A 69 kb Deletion in chr19q13.42 including PRPF31 Gene in a Chinese Family Affected with Autosomal Dominant Retinitis Pigmentosa

Retinitis pigmentosa (RP) is a common form of inherited retinal degeneration (IRD) that affects approximately 1 in 4000 people worldwide. The disease primarily affects rod photoreceptor cells, but cone photoreceptor cells can also be affected. RP is characterized by phenotypic and genotypic heterogeneity, and night blindness is usually the first symptom, followed by tunnel vision and eventually total blindness. RP can be inherited in different modes, including autosomal dominant, autosomal recessive, and X-linked inheritance. Non-mendelian inheritance patterns, such as digenic and maternal inheritance, can also occur in RP. Additionally, non-syndromic RP is linked to genes expressed specifically in the retina and those involved in the functions of the retinal pigment epithelium and photoreceptors. Currently, over 300 genes have been discovered to be associated with RP. Among them, PRPF31 has been identified as a cause of RP, and its subtype has been designated as RP11. Unfortunately, there is currently no known treatment for PRPF31-related autosomal dominant RP. The most well-known gene therapy for inherited retinal degenerations is the use of AAV through subretinal administration for treating Leber congenital amaurosis type 2, which is also the first FDA-approved gene therapy for IRDs.

A five-generation family with early-onset RP with autosomal dominant inheritance mode was described in a recent study published in Journal of Clinical Medicine by Fudan University researchers: Dr. Yuanzheng Lan, Dr. Yuhong Chen, Dr. Yunsheng Qiao, Dr. Qingdan Xu, Dr. Ruyi Zhai, Dr. Xinghuai Sun, Dr. Jihong Wu and Professor Xueli Chen from Fudan University. Of all the documented RP11 families with PRPF31 significant deletions, it had the longest pedigree. Also, it was the first time the early onset (almost 3 years old) generally manifested in this lineage, which was discovered in all affected individuals, has been described.

The present study aimed to investigate the genetic cause of autosomal dominant retinitis pigmentosa (adRP) and the underlying molecular mechanisms of incomplete penetrance in a Chinese family affected with adRP. The authors conducted ophthalmic examinations for all enrolled family members, and performed whole genome sequencing (WGS), multiplex ligation-dependent probe amplification (MLPA), linkage analysis, and haplotype construction in all participants. They also performed RNA sequencing (RNA-seq) to analyze the regulation mechanism of incomplete penetrance among affected patients, mutation carriers, and healthy controls. In the studied family, authors identified a novel heterozygous large deletion of 69 kilobase (kb) in 19q13.42, which encompassed exon 1 of the PRPF31 gene and five upstream genes: TFPT, OSCAR, NDUFA3, TARM1, and VSTM1. We found that 14 individuals in the family carried this deletion.

Interestingly, three family members were sequenced and diagnosed as non-penetrant carriers (NPCs), which means they carried the genetic mutation but did not manifest the disease phenotype. RNA-seq showed significant differential expression of genes in deletion between mutation carriers and healthy controls. They found that the RP11 pedigree in this study was the largest pedigree compared to other reported RP11 pedigrees with large deletions. All affected members in this family showed early onset, which was considered a special phenotype and was firstly reported in an RP11 family. The differential expression of PRPF31 between affected and unaffected subjects indicated haploinsufficiency as a cause of the disease in the family. Researchers also found that other genes with significant differential expression might play a cooperative effect on the penetrance of RP11.

In summary, this study provides novel insights into the genetic cause and underlying molecular mechanisms of incomplete penetrance in adRP. The identification of a novel large deletion in PRPF31 and five upstream genes and the discovery of a special phenotype in this RP11 family are valuable contributions to the field. The findings may lead to the development of more effective genetic counseling and treatment strategies for patients with adRP.