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.
Keywords: GS; GSS; RNA‐seq; fetal; glutathione synthetase deficiency; multiple congenital anomalies.
© 2024 The Author(s). Clinical Genetics published by John Wiley & Sons Ltd.