Arthrogryposis Multiplex Congenita via the UNC50 Gene

Fetal akinesia (FA) describes a clinical syndromic entity characterized by reduced or absent fetal movements with additional 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).

One family has been reported so far with a pathogenic frameshift variant in UNC50. The affected pregnancy presented with bilateral club foot, bilateral flexion of elbows, hips and knees, bilateral extended wrists, cervical hyperextension and diffuse subcutaneous, and edema associated with muscle atrophy of limbs (Abiusi et al. 2017. PubMed ID: 29016857). The pregnancy ended in a stillborn male at 28 weeks gestation. The affected male child was found to be homozygous for the frameshift variant, while unaffected parents and unaffected siblings were heterozygous or carried the wild type allele. Genetic testing may aid in establishing a differential diagnosis and may assist reproductive planning.

Pathogenic variants in the UNC50 gene are associated with autosomal recessive arthrogryposis multiplex congenita. Thus far, only one frameshift variant in the last exon of the gene has been reported to be pathogenic (Abiusi et al. 2017. PubMed ID: 29016857).  This variant was knocked-in to C. elegans and the animals displayed an uncoordinated phenotype, similar to unc-50 null mutants. To date, all pathogenic variants have been inherited from a carrier parent. No structural variants have been reported.

The UNC50 gene encodes a transmembrane protein that is localized to the Golgi apparatus. In C. elegans, unc-50 mutant animals display slow and abnormal locomotion, called an ‘uncoordinated phenotype’, for which the gene was originally named. Inactivation of the unc-50 gene eliminates the expression of heteromeric acetylcholine receptors (AChR) at the neuromuscular junction. UNC50 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 (Abiusi et al. 2017. PubMed ID: 29016857). 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 UNC50 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).