Lethal Congenital Contracture Syndrome via the ERBB3 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 1/3,000 to 1/5,000 live births (Beecroft et al. 2018. PubMed ID: 29959180; Pergande et al. 2020. PubMed ID: 31680123). 

Lethal congenital contracture syndrome 2 was first described in two consanguineous families (Narkis et al. 2007. PubMed ID: 17701904). Clinical features can include micrognathia, high myopia, respiratory insufficiency, cystic kidneys, hydronephrosis, distended urinary bladder, arthrogryposis, neurogenic muscle atrophy, decreased fetal movement, and polyhydramnios. All affected individuals in both kindreds were homozygous for an intronic variant that alters splicing. An additional study identified another patient with dysmorphic features, knee dislocation, and bilateral hip dislocation who was also homozygous for a missense variant (Alfares et al. 2017. PubMed ID: 28454995). ERBB3 compound heterozygous variants were also reported in an individual with a multi-system disorder including developmental delay, growth retardation, facial malformations, bilateral nystagmus and amblyopia, feeding difficulties, immunodeficiency, anemia, and liver damage (Li et al. 2019. PubMed ID: 31752936). This patient did not present with congenital contractures. Genetic testing may aid in establishing a differential diagnosis and may assist reproductive planning.

Pathogenic variants in the ERBB3 gene are associated with autosomal recessive lethal congenital contracture syndrome 2 (LCCS2) and possibly other variable phenotypes. Reported variants include missense, splice, and one small duplication that results in a frameshift (Narkis et al. 2007. PubMed ID: 17701904; Alfares et al. 2017. PubMed ID: 28454995; Li et al. 2019. PubMed ID: 31752936). To date, all pathogenic variants have been inherited from a carrier parent. No structural variants have been reported. 

The ERRB3 gene encodes an epidermal growth factor (EGF) receptor and is one of four transmembrane glycoprotein EGF receptor tyrosine kinases. Members of this family play a key role in regulation of mammalian cell survival, proliferation, adhesion, and differentiation. Erbb3-/- mice are embryonic lethal at day E11.5-13.5 and show severe anomalies in brain development and abnormal development of the stomach, pancreas, and adrenal glands (Li et al. 2019. PubMed ID: 31752936; Erickson et al. 1997. PubMed ID: 9362461; Riethmacher et al. 1997. PubMed ID: 9338783). However, ERRB3 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 (Narkis et al. 2007. PubMed ID: 17701904; Alfares et al. 2017. PubMed ID: 28454995; Li et al. 2019. PubMed ID: 31752936). 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 ERBB3 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).