Abstract
Purpose :
Axenfeld-Rieger (ARS) and Peters plus syndromes (PPS) are distinct genetic conditions causing anterior segment dysgenesis phenotypes in combination with non-ocular anomalies. While specific genetic causes have been identified, in PITX2 (ARS type 1), FOXC1 (ARS type 3), and B3GLCT (PPS), some patients receive a clinical diagnosis based on overlapping clinical features but remain unexplained genetically.
Methods :
Exome sequencing was undertaken in individuals with ARS, PPS, and overlapping phenotypes but negative analysis of known genes.
Results :
We identified pathogenic variants in KMT2D and SETD1A (KMT2F), lysine methyltransferases that mediate methylation of histone H3, in four individuals. Retrospective analysis showed phenotypic overlap with the genetically diagnosed congenital regulopathy, but these conditions were not initially considered, likely due to the lack of previous association with anterior segment ocular anomalies and phenotypic overlap with known anterior segment syndromes of ARS and PPS. KMT2D has been associated with other developmental ocular anomalies and is known to be important in neural crest development, so an expansion to include anterior segment dysgenesis is consistent with known functions. SETD1A is less well-characterized but does show strong enrichment in the developing mouse eye.
Conclusions :
KMT factors are a novel cause of anterior segment dysgenesis. The presence of rare anterior segment anomalies can distract from identification of other known genetic syndromes, thus unbiased genetic analysis is important for accurate diagnosis.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.