Arthrogryposis Multiplex Congenita 4 via the SCYL2 Gene

Fetal akinesia (FA) is characterized by reduced or absent fetal movements usually accompanied by other 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),

Arthrogryposis multiplex congenita 4 has been reported in six individuals from two unrelated, multiplex consanguineous families. Clinical features included decreased fetal movements, arthrogryposis multiplex congenita (contractures of fingers, hands, elbow, and feet), polyhydramnios, globally impaired development, optic atrophy, agenesis of the corpus callosum, seizures, and dysmorphic features (Seidahmed et al. 2020. PubMed ID: 31960134).  Genetic testing may aide in establishing a differential diagnosis and may assist reproductive planning.

Pathogenic variants in the SCYL2 gene are associated with autosomal recessive neurogenic arthrogryposis multiplex congenita 4. A nonsense variant and a frameshift variant which both result in premature protein termination have been reported in 6 individuals with arthrogryposis multiplex congenita 4 (Seidahmed et al. 2020. PubMed ID: 31960134). To date, all pathogenic variants have been inherited from a carrier parent. No structural variants have been reported.

The SCYL2 gene encodes a serine/threonine kinase that is expressed in clathrin-coated vesicles. This protein is necessary for normal function of the nervous system and suppresses excitotoxicity in the developing brain. Neuron specific disruption of the SCYL2 gene in mice resulted in perinatal lethality. Mice surviving to adulthood exhibited severe sensorimotor deficits (Seidahmed et al. 2020. PubMed ID: 31960134). SCYL2 has been cited as a conditional gene for growth of human tissue culture cells (Online Gene Essentiality). SCYL2 is relatively intolerant to loss-of-function variants; no homozygous loss-of-function variants are reported in the gnomAD database (gnomAD).

The clinical sensitivity is difficult to estimate, as to date, a limited number of cases have been described in the literature (Seidahmed et al. 2020. PubMed ID: 31960134). 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 SCYL2 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).