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Researchers from NDM’s Centre for Human Genetics have identified types of genetic variants that lead to a range of rare diseases but are not picked up by standard genetic testing.

team at the Centre for Human Genetics (CHG) analysed whole genome sequencing data from the 100,000 Genomes Project. They were specifically looking for a particular type of variant, called inversions. These are structural variants in which segments of the genetic code in DNA are reversed in the sequence, disrupting the function of the encoded gene.

From the 33,924 families whose genetic data were investigated, 47 inversions were identified. This led not only to a genetic diagnosis – often after many years of uncertainty – but also changes in clinical management for several affected individuals.

Some of these were people with colorectal cancer, and the diagnosis enabled family members to be offered screening, including regular surveillance and colonoscopies, and potentially facilitating the early removal of polyps before they progress to cancer.

The findings of the study, which was supported by the National Institute for Health and Care Research (NIHR) Oxford Biomedical Research Centre (BRC), were published in the American Journal Human Genetics.

Whereas many genetic conditions are caused by structural variations that involve deletions, insertions or duplications of segments of DNA, the Oxford team found that the genes were partially inverted – the DNA sequence was in the correct place but flipped over back-to-front. Most genetic testing methods are focused on identifying structural variants that alter the copy number; most genes come in pairs with one copy from each parent, and so the copy number normally equals two. However, with inversions, the copy number remains the same, and so these variants are easily missed.

This study expands on an earlier paper where genomic inversions were found to be responsible for rare skeletal disorders in three families.

Professor Jenny Taylor, Professor at the Centre for Human Genetics and senior author of the study, said: ‘This long-running study demonstrates the importance of assessing genome sequencing data for this unusual class of genetic variant, which is not picked up by genetic testing methods commonly used in clinical testing laboratories. The sizes of these inverted segments of DNA range from 24 letters of DNA to 36 million base-pairs and overall, we found 45 families in the 100,000 Genomes Projects whose condition we believe to be a consequence of inversions that disrupt a well-known set of genes.’

Among the genetic inversions identified by the research team were:

Chromosome 2 inversion disrupting the MSH2 gene: This affected two families in the UK and two who had been previously identified in Australia. These families are all distantly related, with a common ancestor an estimated 30 generations ago. This inversion is linked to Lynch syndrome, which is associated with a genetic predisposition to different cancer types, including colorectal cancer. The children of one of the patients are now undergoing cascade testing. MRC Holland, the Dutch company who produce the kits used for clinical genetics testing are, based on the study findings, including probes for this variant in their latest product.

X chromosome rearrangements disrupting MECP2: This gene is known to be linked to Rett syndrome, a rare genetic disorder that affects the way the brain develops and can cause loss of motor skills and language. Two individuals in the 100,000 Genomes Project had complex structural variants that appeared to disrupt this gene, but standard genetic testing was unable to solve the puzzle. The full solution to this puzzle was only possible using long-read sequencing, which improved the understanding of how the DNA segments fitted together and helped to alter the clinical interpretation.

Inversion of the HOXD gene cluster: One family had a very characteristic skeletal condition that was first described in the 1990s. This is a very rare and specific set of clinical features, so variants in this region of genome had been suspected since 2004. This type of regulatory variant is very hard to pick up with normal testing. As well as ending the family’s long diagnostic odyssey, this result helps shed light on how the 3D structure of the genome affects how genes are turned on and off in early limb development.

Complex rearrangement of chromosomes 5 & 11, disrupting the APC gene: As well as a segment of DNA being inverted, this variant also involved the exchange of genetic material between two different chromosomes, known as a complex translocation. Members of the family had hundreds or polyps and colorectal cancer. One brother only had one polyp, so it was unclear if he was affected. Once the variant was identified, he was tested and found not to have inherited the variant. Like the HOXD variant, the APC gene was suspected all along, but no variants were found with other testing approaches. A member of this family said: ‘It was very important for our family that the diagnosis was established after over a decade-long journey to identify the cause of the polyps.’

Dr Alistair Pagnamenta, a Post-Doctoral researcher at CHG, and lead author on the study, said: ‘Long-read sequencing has been shown to be important to better characterise some of the most complex inversions. In future, we hope to develop analysis pipelines to improve detection rates for this poorly understood class of genomic alteration.’

Professor Sir John Burn, Professor of Clinical Genetics at Newcastle University, who is an expert on Lynch syndrome, said: ‘Structural variants are the hidden part of the iceberg in genomic medicine. This important paper has identified changes of major clinical value and presents a clear challenge to further evolve our diagnostic services.’

Read the full paper here: