Conclusion of diagnostic odysseys due to inversions disrupting GLI3 and FBN1

In this study, manual review prompted by a virtual multidisciplinary team meeting and subsequent bioinformatic prioritisation of data from the 100K Genomes Project was performed across 43 genes linked to well-characterised skeletal disorders. Ten individuals from three independent families were found to harbour diagnostic inversions. In two families, inverted segments of 1.2/14.8 Mb unequivocally disrupted GLI3 and segregated with skeletal features consistent with Greig cephalopolysyndactyly syndrome. For one family, phenotypic blending was due to the opposing breakpoint lying ~45 kb from HOXA13. In the third family, long suspected to have Marfan syndrome, a 2.0 Mb inversion disrupting FBN1 was identified. These findings resolved lengthy diagnostic odysseys of 9–20 years and highlight the importance of direct interaction between clinicians and data-analysts. These exemplars of a rare mutational class inform future SV prioritisation strategies within the NHS Genomic Medicine Service and similar genome sequencing initiatives. In over 30 years since these two disease-gene associations were identified, large inversions have yet to be described and so our results extend the mutational spectra linked to these conditions.

Source: Journal of Medical Genetics - April 20, 2023 Category: Genetics & Stem Cells Authors: Pagnamenta, A. T., Yu, J., Evans, J., Twiss, P., Genomics England Research Consortium, Musculoskeletal GeCIP MDT, Offiah, A. C., Wafik, M., Mehta, S. G., Javaid, M. K., Smithson, S. F., Taylor, J. C., Ambrose, Arumugam, Bevers, Bleda, Boardman-Pretty, Bou Tags: Open access Structural variation Source Type: research