PGmax^TM - Skeletal Disorders and Joint Problems Panel

Skeletal disorders are a clinically and genetically heterogeneous group of diseases that impair skeletal or joint function. The diagnosis of these patients is based on clinical presentation, ultrasound/X-ray findings, and genetic testing. Genetic skeletal disorders can be divided into 461 groups based on Nosology and Classification of Genetic Skeletal Disorders: 2019 Revision (Mortier et al. 2019. PubMed ID: 31633310).

This panel includes genes associated with a variety of genetic skeletal conditions as described in the article “Nosology and Classification of Genetic Skeletal Disorders: 2019 Revision.” (Mortier et al. 2019. PubMed ID: 31633310) along with some other genes that are known to be implicated in a variety of skeletal conditions by literature search.

Genetic skeletal disorders are genetically heterogenous and can be inherited in an autosomal dominant (AD), autosomal recessive (AR), and X-linked (XL) manner.

The majority of the genes in this panel have no or very few large deletions/duplications reported. But for some genes, deletion/duplication testing detection rates are relatively high. 16 to 25% of reported pathogenic variants in NSD1, NSDHL, TRAPPC2, ARSL/ARSE, and TRPS1 genes are large deletions/duplications (Human Gene Mutation Database). 16p13.3 microdeletions (ranging from 3.3kb to 3900kb) involving CREBBP were found 17 out of 83 patients with typical features of Rubinstein–Taybi syndrome using array CGH and quantitative multiplex fluorescent-PCR (Stef et al. 2007. PubMed ID: 17473832). The majority of reported variants in NPPC and SULF1 genes are gross deletions or complex rearrangements (Human Gene Mutation Database).

See individual gene test descriptions for information on molecular biology of gene products, and spectra of pathogenic variants.

COL3A1 pathogenic variants have been identified in approximately 95% of individuals with Ehlers Danlos Syndrome IV (Pepin et al. 2014. PubMed ID: 24922459). COL5A1 or COL5A2 pathogenic variants have been identified in at least 50% of affected individuals with classic EDS (Malfait et al. 2011. PubMed ID: 20301422).

Causative variants in COL2A1 and COL11A1 account for 80-90% and 10-20% of variants identified in autosomal dominant Stickler syndrome, respectively (Robin et al. 2014. PubMed ID: 20301479).

Sequence analysis can detect CREBBP pathogenic variants in 40%-50% of Rubinstein-Taybi syndrome cases. Pathogenic variants in EP300 are identified in ~3%-8% of patients with Rubinstein–Taybi syndrome (Stevens and Stevens. 2014. PubMed ID: 20301699).

TCOF1 pathogenic variants were found in ~70% of clinical diagnosed Treacher Collins Syndrome cases, and large deletions are ~5% of reported TCOF1 pathogenic variants (Bowman et al. 2012. PubMed ID: 22317976; Katsanis and Jabs. 2012. PubMed ID: 20301704).

Approximately 61% (111/182) of 182 Spanish craniosynostosis probands harbor a pathogenic variant in one of the FGFR2, FGFR3, TWIST1 and TCF12 genes. Pathogenic variants in FGFR2, FGFR3, TWIST and TCF12 account for 36%, 16%, 8% and 3% of pathogenic variants identified in this study, respectively (Paumard-Hernández et al. 2015. PubMed ID: 25271085).

One study reported that six unique FGFR1 pathogenic missense variants were found in seven unrelated patients affected with Hartsfield syndrome (Simonis et al. 2013. PubMed ID: 23812909).

TCF12 explains 32% and 10% of patients affected with bilateral and unilateral Craniosynostosis, respectively (Sharma et al. 2013. PubMed ID: 23354436).

Over 70% of all Cornelia de Lange Syndrome patients harbor a pathogenic variant in NIPBL, SMC3, RAD21, SMC1A, or HDAC8 (Boyle et al. 2015. PubMed ID: 25209348).

For other condition-related clinical sensitivities, please refer to individual gene test descriptions or to smaller disorder-specific panels.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 98.9% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Some genes have multiple copies in the haploid genome. In these cases, we may only analyze part of these genes. For example, exons 32 to 44 of the TNXB gene are highly homologous to the pseudogene TNXA, therefore, this region cannot be accurately analyzed in this NGS panel.

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).

Reporting: Reports will consist of two different sections:

• Variants in genes known to be associated with the provided phenotype
• Variants in genes possibly associated with the provided phenotype

All differences from the reference sequences (sequence variants) are assigned to one of five interpretation categories (Pathogenic, Likely Pathogenic, Variant of Uncertain Significance, Likely Benign and Benign) per ACMG Guidelines (Richards et al. 2015. PubMed ID: 25741868). Pathogenic, Likely Pathogenic and Variants of Uncertain Significance considered to contribute to the proband's phenotype will be reported in the first and second sections. 

Human Genome Variation Society (HGVS) recommendations are used to denote sequence variants (http://www.hgvs.org).