Lethal Congenital Contracture Syndrome 9 via the ADGRG6 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 9 (LCCS9) was first described in three consanguineous families (Ravenscroft et al. 2015. PubMed ID: 26004201). All affected individuals were homozygous for missense, nonsense, or frameshift variants. Clinical features can include intrauterine growth retardation; micrognathia; dysmorphic features; pulmonary hypoplasia; contractures of wrists, elbows, and fingers; talipes equinovarus; decreased fetal movements; and polyhydramnios. Onset is in utero and fetal anomalies are typically observed on prenatal ultrasound. Respiratory failure typically results in death soon after birth. Additional compound heterozygous or homozygous patients with ADGRG6 variants and features of LCCS9 have been reported in several additional families (Daum et al. 2019. PubMed ID: 29947050; Vora et al. 2020. PubMed ID: 31974414; Normand et al. 2018. PubMed ID: 30266093). Genetic testing may aid in establishing a differential diagnosis and may assist reproductive planning.

Pathogenic variants in the ADGRG6 gene (also referred to as GPR126 in the literature) are associated with autosomal recessive lethal congenital contracture syndrome 9 (LCCS9). Reported variants include nonsense, missense, and a small duplication that results in a frameshift (Ravenscroft et al. 2015. PubMed ID: 26004201; Daum et al. 2019. PubMed ID: 29947050; Vora et al. 2020. PubMed ID: 31974414; Normand et al. 2018. PubMed ID: 30266093). To date, all pathogenic variants have been inherited from a carrier parent. No structural variants have been reported. 

The ADGRG6 gene encodes adhesion G protein-coupled receptor G6 which is essential for myelination of axons in the peripheral nervous system. ADGRG6 drives the differentiation of promyelinating Schwann cells by elevating cyclic AMP levels (Monk et al. 2009. PubMed ID: 19745155; Glenn and Talbot. 2013. PubMed ID: 23804499). Affected individuals from one family were found to lack myelin basic protein, providing evidence that ADGRG6 is critical for myelination of the peripheral nerves. Gpr126-null mice have abnormal joint contractures of the limbs by P4 (Ravenscroft et al. 2015. PubMed ID: 26004201; Monk et al. 2011. PubMed ID: 21613327). The ADGRG6 gene (listed as GPR126 in the study) is not considered an essential gene in the human genome (CS = 0.254 in Wang et al. 2015. PubMed ID: 26472758).

The clinical sensitivity is difficult to estimate, as to date, a limited number of cases have been described in the literature (Ravenscroft et al. 2015. PubMed ID: 26004201; Daum et al. 2019. PubMed ID: 29947050; Vora et al. 2020. PubMed ID: 31974414; Normand et al. 2018. PubMed ID: 30266093). 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 99.4% coverage of the ADGRG6 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  coverage as ≥20X NGS reads or Sanger sequencing. Of note, this test does not analyze the 2 nucleotides of exon 1 due to paralogy.

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).