Conclusion of diagnostic odysseys due to inversions disrupting GLI3 and FBN1

J Med Genet. 2023 May;60(5):505-510. doi: 10.1136/jmg-2022-108753. Epub 2022 Nov 21.

Abstract

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.

Keywords: Gene Rearrangement; Genomics; Molecular Diagnostic Techniques; Musculoskeletal Diseases; Sequence Inversion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Bone Diseases, Developmental* / diagnosis
  • Bone Diseases, Developmental* / genetics
  • Chromosome Inversion* / genetics
  • Chromosome Mapping
  • Fibrillin-1 / genetics
  • Genetic Testing
  • Humans
  • Mutation
  • Nerve Tissue Proteins / genetics
  • Zinc Finger Protein Gli3 / genetics

Substances

  • FBN1 protein, human
  • Fibrillin-1
  • GLI3 protein, human
  • homeobox protein HOXA13
  • Nerve Tissue Proteins
  • Zinc Finger Protein Gli3

Supplementary concepts

  • Greig cephalopolysyndactyly syndrome