A frequent variant in the Japanese population determines quasi-Mendelian inheritance of rare retinal ciliopathy

Abstract

ABSTRACT

Evidence for secondary-variant genetic burden and non-random distribution across biological modules in a recessive ciliopathy

“…Focusing on comprehensive set of known disease-causing genes allows a sensible, functionally-driven hypothesis to be tested that also avoids the well-established pitfalls of single-gene candidate studies. Indeed, our findings are concordant with recent studies of other genetic disorders, including Charcot-Marie-Tooth disease 24 and retinitis pigmentosa 25 . We speculate that the systematic measurement of burden of other genetically-heterogeneous disorders in which all the causal genes are considered as one "baseline" entity (essentially a functional operon) will reveal similar burden observations, which in turn can be used to understand biological and biochemical substructure.…”

Systematic detection of Mendelian and non-Mendelian variants associated with retinitis pigmentosa by genome-wide association study

“…Recently, enrichment of the G843E variant in EYS in a group of patients with hereditary retinal degenerations (HRD) that carried a quasi-Mendelian allele in another gene (c.5797C>T/p.R1933* in RP1), has been reported 4 , suggesting indeed a non-Mendelian, oligogenic role of EYS in retinal degeneration. In our study, RP1-R1933* was infrequent among carriers of EYS-G843E, but this maybe attributable to gross differences in the clinical phenotypes considered (macular degeneration or cone-rod dystrophy in the RP1 report 4,37 vs. canonical ARRP, studied here) Furthermore, while in heterozygous carriers RP1-R1933* seems to exert its pathogenic functions via the co-presence of EYS-G843E and other hypomorphic alleles outside of the RP1 locus 4 , a reciprocal mechanism is not forcibly true, since molecular pathology of EYS-G843E in ARRP may follow different routes, as clearly shown above. Taken together, these results emphasize the unexpected pleiotropic role of EYS-G843E with respect to the range of unconventional genetic influence and its effect on clinical phenotypes.…”

“…GWAS also identified a novel RP-associated EYS signal (Peak 2) with no rare exonic or splice site variants in LD that could account for ARRP. It is possible that another quasi-Mendelian mutation in LD with Peak 2 in the non-coding regions remains undetected after targeted re-sequencing 4,7,19 . However, the higher frequency of the lead variant (AF = 0.216) for this peak is distinct from those of the other peaks (AF = 0.041 and 0.0005), resulting in a lower OR (1.83) well within the range of those for more common retinal diseases 38 .…”

“…RP affects approximately 1 in 3,000 people worldwide. The disease is highly heterogenous presenting with a various hereditary pattern 1 ranging from classical Mendelian inheritance to non-Mendelian inheritance due to incomplete penetrance 2, 3 , hypomorphic allele 4,5,6,7,8 , or oligogenecity 4,5,9,10 . However, despite numbers of reports of non-Mendelian inheritance causing RP, its significance in the context of overall genetic pathology of the disease is yet to be demonstrated.…”

“…However, despite numbers of reports of non-Mendelian inheritance causing RP, its significance in the context of overall genetic pathology of the disease is yet to be demonstrated. In Japan, the genetic basis of RP remains unknown in up to 70% of cases even after targeted re-sequencing, whole-exome sequencing, or whole-genome sequencing 4,11,12,13 . There is an urgent need for genetic diagnosis of these unsolved cases, particularly those with the autosomal recessive (AR) inheritance pattern of RP (ARRP), caused by lossof-function mutations, because such patients may be amenable to adeno-associated virus (AAV)-mediated gene supplementation therapy 14 .…”