GNAT2 – Achromatopsia

GNAT2 encodes the cone photoreceptor transducin α-subunit and is the third gene implicated in autosomal recessive Achromatopsia after CNGA3 and CNGB3. Protein-truncating GNAT2 variants were first reported in five unrelated families with biallelic loss-of-function mutations, demonstrating segregation with disease in each pedigree (PMID:12077706). Subsequent multicenter screening identified 23 additional patients from 19 independent families harboring likely pathogenic GNAT2 variants, accounting for 1.7% of over 1,100 ACHM families screened (PMID:31058429). A case report in a Japanese patient confirmed structural cone preservation with functional loss in vivo for a homozygous c.730_743del allele (PMID:27718025).

Inheritance is autosomal recessive, with segregation demonstrated across at least five pedigrees. Functional characterization identified a core set of loss-of-function alleles including nonsense (e.g., c.481C>T (p.Arg161Ter)), frameshift, and splice-site mutations, as well as copy-number variants affecting exon 4 (PMID:31058429). Twenty-two distinct potentially pathogenic variants—including 12 novel changes—span coding and noncoding regions, with most predicted to abrogate GNAT2 function.

Functional studies support pathogenicity: heterologous splicing assays of the intronic c.461+24G>A variant reveal leaky splicing and early chain termination, explaining variable phenotypes (PMID:15557429); adaptive optics imaging displays a contiguous but nonfunctional cone mosaic in GNAT2-related ACHM, contrasting the disorganized mosaics observed in CNGA3/CNGB3 cases (PMID:27718025).

A cohort screening of 36 achromats identified no GNAT2 mutations, underscoring locus heterogeneity and indicating GNAT2 accounts for a minority of ACHM cases (PMID:15712225).

Overall, comprehensive genetic and experimental evidence establishes a Strong ClinGen gene–disease validity for GNAT2-associated achromatopsia. GNAT2 should be included in diagnostic gene panels for congenital cone dysfunction, enabling precise molecular diagnosis, carrier screening, and informing future gene-targeted therapies.

Key take-home: GNAT2 loss-of-function variants cause autosomal recessive achromatopsia with preserved cone structure but absent function, supporting its clinical testing utility.

References

• American Journal of Human Genetics • 2002 • Mutations in the cone photoreceptor G-protein alpha-subunit gene GNAT2 in patients with achromatopsia PMID:12077706
• Human Mutation • 2019 • Mutation spectrum and clinical investigation of achromatopsia patients with mutations in the GNAT2 gene PMID:31058429
• Japanese Journal of Ophthalmology • 2017 • In vivo imaging of a cone mosaic in a patient with achromatopsia associated with a GNAT2 variant PMID:27718025
• Investigative Ophthalmology & Visual Science • 2004 • Variant phenotypes of incomplete achromatopsia in two cousins with GNAT2 gene mutations PMID:15557429
• Human Mutation • 2005 • Cone cGMP-gated channel mutations and clinical findings in patients with achromatopsia, macular degeneration, and other hereditary cone diseases PMID:15712225

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