Description
Introduction
A significant proportion of individuals with inherited retinal dystrophies (IRD) remain genetically unsolved. New technologies offer the opportunity to identify and characterise previously inaccessible areas of the genome that could harbour disease-causing variants. We investigated five families affected by autosomal dominant cone-rod dystrophy (adCRD); one family from the UK, which has remained genetically unsolved for decades, and four families originating from a single village in Greece.
Methods
The genetic cause of IRD in these families was investigated using a combination of whole-genome sequencing, optical genome mapping (OGM) and long read Nanopore sequencing.
Results
We identified two distinct mobile element insertions (MEI) ~16Kb upstream of CRX in the UK and Greek families, located ~200bp apart. OGM and long-read sequencing enabled characterization of these MEIs as SINE-VNTR-Alu (SVA) insertions. The UK family carried a ~2.5Kb SVA type D insertion whereas the Greek families carried a ~3Kb SVA type F insertion. Based on retina-specific chromatin architecture and cis-regulatory interactions, we hypothesize that these insertions disrupt CRX expression.
Conclusion
The MEIs we identified represent a new genomic mechanism of disease at this locus. The localisation of these variants within a shared regulatory region upstream of CRX supports a cis-regulatory pathogenic effect.
Lay Abstract
Inherited retinal dystrophies (IRDs) are rare eye conditions affecting the light-sensitive cells in the retina, leading to blindness. IRDs are genetic, resulting from DNA alterations. Despite advances in genetic testing many IRDs remain unsolved owing to certain changes that are undetectable by standard techniques. Newer technologies, however, offer an opportunity to identify such hidden DNA modifications in affected individuals. We investigated five unsolved cone-rod dystrophy families with severe visual loss, one from UK and four originating from a single village in Greece.
Using the latest genetic techniques, we identified insertions of ‘jumping genes’ in the UK and Greek families. These are mobile DNA elements, capable of inserting into different regions of the genome. In the UK and Greek families, the jumping elements are very similar and have relocated to similar locations in the human genome, next to an eye-specific gene called CRX. They do not interfere with the genetic code, instead we hypothesise they cause disease by disrupting the ON/OFF switch for CRX.
We have identified the molecular basis of cone-rod dystrophy in five families. These findings demonstrate the importance of applying new cutting-edge techniques to find the genetic cause of IRD in families that have remained unresolved for decades.
| Lay Title | Jumping gene is associated with autosomal dominant cone rod dystrophy |
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| Role | Postdoctoral Researcher |