Conclusion of diagnostic odysseys due to inversions disrupting <i>GLI3</i> and <i>FBN1</i>

Journal article

Many genetic testing methodologies are biased towards picking up structural variants (SVs) that alter copy number. Copy-neutral rearrangements such as inversions are therefore likely to suffer from underascertainment. 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

Authors: Pagnamenta, AT; Yu, J; Evans, J; Twiss, P; MDT, MG

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: BMJ Publishing Group
• Journal: Journal of Medical Genetics
• Volume: 60
• Issue: 5
• Pages: 505-510
• Publication date: 2022-11-21
• Acceptance date: 2022-10-14
• DOI: 10.1136/jmg-2022-108753
• EISSN: 1468-6244
• ISSN: 0022-2593
• Language: English
• Keywords: Chemistry; Medicine; GLI3; Biology; Gene; Genetics