Klippel-Feil Syndrome Panel

Congenital vertebral malformation (CVM) is a birth defect of the vertebral column with an estimated prevalence of 0.13-0.51 per 1,000 live births (Giampietro et al. 2009. PubMed ID: 19154516). It can be further divided into several groups such as Klippel-Feil syndrome and Spondylocostal Dysostosis. Fetal ultrasound can detect vertebrae defects as early as 13 weeks gestation (Turnpenny et al. 2017. PubMed ID: 20301771).

Patients with Klippel-Feil syndrome (KFS) share the defining characteristic of fused cervical vertebrae. (Tracy et al. 2004. PubMed ID: 15241163). Common clinical features include a short neck, low posterior hairline, restricted range of head movement, and scoliosis (60% of patients). Some scoliosis occurs congenitally. Less common clinical features include rib abnormalities, kidney and heart malformations, deafness, ocular anomalies and respiratory problems (Lewis et al. 2009. hmedscape.com). In one series of patients, the average age at onset of symptoms was 7.1 years, and mean age at onset of cervical spine related symptoms was 11.9 years (Samartzis et al. 2006. PubMed ID: 17023841).

Molecular genetic testing is advantageous to establish an accurate diagnosis for individuals with KFS or related conditions.

Pathogenic variants in the GDF6 gene have been reported in patients with both autosomal dominant and recessive KFS (Tracy et al. 2004. PubMed ID: 15241163; Tassabehji et al. 2008. PubMed ID: 18425797; Asai-Coakwell et al. 2009. PubMed ID: 19129173). GDF6 encodes growth differentiation factor 6, a member of the bone morphogenetic protein family. More than 10 missense variants, one splicing, one small truncating variant were reported Human Gene Mutation Database (HGMD). Missense variants in GDF6 have also been reported in a few patients with synostoses syndrome (Terhal. 2018. PubMed ID: 29130651; Wang et al. 2016. PubMed ID: 26643732) and retinal dystrophies (Asai-Coakwell et al. 2013. PubMed ID: 23307924). In addition, two large duplications involving GDF6 and a few other genes were found in two patients with Leri's pleonosteosis (Banka et al. 2015. PubMed ID: 24442880). One large complex arrangement involving the GDF6 gene has been reported in a patient with KFS (Tassabehji et al. 2008. PubMed ID: 18425797).

Several variants in GDF3 (mostly missense) were reported to be associated with autosomal dominant ocular and skeletal anomalies. Some of these variants are probably too common in the healthy population to be a primary cause of disease (Ye et al. 2010. PubMed ID: 19864492; Patel et al. 2018. PubMed ID: 29450879). The GDF3 protein, coded by GDF3, is a member of bone morphogenetic protein family in the transforming growth factor beta (TGFβ) superfamily, which regulates the growth and maturation of bone and cartilage.

MEOX1, coded by MEOX1, is a homeodomain-containing protein that is highly expressed in mesodermally derived embryonic tissues and plays a key role in all somite development (Skuntz et al. 2009. PubMed ID: 19520072). To date, four homozygous causative variants (1 missense, 3 truncating) have been reported in four presumably unrelated consanguineous KFS families (Bayrakli et al. 2013. PubMed ID: 24073994; Mohamed et al. 2013. PubMed ID: 23290072; Lefebvre et al. 2018. PubMed ID: 29459493).

MYO18B is not a well-studied gene. Only a few variants are documented in HGMD, but one homozygous nonsense variant was reported in one consanguineous family with Klippel-Feil anomaly, myopathy, and characteristic facies (Alazami et al. 2015. PubMed ID: 25748484).

The PAX1 protein coded by the PAX1 gene is a member of the paired box family of transcription factors that plays a key role in pattern formation during embryogenesis and development of the vertebral column. Homozygous defects of PAX1 in mice showed mild vertebral defects (Adham et al. 2005. PubMed ID: 16093716). Rare variants in the PAX1 gene have been reported in a few patients with KFS, autosomal recessive otofaciocervical syndrome (McGaughran et al. 2003. PubMed ID: 12774041; Pohl et al. 2013. PubMed ID: 23851939). The inheritance pattern of PAX1 related KFS is not fully defined (McGaughran et al. 2003. PubMed ID: 12774041). The documented PAX1 variants are: missense (5), truncating (3) and splicing (2).

Only two RIPPLY2 truncating variants and one splicing variant were reported in three patients from two families with autosomal recessive vertebral segmentation defects or KFS (Karaca et al. 2015. PubMed ID: 26238661; McInerney-Leo et al. 2015. PubMed ID: 25343988).

De novo pathogenic variants do not seem to be a major contributing factor for KFS as to our knowledge, none have been reported (HGMD).

See individual gene summaries for more information about molecular biology of gene products and spectra of pathogenic variants.

Clinical sensitivity is difficult to estimate because only a small number of patients with KFS have been reported. Analytical sensitivity should be high.

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

This panel provides 100% 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).