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A new interesting article has been published in Mol Genet Genomic Med. 2019 Dec; 7(12):e912. doi: 10.1002/mgg3.912. Epub 2019 Sep 30. and titled:

Developing pathways to clarify pathogenicity of unclassified variants in Osteogenesis Imperfecta genetic analysis.

Authors of this article are:

Balasubramanian M, Hobson E, Skae M, McCaughey J, Stephens DJ.

A summary of the article is shown below:

BACKGROUND: With increased access to genetic testing, variants of uncertain significance (VUS) where pathogenicity is uncertain are being increasingly identified. More than 85% Osteogenesis Imperfecta (OI) patients have pathogenic variants in COL1A1/A2. However, when a VUS is identified, there are no pathways in place for determining significance.OBJECTIVE: Define a diagnostic pathway to confirm pathogenicity, providing patients with definitive genetic diagnosis, accurate recurrence risks, and prenatal testing options.METHODS: Functional studies on collagen secretion from cultured patient fibroblasts combined with detailed phenotyping and segregation family studies.RESULTS: We demonstrate data from a family with a VUS identified in type I collagen. FAMILY-1: Six-year-old boy with failure-to-gain weight, talipes, fractures, on and off treatment with Pamidronate as diagnosis of OI uncertain. Transiliac bone biopsy at 2 years of age demonstrated active new bone formation within periosteum; bone cortices were normal thickness but increased porosity. Trabecular bone showed features of advanced osteoporosis. Genetic testing identified a de novo COL1A1 c.206_208delTGT, p.Leu69del variant. Sibling with similar phenotype but no fractures as yet, tested positive for variant raising concerns regarding her diagnosis, and management. Results from three independent experiments (cell immunofluorescence, collagen secretion assay by Western Blot, and unbiased proteomics) from cultured patient fibroblasts demonstrate COL1A1 c.206_208delTGT, p.Leu69del variant causing a substantial defect to collagen extracellular matrix assembly confirming variant pathogenicity.CONCLUSION: Access to genetic testing in OI is increasing as advances in genetic technologies decreases cost; a clinical diagnostic pathway needs to be implemented for managing variants identified by such testing.© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.

Check out the article’s website on Pubmed for more information:

[link-preview url=https://www.ncbi.nlm.nih.gov/pubmed/31568717 forceshot=true]

This article is a good source of information and a good way to become familiar with topics such as: Variant of uncertain significance; fractures; genetic analysis; osteogenesis imperfecta; targeted gene panel testing.

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