Short Rib Skeletal Dysplasia Panel

Short rib-polydactyly syndrome (SRTD) is a group of skeletal ciliopathies characterized by markedly short ribs, short limbs, with or without polydactyly. Some patients may also present abnormalities involving the brain, eyes, heart, kidneys, liver, pancreas, intestines, and genitalia. SRTD includes Ellis-van Creveld syndrome, Jeune syndrome (asphyxiating thoracic dystrophy), and Mainzer-Saldino syndrome. Some forms of SRTD are lethal in the neonatal period due to respiratory insufficiency secondary to a severely restricted thoracic cage, whereas others are compatible with life (Huber and Cormier-Daire 2012).

This Short Rib Skeletal Dysplasia NextGen Panel focuses on, but is not limited to the following conditions: Short-rib thoracic dysplasia, Short-rib thoracic dysplasia with or without polydactyly types, Ellis-van Creveld syndrome, Cranioectodermal dysplasia, asphyxiating thoracic dystrophy, Mainzer-Saldino syndrome, Verma-Naumoff, Brachyolmia 4 with mild epiphyseal and metaphyseal changes, diastrophic dysplasia, atelosteogenesis type II, achondrogenesis type IB, campomelic dysplasia, Pfeiffer syndrome type 3 and thanatophoric dysplasia.

This test analyzes 19 genes involved in Short Rib Skeletal Dysplasia.

16 out of the 19 genes are related to Autosomal Recessive conditions: DYNC2H1, EVC, EVC2, IFT122, IFT140, IFT172, IFT80, NEK1, PAPSS2, SLC26A2, TCTN3, TTC21B, WDR19, DYNC2I2/WDR34, WDR35, and DYNC2I1/WDR60.

EVC and EVC2: Ellis-van Creveld syndrome, Weyers acrodental dysostosis

IFT122: Cranioectodermal dysplasia 1 (also called Sensenbrenner syndrome)

IFT80: Short-rib thoracic dysplasia 2 with or without polydactyly (also called Jeune syndrome)

DYNC2H1: Short-rib thoracic dysplasia 3 with or without polydactyly

TTC21B: Short-rib thoracic dysplasia 4 with or without polydactyly

WDR19: Short-rib thoracic dysplasia 5 with or without polydactyly, Senior-Loken syndrome 8, Cranioectodermal dysplasia

NEK1: Short-rib thoracic dysplasia 6 with or without polydactyly

WDR35: Short-rib thoracic dysplasia 7 with or without polydactyly, Cranioectodermal dysplasia 2

DYNC2I1/WDR60: Short-rib thoracic dysplasia 8 with or without polydactyly

IFT140: Short-rib thoracic dysplasia 9 with or without polydactyly (also called Mainzer-Saldino syndrome, Majewski type)

IFT172: Short-rib thoracic dysplasia 10 with or without polydactyly

DYNC2I2/WDR34: Short-rib thoracic dysplasia 11 with or without polydactyly

PAPSS2: Brachyolmia 4 with mild epiphyseal and metaphyseal changes (also called spondyloepimetaphyseal and premature pubarche)

SLC26A2: Diastrophic dysplasia broad bone-platyspondylic variant, Achondrogenesis Ib, Atelosteogenesis II (also called De la Chapelle dysplasia)

TCTN3: Joubert syndrome 18, Orofaciodigital syndrome IV

Three out of the 19 genes are related to Autosomal Dominant conditions: FGFR2, FGFR3 and SOX9.

FGFR2: Pfeiffer syndrome type 3

FGFR3: Thanatophoric dysplasia, type I and Thanatophoric dysplasia, type II

SOX9: Campomelic dysplasia, Acampomelic campomelic dysplasia

NOTE: FGFR3 pathogenic variants can also cause autosomal recessive Camptodactyly, Tall Stature, Scoliosis, and Hearing Loss Syndrome (also called CATSHL syndrome).

See individual gene test descriptions for information on clinical features and molecular biology of gene products.

Genes tested in this panel have been implicated in Short Rib Skeletal Dysplasia and although individually these genes may be involved in a minority of Short Rib Skeletal Dysplasia, the combination of pathogenic variants may be responsible for a significant portion of Short Rib Skeletal Dysplasia.

In one study, DYNC2H1 pathogenic variants were identified in 19 out of 57 (33%) of studied families with a clinical diagnosis of asphyxiating thoracic dystrophy (Schmidts et al. 2013).

Combining EVC and EVC2, this test is predicted to detect pathogenic variants in at least two thirds of affected individuals with EVC (Tompson et al. 2007; Valencia et al. 2009). In one study, EVC and EVC2 pathogenic variants were found in 74% (20/27) and 26% (7/27) of EVC patients, respectively (D'Asdia et al. 2013).

SOX9 pathogenic variants were identified in 7 out of 9 campomelic dysplasia patients (Mattos et al. 2015).

SLC26A2 pathogenic variants were identified in >95% of individuals affected with Achondrogenesis type 1B (Rossi & Superti-Furga. 2001).

Analytical sensitivity for FGFR2 should be high, because almost 97% of known pathogenic variants are missense, splicing site and small deletions/insertions (Human Gene Mutation Database).

FGFR3 pathogenic variants were found in >99% of patients with Achondroplasia, Thanatophoric dysplasia and Muenke syndrome (Karczeski and Cutting 2013).

9 gross deletions/duplications and three complex rearrangements have been reported in EVC (D'Ambrosio et al. 2015, HGMD). Five gross deletions have been reported in EVC2 (Valencia et al. 2009; HGMD).

Only five documented pathogenic FGFR2 variants are large deletions/insertions (HGMD; Bochukova et al. 2009).

Only one large deletion was reported in the WDR35 gene (Mill et al. 2011).

To date, no gross deletions or duplications have been reported in FGFR3, ITF122, and SLC26A2 (HGMD).

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

This panel typically provides 98.8% 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).

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).