Axenfeld‐Rieger syndrome: Further clinical and array delineation of four unrelated patients with a 4q25 microdeletion

Abstract

Axenfeld-Rieger syndrome (ARS) is an autosomal dominant disorder with variable expressivity. It is characterized by dysgenesis of the anterior segment of the eye together with dental, cardiac, and umbilical anomalies. There is a high incidence of secondary high tension glaucoma. It is a genetically heterogeneous condition due to deletion or mutations of FOXC1 (6p25) or PITX2 (4q25). We report on four unrelated patients with overlapping microdeletions encompassing PITX2 at 4q25. We compare the genotypes and phenotypes of these newly described ARS patients and discuss the involvement of contiguous genes. Patients 1, 2, and 3 had mild learning difficulties, not typically seen in patients with ARS. We implicate the adjacent neuronally expressed genes; NEUROG2, UGT8, NDST3, and PRSS12 as potentially causal. Our findings support the use of microarray analysis in ARS patients for full prognostic information in infants presenting with ARS-like phenotypes.

A novel 4q25 microdeletion encompassing PITX2 associated with Rieger syndrome

“…Previous studies have found that patients with gene microdeletions including PITX2 had some phenotypes that do not occur in patients with classic RS, such as short stature and learning or behavioral difficulties (Lines et al., ; Titheradge et al., ). However, the patient in our study, who had gene microdeletions, did not show these non‐RS symptoms.…”

“…In the present study, we reported a novel deletion involving PITX2 and ENPEP in a Chinese patient with RS. To date, about 11 microscopic deletions including PITX2 have been reported in relation to RS, accounting for 13% of all patients with this condition (D'Haene et al., ; de la Houssaye et al., ; Engenheiro et al., ; Lines et al., ; Seifi et al., ; Titheradge et al., ). To our knowledge, our study represents the first case of RS caused by CNV of the PITX2 gene in a proband of Chinese pedigree.…”

“…Titheradge et al. () reported four patients with deletions that overlapped PITX2 at 4q25 and observed that three of them had learning difficulties (Titheradge et al., ). On comparing the contiguous genes of the deletion regions, they found that the patient with no learning difficulties had the smallest microdeletion, including only PITX2 , ENPEP , and two other pseudogenes, while the other three patients had a deletion region encompassing more contiguous genes.…”

“…On comparing the contiguous genes of the deletion regions, they found that the patient with no learning difficulties had the smallest microdeletion, including only PITX2 , ENPEP , and two other pseudogenes, while the other three patients had a deletion region encompassing more contiguous genes. Through genotype–phenotype correlation, NEUROG2 , UGT8 , NDST3 , and PRSS12 were proposed as candidate genes responsible for cognitive impairment and congenital anomalies (Titheradge et al., ). In the present study, the deletion region was comparatively small (encompassing only PITX2 and ENPEP ) and did not include these five neuronal genes, which could explain why our patient had no learning difficulties.…”

“…The genes included in the deleted region may have contributed to this difference. Titheradge et al (2014) reported four patients with deletions that overlapped PITX2 at 4q25…”