Lethal Contracture Syndrome 7 via the CNTNAP1 Gene

Fetal akinesia (FA) describes a clinical syndromic entity characterized by reduced or absent fetal movements resulting in multiple phenotypic abnormalities. These secondary defects may include intrauterine growth restriction (IUGR), craniofacial dysmorphic features (cleft palate or retromicrognathia), limb pterygia, pulmonary hypoplasia, and arthrogryposis. This group of disorders contains several overlapping conditions ranging from distal arthrogryposis, multiple pterygium syndrome, and arthrogryposis multiplex congenita (AMC) to the more severe lethal congenital contracture syndrome and fetal akinesia deformation sequence (FADS; Beecroft et al. 2018. PubMed ID: 29959180; Pergande et al. 2020. PubMed ID: 31680123). 

AMC is defined by congenital, non-progressive contractures in more than two joints and in multiple body areas. These contractures and reduced fetal movement can lead to secondary polyhydramnios or fetal hydrops. The underlying defect can be genetic or environmental. Causes can include muscle disorders, neurological disorders, connective tissue disorders, fetal vascular compromise, uterine space limitations, and maternal disease or drug use. The overall incidence of AMC ranges from 1 in 3,000 to 1 in 5,000 live births (Beecroft et al. 2018. PubMed ID: 29959180; Pergande et al. 2020. PubMed ID: 31680123). 

Lethal congenital contracture syndrome 7 was first described in four consanguineous families (Laquérriere et al. 2014. PubMed ID: 24319099). Clinical features included polyhydramnios, distal joint contractures, severe hypotonia, facial diplegia and lack of swallowing, respiratory distress due to motor nerve paralysis, and death within the first 2 months of age. Additional CNTNAP1 variants were reported for congenital hypomyelinating neuropathy-3 in which some patients have survived into childhood (Hengel et al. 2017. PubMed ID: 28374019; Nizon et al. 2017. PubMed ID: 27782105; Low et al. 2018. PubMed ID: 29511323). Additional clinical features can include muscle atrophy, neurogenic muscle weakness, cerebral and cerebellar atrophy, thin corpus callosum, areflexia, reduced motor nerve conduction velocities, motor paralysis, and fetal akinesia. The phenotypic spectrum ranges from severe lethal contracture syndrome to a CNS disorder with hypomyelinating leukodystrophy and peripheral neuropathy with or without arthrogryposis. See Lesmana et al. and Low et al. for detailed clinical features from systematic review of CNTNAP1 cases (Lesmana et al. 2019. PubMed ID: 30686628; Low et al. 2018. PubMed ID: 29511323). Genetic testing may aid in establishing a differential diagnosis and may assist reproductive planning.

Pathogenic variants in the CNTNAP1 gene are associated with autosomal recessive lethal congenital contracture syndrome 7 (LCCS7) and congenital hypomyelinating neuropathy-3 (CHN3). These two disorders represent a phenotypic spectrum for CNTNAP1 variants. Reported variants include missense, nonsense, splice, and small deletions and duplications that result in a frameshift (Lesmana et al. 2019. PubMed ID: 30686628; Laquérriere et al. 2014. PubMed ID: 24319099; Low et al. 2018. PubMed ID: 29511323; Hengel et al. 2017. PubMed ID: 28374019). To date, all pathogenic variants have been inherited from a carrier parent. No structural variants have been reported. 

The CNTNAP1 gene encodes contactin-associated protein 1 (CASPR-1). This cell adhesion protein is needed for the proper formation of paranodal junctions in myelinated axons and is required for high-velocity nerve conduction.  Ncp1 -/- mice show progressive neurologic defects and mislocalization of the paranodal junction proteins, contactin and neurofascin (Bhat et al. 2001. PubMed ID: 11395000). Overall, however, CNTNAP1 has been cited as a non-essential gene for growth of human tissue culture cells (Online Gene Essentiality).

The clinical sensitivity is difficult to estimate, as to date, a limited number of cases have been described in the literature (Lesmana et al. 2019. PubMed ID: 30686628; Laquérriere et al. 2014. PubMed ID: 24319099; Low et al. 2018. PubMed ID: 29511323; Hengel et al. 2017. PubMed ID: 28374019). Analytical sensitivity should be high as all pathogenic variants reported to date are detectable by sequencing.

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

This test provides full coverage of all coding exons of the CNTNAP1 gene plus 10 bases flanking noncoding DNA in all available transcripts in addition to 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).