Multiple congenital anomalies in two fetuses with glutathione‐synthetase deficit (GSS)

Abstract Glutathione synthetase deficiency is a rare inborn metabolic disease usually caused by biallelic variants in GSS . Clinical severity varies from isolated hemolytic anemia, sometimes associated with chronic metabolic acidosis and 5‐oxoprolinuria, to severe neurological phenotypes with neonatal lethality. Here we report on two fetal siblings from two pregnancies with glutathione synthetase deficiency exhibiting similar multiple congenital anomalies associating phocomelia, cleft palate, intra‐uterine growth retardation, genito‐urinary malformations, and congenital heart defect. Genome sequencing showed that both fetuses were compound heterozygous for two GSS variants: the previously reported pathogenic missense substitution NM_000178.4 c.800G>A p.(Arg267Gln), and a 2.4 kb intragenic deletion NC_000020.11:g.34944530_34946833del. RNA‐seq on brain tissue revealed the out‐of‐frame deletion of the exon 3 and an almost monoallelic expression of the missense variant (88%), suggesting degradation of the deletion‐harboring allele by nonsense‐mediated mRNA decay. 5‐oxoproline (pyroglutamic acid) levels in amniotic fluid were elevated, suggesting an alteration of the gamma‐glutamyl cycle, and corroborating the pathogenicity of the two GSS variants. Only one case of glutathione synthetase deficiency with limb malformations has previously been reported, in a newborn homozygous for the c.800G>A variant. Thus, our data allow us to discuss a potential phenotypic extension of glutathione synthetase deficiency, with a possible involvement of the c.800G>A variant.