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

Autor: Jury J; Service de Génétique médicale, Nantes Université, CHU de Nantes, Nantes, France., Benoist JF; Laboratoire de Biochimie Métabolique, Hôpital Necker-Enfants-Malades, APHP, Paris, France.; CEA, INRAE, DMTS, SPI, MetaboHUB-IDF, Université Paris-Saclay, Gif-sur-Yvette, France., Joubert M; Unité de Fœtopathologie et Génétique, CHU de Nantes, Nantes, France., Quelin C; Service de Génétique Clinique, CLAD Ouest, CHU Rennes, Hôpital Sud, Rennes, France., Besnard T; Service de Génétique médicale, Nantes Université, CHU de Nantes, Nantes, France.; l'institut du thorax, Nantes Université, CHU de Nantes, CNRS, INSERM, Nantes, France., Conrad S; Service de Génétique médicale, Nantes Université, CHU de Nantes, Nantes, France., Le Vaillant C; Service de Gynécologie et Obstétrique, CHU Nantes, Nantes, France., Bézieau S; Service de Génétique médicale, Nantes Université, CHU de Nantes, Nantes, France.; l'institut du thorax, Nantes Université, CHU de Nantes, CNRS, INSERM, Nantes, France., Isidor B; Service de Génétique médicale, Nantes Université, CHU de Nantes, Nantes, France.; l'institut du thorax, Nantes Université, CHU de Nantes, CNRS, INSERM, Nantes, France., Attié-Bitach T; Imagine Institute, INSERM UMR1163, Paris, France.; Service de Médecine Génomique des Maladies Rares, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Faculté de Médecine, Université de Paris Cité, Paris, France.; Laboratoire SeqOIA (PFMG 2025), Paris, France., Cogné B; Service de Génétique médicale, Nantes Université, CHU de Nantes, Nantes, France.; l'institut du thorax, Nantes Université, CHU de Nantes, CNRS, INSERM, Nantes, France.; Laboratoire SeqOIA (PFMG 2025), Paris, France., Vincent M; Service de Génétique médicale, Nantes Université, CHU de Nantes, Nantes, France.; l'institut du thorax, Nantes Université, CHU de Nantes, CNRS, INSERM, Nantes, France.
Jazyk: angličtina
Zdroj: Clinical genetics [Clin Genet] 2024 Dec; Vol. 106 (6), pp. 776-781. Date of Electronic Publication: 2024 Sep 02.
DOI: 10.1111/cge.14613
Abstrakt: 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.
(© 2024 The Author(s). Clinical Genetics published by John Wiley & Sons Ltd.)
Databáze: MEDLINE
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