Severe Skeletal Conditions Panel

About Severe Skeletal Conditions

Genetic skeletal disorders comprise a heterogeneous group of diseases affecting skeletal and joint function. Based on the 2023 Nosology and Classification, there are 771 distinct skeletal disorder entities¹. These conditions can present with various skeletal abnormalities detectable through clinical examination, ultrasound, and X-ray findings. Major genes involved include COL1A1, COL1A2, FGFR3, and COL2A1, which are associated with conditions such as thanatophoric dysplasia, osteogenesis imperfecta, achondrogenesis, and various forms of skeletal dysplasia^2,3. Inheritance patterns include autosomal dominant, autosomal recessive, and X-linked, with autosomal dominant inheritance and de novo variants being frequently observed⁴. Causative variants can be both sequence variants and copy number variations, with some genes showing higher frequencies of large deletions/duplications. The clinical sensitivity of this panel will vary based on the clinical phenotype of the patient and is approximately 39% to 52.5% ⁵ for patients with skeletal conditions.

All genetic tests have limitations. Please refer to our Test Methods page for limitations relevant to this methodology.

The analytical sensitivity of the PGxome platform has been validated at >99% for single nucleotide variants, >95% for indels <49 bp, and >99% for CNV ≥3 exons in size. Sensitivity is reduced in regions with repetitive elements or paralogy.

The analytical sensitivity of the PGnome platform has been validated at >99% for sequence variants and >99% for structural variants (SV) 1kb-10Mb in size. Sensitivity is reduced in regions with repetitive elements or paralogy.

PGxome® platform: Capture and amplification based next-generation sequencing (NGS) is used to sequence the coding regions of nearly all genes and immediate flanking non-coding DNA (± 10 bp) in all available transcripts along with other non-coding regions harboring known disease-causing variants. Results are filtered to defined genes on the panel. Reportable variants include both sequence variants and NGS-detected copy number variants (CNVs).

PGnome® platform: PCR-free next-generation sequencing (NGS) is used to sequence the coding regions of nearly all genes as well as intronic and intergenic regions. Detailed variant analysis and interpretation is focused on the coding exons and ± 10 bp into introns. Genomic variants outside of these coding regions are not investigated unless warranted (for example, if a gene of interest is highlighted by the provider, or if a single-hit pathogenic variant is found in a recessive gene). Results are filtered to defined genes on the panel. Reportable variants include sequence variants; NGS-detected structural variants (SV), including copy number variants (CNVs) and inversions; and repeat expansion variants in currently available relevant genes.

Variants not meeting our quality threshold through NGS alone are confirmed with an orthogonal method, including but not limited to Sanger and array.

All variants within the analyzed genes which are classified as pathogenic, likely pathogenic, risk, or variant of uncertain significance will be reported.