Fetal Akinesia Deformation Sequence (FADS)/Lethal Multiple Pterygium Syndrome Panel

Fetal akinesia deformation sequence (FADS, known also as Pena-Shokeir syndrome, type I) is characterized by prenatal onset growth deficiency, multiple joint contractures, facial anomalies, hypoplastic dermal ridges, and pulmonary hypoplasia. Patients are often stillborn and most live-born patients succumb to the effects of pulmonary hypoplasia in the first month of life. Limbs are also affected by camptodactyly, rocker bottom feet and clubfoot. Affected pregnancies may be complicated by polyhydramnios and some patients are born prematurely. Lethal congenital contracture syndrome 1 (LCCS1) and lethal arthrogryposis with anterior horn cell disease (LAAHD) are GLE1-associated disorders that closely resemble FADS. Findings that differentiate GLE1 disorders from FADS are fetal hydrops and generalized thinning of tubular bones. Fetal death often occurs before 32 weeks gestation, and diminished numbers of anterior motor neurons have been reported (Vuopala et al. 1995). Lethal multiple pterygium syndrome (LMPS) is characterized by prenatal growth deficiency, contractures, pterygia, and dysmorphic facies. Contractures and pterygia are universal findings. Patients are stillborn or do not survive beyond the newborn period. Pulmonary hypoplasia is likely the primary cause of mortality. LMPS pregnancies are complicated by hydrops. A markedly severe form of nemaline myopathy (NEM-8), caused by mutations of the KLHL40 gene, presents with fetal akinesia or hypokinesia and deformations, including contractures and fractures, at birth (Ravenscroft et al. 2013). Compton-North congenital myopathy is a severe, congenital myopathy with fetal akinesia and distinct secondary losses of beta-2-syntrophin and alpha-dystrobrevin observed in muscle biopsy. Clinical findings include reduced fetal movement, polyhydramnios, premature birth, severe hypotonia, absent deep tendon reflexes, and skeletal, bulbar, and respiratory weakness (Compton et al. 2008; Jones et al. 2003).

Each of these disorders is inherited in an autosomal recessive manner. Abnormalities in genes encoding proteins involved with neuromuscular transmission (CHRNA1, CHRND, CHRNG, DOK7, RAPSN, MUSK) underlie some cases of FADS and LMPS. Other causes include primary neurogenic (Hageman et.al. 1987), prenatal exposure (Lavi et.al. 1991), and circulating maternal antibodies to the acetylcholine receptor (Brueton et al. 2000). LCCS1 and LAAHD result from defective export of polyadenylated mRNA secondary to GLE1 mutations. KLHL40 encodes a Kelch repeat containing protein that is expressed in striated muscle predominately during fetal development (Ravenscroft et al. 2013). CNTN1 encodes contactin-1, a neural immunoglobulin family adhesion protein that is expressed at the neuromuscular junction as well as in the central and peripheral nervous system. Mutations in CHRNE and COLQ are leading causes of congenital myasthenic syndrome and can lead to severe clinical condition which may mimic FADS (Byring et al. 2002). See individual gene test descriptions for additional information on molecular biology of gene products.

Because of extensive genetic heterogeneity for these disorders and because an undetermined number of cases are non genetic, sensitivity cannot be accurately predicted. Analytical sensitivity should be high because nearly all mutations reported are detectable by sequencing (Human Gene Mutation Database).

Clinical sensitivity for del/dup testing is expected to be low as few gross duplications or deletions have been reported (Human Gene Mutation Database).

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

This panel typically 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).