Congenital Myopathy with Diaphragmatic Defects, Respiratory Insufficiency, and Dysmorphic Facies via the MYOD1 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). 

Congenital myopathy with diaphragmatic defects, respiratory insufficiency, and dysmorphic facies was first reported in a consanguineous family in which three neonates from two sibships presented with lethal fetal akinesia, cleft palate, and arthrogryposis (Watson et al. 2016. PubMed ID: 26733463). In an additional patient with a homozygous nonsense variant, a less severe course was described. This patient presented with respiratory infections, hypotonia, ptosis, motor delay, failure to thrive and diaphragm musculature being severely affected (Lopes et al. 2018. PubMed ID: 30403323). In another family, two siblings homozygous for a frameshift variant presented with motor delays, poor weight gain, triangular face, pectus excavatum, and distal arthrogryposis (Shukla et al. 2019. PubMed ID: 31260566). This indicates there is likely phenotypic variability from severe fetal akinesia to a more mild congenital myopathy. Genetic testing may aide in establishing a differential diagnosis and may assist reproductive planning.

Pathogenic variants in MYOD1 are associated with autosomal recessive congenital myopathy with diaphragmatic defects, respiratory insufficiency, and dysmorphic facies. To date, only nonsense variants and one small duplication resulting in a frameshift variant have been reported to be causative (Watson et al. 2016. PubMed ID: 26733463; Lopes et al. 2018. PubMed ID: 30403323; Shukla et al. 2019. PubMed ID: 31260566).  All pathogenic variants have been inherited from a carrier parent. No structural variants have been reported.

MYOD1 encodes myogenic differentiation antigen 1, which is exclusively expressed in skeletal muscle. MYOD1 belongs to a family of transcription factors that are essential for myogenic differentiation and repair. A MyoD knockout mouse is viable, fertile, and produces offspring that do not exhibit overt muscle abnormalities. However, a double knockout of MyoD and Myf-5 created a lethal phenotype with complete absence of skeletal muscle indicating these two genes may have some functional redundancy (Rudnicki et al. 1992. PubMed ID: 1330322). MYOD1 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 (Watson et al. 2016. PubMed ID: 26733463; Lopes et al. 2018. PubMed ID: 30403323; Shukla et al. 2019. PubMed ID: 31260566). 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 MYOD1 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).