) via the ATF6 Gene

Achromatopsia (ACHM) is a congenital, autosomal recessive retinal disorder characterized by total color blindness, decreased visual acuity (lower than 20/200), photophobia, nystagmus and absence of cone-mediated electroretinographic amplitudes at birth or early infancy (Kohl et al. 2005. PubMed ID: 15657609; Kohl et al. 2015. PubMed ID: 26029869; Pang et al. 2010. PubMed ID: 20238068). Estimated prevalence is 1/30,000 (Kohl et al. 2002. PubMed ID: 12077706).

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

Please see the links for clinical trials and management options below:

Management

ACHM Clinical trials

ACHM is a heterogeneous disorder. To date, pathogenic variants in CNGA3, CNGB3, GNAT2, PDE6C, ATF6 and PDE6H have been reported to be causative for autosomal recessive ACHM (Ouechtati et al. 2011. PubMed ID: 21107338; Greenberg et al. 2014. PubMed ID: 24504161; Mastey et al. 2019. PubMed ID: 31237654). CNGA3 and CNGB3 are the major causative genes for ACHM (Kohl et al. 2005. PubMed ID: 15657609). A frameshift protein truncating variant in CNGB3 (c.1148del, p.Thr383Ilefs*13) has been reported as a predominant pathogenic variant (Kohl et al. 2005. PubMed ID: 15657609; Nishiguchi et al. 2005. PubMed ID: 15712225; Wiszniewski et al. 2007. PubMed ID: 17265047). This variant has been reported at a frequency of 0.2% in general population (http://gnomad.broadinstitute.org/variant/8-87656008-AG-A). To our knowledge, de novo variants have not been documented causative in the genes associated with ACHM (HGMD-Human Gene Mutation Database).

ATF6 encodes photoreceptor specific- activating transcription factor 6A, which is a key regulator of the unfolded protein response (UPR) and cellular endoplasmic reticulum (ER) homeostasis. These functions are essential for retina and photoreceptor survival (Kohl et al. 2015. PubMed ID: 26029869; Xu et al. 2015. PubMed ID: 26070061). Mice lacking ATF6 have been shown to have normal retinal morphology and function at a young age, but with increasing age they develop dysfunction of photoreceptor cells (Xu et al. 2015. PubMed ID: 26070061).

So far, about 15 causative ATF6 variants have been identified (missense/nonsense, splicing, small deletions and duplications that result in frameshift and protein truncation) (HGMD).

Pathogenic variants in ATF6 are a rare cause of Achromatopsia. Kohl et al. reported that in their patient cohort, ~1% of European-ancestry individuals with Achromatopsia carried pathogenic variants in ATF6 (Kohl et al. 2015. PubMed ID: 26029869).

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 ATF6 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).