Lethal contracture syndrome 9 is caused by bi-allelic variants in ADGRG6 (previously known as GPR126). The presenting features of the disease are reduced fetal movements and joint contractures from 18 weeks gestation. There are also a range of other features which are likely secondary to the reduced fetal movements, including: pterygia, micrognathia, rockerbottom feet, talipes. Pregnancy can also be complicated by polyhydramnios.
Of the previously reported cases: two probands were born in the third trimester (31 and 36 weeks gestation and survived for only an hour after birth). A third proband was detected on ultrasound to have distal joint contractures and reduced fetal motility and the pregnancy was terminated at 20 weeks (Pubmed ID 26004201). A fourth proband (reported in Baynam et al. 2016) was diagnosed with an unclassified distal arthrogryposis and died postnatally (Pubmed ID 26752647).
Three probands were homozygous for null alleles (one an essential splice site variant and two for the same nonsense variant, c.19C>T, p.Arg7*). A third proband was homozygous for a missense variant within the GAIN domain of the protein and it was shown that this variant resulted in loss of the autolytic cleavage of the protein and hence loss of the active form of the protein.
SNPs in ADGRG6 have also been associated, by more than one study, with adolescent idiopathic scoliosis.
A homozygous missense variant in ADGRG6 has also recently been reported in one consanguineous family in which two siblings presented with profound intellectual disability, severe speech delay, seizures in infancy and microcephaly. No functional studies were performed. Further studies are needed to support the link between ADGRG6 and the intellectual disability/CNS phenotype observed in this family.