A case series found that isolated congenital keratoglobus is likely an inherited, autosomal recessive disorder. These findings were published in JAMA Ophthalmology.
Unrelated nonconsanguineous families (N=3) who had members with isolated congenital keratoglobus were recruited between 2019 and 2021 at the Shamir Medical Center in Israel. Whole exome sequencing was performed and results from affected (n=4) and unaffected (n=3) family members were compared. A knockout mouse model was used to assess for a possible ocular phenotype.
All families had some Ashkenazi descent and affected individuals exhibited thin corneas, high corneal astigmatism, and protruding corneas with deep anterior chambers.
From family 1, sequencing revealed that both unaffected parents were heterozygous carriers of a truncating variant in transmembrane protein 45A (TMEM45A) at site rs201699180. The 2 affected children in this family were homozygous carriers for the variant and the unaffected child was a heterozygous carrier.
The affected individual from family 2 was found to be homozygous for the same variant and the affected individual from family 3 was heterozygous for the variant with an additional variant at rs766210908 which was an intron acceptor site. Data from unaffected individuals from families 2 and 3 were not available.
A polymerase chain reaction (PCR) analysis of the variant at rs766210908 carried by the heterozygous affected individual revealed a shorter than expected product by ~907 bases.
Using a mouse model, mice that were deficient of TMEM45A exhibited thinner stroma than wildtype mice (40 to 50 µm vs 80 to90 μm). No evidence of anterior stromal disruption was observed, and the epithelial and endothelial layers of the cornea appeared normal.
This study was limited by the low sample size and lack of corneal tissue samples from affected individuals, however, due to the rarity of the condition, recruitment was difficult.
These data confirmed previous studies which related keratoglobus with TMEM45A variants and indicated that the condition is likely inherited in an autosomal recessive manner. Screening for rare variants may improve early diagnosis and allow for genetic counseling of individuals at high risk.
Weiner C, Hecht I, Kotlyar A, et al. Association of variants in TMEM45A with keratoglobus. JAMA Ophthalmol. Published online August 9, 2021. doi:10.1001/jamaophthalmol.2021.3172