Neurogenic Arthrogryposis Multiplex Congenita-1 with Myelin Defect via the LGI4 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, 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 1/3,000 to 1/5,000 live births (Beecroft et al. 2018. PubMed ID: 29959180; Pergande et al. 2020. PubMed ID: 31680123). 

Autosomal recessive neurogenic arthrogryposis multiplex congenita-1 with myelin defect (AMC1) is a severe neurogenic disorder with onset typically occurring in utero (Karakaya et al. 2018. PubMed ID: 29858556; Xue et al. 2017. PubMed ID: 28318499). At least 10 individuals with AMC1 have been described in the literature with the majority of cases not surviving past infancy. Clinical features include distal arthrogryposis and fetal akinesia sequence with camptodactyly, adduction of thumbs, clubfeet, flexion of feet, knees, wrists, and elbows, microretrognathia, and pulmonary hypoplasia. One 6 year old patient that survived also presented with verbal developmental delay, onset of seizures at age 1 year,  prominent ears, narrow forehead, high-arched palate, reduced mouth opening, dental crowding, esotropia, strabismus, and ptosis. Genetic testing may aide in establishing a differential diagnosis and may assist reproductive planning.

Pathogenic variants in LGI4 are associated with autosomal recessive neurogenic arthrogryposis multiplex congenita-1 with myelin defect (AMC1). Splice variants, missense variants, and nonsense variants have been reported in 10 individuals with AMC1 from 5 families (Karakaya et al. 2018. PubMed ID: 29858556; Xue et al. 2017. PubMed ID: 28318499). All of these cases were either homozygous or compound heterozygous for LGI4 variants. To date, all pathogenic variants have been inherited from a carrier parent. No structural variants have been reported.

The LGI4 gene encodes the leucine-rich glioma-inactivated 4 protein which is a ligand secreted by Schwann cells and regulates peripheral nerve myelination. This ligand binds to the cell surface receptor Adam22, which is expressed in neurons and drive myelin formation. LGI4 deficient mice exhibit an arthrogryposis phenotype due to peripheral hypomyelination (Nishino et al. 2010. PubMed ID: 21068328). LGI4 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 (Karakaya et al. 2018. PubMed ID: 29858556; Xue et al. 2017. PubMed ID: 28318499). 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 LGI4 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).