Distal Arthrogryposis Type 1C via the MYL11/MYLPF 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). 

Distal arthrogryposis type 1C has been reported in eight families with distal arthrogryposis and MYL11/MYLPF pathogenic variants. In six of these families autosomal recessive inheritance was observed, while in two families autosomal dominant inheritance was observed. Common clinical features include multiple congenital contractures, scoliosis, and short stature; in limited cases undescended testicles and a small mouth were also observed (Chong et al. 2020. PubMed ID: 32707087). Genetic testing may aide in establishing a differential diagnosis and may assist reproductive planning.

Pathogenic variants in the MYL11 gene are associated with both autosomal recessive and autosomal dominant distal arthrogryposis type 1C. To date, only missense variants have been reported in the MYL11 gene. In six of the reported families, homozygous variants were reported. One reported variant was found to have occurred de novo while another variant was inherited in an autosomal dominant family (Chong et al. 2020. PubMed ID: 32707087). No other large structural variants have been reported. MYL11 is relatively intolerant to loss of function variants (Genome Aggregation Database).

MYL11 encodes fast-type skeletal muscle regulatory light chain, which is a component of skeletal muscle myosin. Zebrafish with mylpfa knocked out  exhibit reduced trunk contractile force and complete pectoral fin paralysis consistent with muscle weakness and reduced myosin activity. MYL11 has been cited as a non-essential gene for growth of human tissue culture cells (Online Gene Essentiality).

Clinical sensitivity is difficult to estimate, as to date, a limited number of cases have been described in the literature (Chong et al. 2020. PubMed ID: 32707087). In Chong et al., they found two families with MYL11 variants out of 172 families with undiagnosed distal arthrogryposis after Sanger sequencing. 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 MYL11 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).