Complex genomic rearrangement with deletion of PITX2 in a Chinese family with Axenfeld-Rieger syndrome: A case report and literature review.

Purpose: This study identified the genetic causes of Axenfeld-Rieger syndrome (ARS) in a Chinese family and evaluated their clinical phenotype and clinical treatment.

Methods: We recruited a Chinese family with ARS. The proband presented with bilateral ectopic pupils, periumbilical redundancy, craniofacial abnormalities, and dental abnormalities after birth and was diagnosed with ARS. The symptoms were the same for her younger brother. Blood samples were collected from four family members: the proband, her brother, and her parents. Whole-genome sequencing (WGS) was performed to identify probable genetic variants in the proband. To confirm the identified variants, samples from the other family members were subjected to quantitative polymerase chain reaction (qPCR) and Sanger sequencing.

Results: Based on the results of WGS, we suspected a deletion region and an inversion region around the PITX2 gene. Through qPCR and Sanger sequencing, we identified a complex rearrangement involving a 6.15 Mb deletion on Chromosome 4, including the PITX2 coding region (Hg38; chr4:110617776-116769011), a 45.71 Mb inversion (Hg38; chr4:116769011-162481408), and a 14-bp deletion (Hg38; chr4:162481409-162481422). Interestingly, the father's copy number was normal, but Sanger sequencing revealed the same breakpoints. This indicated that the father is a balanced rearrangement carrier, and the children are unbalanced rearrangement carriers. While similar deletions and many breakpoints in this region have been reported, this specific rearrangement is novel.

Conclusions: Using WGS, qPCR, and Sanger, we found a complex genomic rearrangement with the deletion of PITX2 in a Chinese family with ARS. The clinical characteristics of the affected individuals were reported. The current findings broaden our understanding of the phenotype and variant spectrum associated with ARS caused by PITX2 deletion.