Klippel-Feil Syndrome via the GDF6 Gene

Patients with Klippel-Feil syndrome (OMIM 118100) share the defining characteristic of fused cervical vertebrae. Klippel-Feil may be a heterogeneous collection of disorders rather than a single disease entity (Tracy et al. Clin Orthopedics Related Res 424:183-190, 2004). Common clinical features include a short neck, low posterior hairline, restricted range of head movement, and scoliosis. Less common clinical features include rib abnormalities, kidney and heart malformations, deafness, ocular anomalies, and respiratory problems (Sullivan, http://www.emedicine.com/orthoped/TOPIC408.htm). In one series of patients, the average age at onset of symptoms was 12 years (Samartzis et al. Spine 31:E798-E804, 2006).

Although autosomal recessive inheritance of Klippel-Feil has been reported (Tracy et al. 2004), families which appear to exhibit autosomal dominant inheritance with reduced penetrance have also been reported (Tassabehji et al. Hum Mut 29:1017-1027, 2008; Asai-Coakwell et al. Hum Mol Genet 18:1110-1121,2009). GDF6 encodes growth differentiation factor 6, a member of the bone morphogenetic protein family. Eight causative point variants have been reported to date in this gene; all have been missense. A patient with chorioretinal coloboma was shown to have a deletion encompassing the GDF6 gene (Asai-Coakwell et al. Am J Hum Genet 80:306-315, 2007).

Tassabehji et al. reported detecting point variants within the gene in 1 of 6 dominant families and 2 of 121 sporadic cases. Asai-Coakwell et al. (2009) reported detecting GDF6 variants in 1% of 489 patients with ocular anomalies (microphthalmia, coloboma, and anophthalmia) and in 4% of 81 patients with vertebral segmentation disorders.

This test provides full coverage of all coding exons of the GDF6 gene 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 full 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).