Ehlers-Danlos Syndrome, Kyphoscoliotic Form via the PLOD1 Gene

Ehlers-Danlos syndrome, kyphoscoliotic form (EDS VIA; OMIM#225400) is a rare connective tissue disorder characterized by progressive kyphoscoliosis, joint hypermobility, smooth, hyperelastic and fragile skin, muscular hypotonia and scleral fragility and rupture of the globe. It should be also noted that clinical manifestations overlap among different types of EDS. Some patients may also present Marfanoid habitus, congenital myopathy, delayed motor development, and dysmophic features. Patients with severe kyphoscoliotsis are at risk for rupture of medium-sized arteries (Pousi et al. Mutat Res 432:33-37, 2000; Rohrbach et al, Orphanet J Rare Disease 6:46, 2011; Yeowell & Steinmann. GeneReviews. 2013).

Ehlers-Danlos syndrome (EDS), kyphoscoliotic type is inherited in an autosomal recessive manner and is caused by mutations in PLOD1. PLOD1, located on 1p36.2 (OMIM#153454), encodes the enzyme procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1 (PLOD1, or lysyl hydroxylase 1). Deficiency of the enzyme PLOD1 results in a deficiency in hydroxylysine-based pyridinoline cross-links in collagens. An intragenic duplication of exons 10-16 caused by an Alu-Alu recombination in introns 9 and 16 is the most common causative allele, with a frequency of ~18% among patients with EDS VI (Pousi et al, Am J Hum Genet 55:899-906, 1994; Yeowell et al. Eur J Dermatol 15:353–358, 2005). The second most common causative mutation in PLOD1 occurs in exon 14 and results in chain termination at codon 511 for tyrosine (p.Tyr511*). The allele frequency of this mutation in EDS VI cases is about 10% (Yeowell et al. Eur J Dermatol 15(5): 353-358, 2005). The remaining reported mutations include missense, nonsense, splicing, frameshift mutations as well as gross deletions of single or multiple exons.

Using cDNA analysis, duplication analysis and DNA sequencing, Giunta et al. (Molecular Genetics and Metabolism 86(1-2):269-276, 2005) identified POLD1 mutations in 9 out of 12 unrelated patients who were clinically diagnosed with EDS type VIA. PLOD1 mutations were also detected in 13 patients who had an abnormal ratio of urinary lysyl pyridinolines to hydroxylysyl pyridinolines crosslinks (Rohrbach et al, Orphanet J Rare Disease 6:46, 2011). The common intragenic duplication of exons 10-16 in the PLOD1 gene cannot be detected by this method.

This test provides full coverage of all coding exons of the PLOD1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.