Ehlers-Danlos Syndrome with Progressive Kyphosis, Myopathy, and Hearing Loss (EDSKMH) via the FKBP14 Gene

Ehlers-Danlos syndrome (EDS) pertains to a clinically and genetically heterogeneous group of heritable connective tissue disorders that mainly affect the skin, joints, ligaments, blood vessels, and internal organs (Byers and Murray 2012). The clinical hallmarks of EDS include skin hyperelasticity, joint hypermobility, and pronounced tissue fragility. One of the six major types of EDS, Ehlers-Danlos syndrome with kyphoscoliosis or EDS type VIA (OMIM 225400), is characterized by severe congenital muscle hypotonia, progressive kyphoscoliosis, extensive skin hyperelasticity with widened atrophic scars, and joint hypermobility. Other common features include osteopenia without a tendency to fractures, a Marfanoid habitus, microcornea, as well as occasional rupture of the arteries and the eye globe. The features of severe muscle hypotonia and delayed motor development in children often lead to a misdiagnosis of EDS VIA as a primary neuromuscular disease. A neuromuscular workup during the neonatal period generally yields normal results. Muscle weakness and fatigability are common symptoms of EDS, which are mainly due to increased distensibility of tendons, a decline in mechanical efficiency due to inadequate intramuscular connective tissue, and avoidance of exercise because of joint instability and/or weak connective tissue surrounding the muscle spindles (Castori and Voermans 2014). Recent studies have shown that the neuromuscular symptoms of EDS may be partly attributable to mild to moderate myopathic and/or neuropathic alterations caused by changes in composition of the extracellular matrix in muscles and peripheral nerves (Byers and Murray 2014).

One rare variant of EDS VIA is Ehlers-Danlos syndrome with progressive kyphoscoliosis, myopathy, and hearing loss (EDSKMH; OMIM 614557), which presents with the common features of EDS VIA, but with the additional characteristic of sensorineural hearing loss (Baumann et al. 2012). Patients with EDSKMH present with myopathy as determined by clinical, electrophysiological, imaging, as well as muscle biopsy testing.

EDSKMH is an autosomal recessive connective tissue disorder that is caused by pathogenic sequence variants in the FK506-binding protein 14 (FKBP14) gene, which encodes for a 22 kDa peptidyl-prolyl cis-trans isomerase (PPIase) that is mainly located in the endoplasmic reticulum (ER) (Baumann et al. 2012). Cis-trans isomerization involving peptidyl-prolyl bonds has been determined to be the rate-limiting step of protein folding, particularly for procollagens, which are largely influenced by the availability of prolyl-residues. The process of protein folding is accelerated by the action of PPIases, which serve as folding catalysts, as well as act as molecular chaperones. In silico analysis has indicated that the putative FKBP14 protein possesses a PPIase FKBP-type domain that comprises two elongation factor (EF)-hand motifs and one retention signal (Boudko et al. 2014). Pathogenic sequence variants in the FKBP14 gene result in FKBP14 deficiency, which in turn causes enlargement of ER cisterns as well as disarray of the extracellular matrix (Baumann et al. 2012).

To date, only two studies have been conducted on EDSKMH via the FKBP14 gene, describing two pathogenic small deletions and one small insertion. In one study, five patients from four families with EDSKMH were determined to be homozygous for a 1-bp insertion within exon 3 (c.362dupC), resulting in a frameshift that is predicted to generate a premature termination codon (p.Glu122Argfs*7) (Baumann et al. 2012). Further examination of another unrelated patient with EDSKMH showed compound heterozygosity for the same 1-bp insertion and a 19-bp deletion (c.42_60del19) that leads to a premature stop codon (p.Thr15*). Electron microscopy and immunofluorescence studies of fibroblasts from these patients showed abnormal distribution and organization of the extracellular matrix, including types I and III collagens, as well as fibronectin. In another study, a three-year-old boy with EDSKMH was determined to be homozygous for a 4-bp deletion (c.197+5_197+8delGTAA) affecting splicing (Aldeeri et al. 2014).

Because only two reports (Baumann et al. 2012; Aldeeri et al. 2014) have described three pathogenic sequence variants in a total of seven patients, it is difficult to estimate the clinical sensitivity of this test. Analytical sensitivity should be high because all mutations reported are detectable by sequencing.

This test provides full coverage of all coding exons of the FKBP14 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.