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GBA1-related perinatal lethal Gaucher disease is an autosomal recessive condition characterized by near-complete glucocerebrosidase deficiency leading to nonimmune hydrops fetalis, ichthyosis, hepatosplenomegaly and rapid neonatal demise. The genetic basis involves biallelic loss-of-function variants in GBA1.
Autosomal recessive inheritance is supported by carrier status in unaffected parents in all reported cases. Three unrelated probands have been documented ([PMID:20924719]; [PMID:31192173]; [PMID:36720536]), each presenting with nonimmune hydrops fetalis, generalized ichthyosis, hepatosplenomegaly and early death. Parental segregation confirms trans inheritance of two pathogenic alleles in each family.
Biallelic deleterious variants include splicing mutations c.1505+5G>C in exon 10 and c.308-1G>A in intron 3 observed in two fetuses with hydrops and cerebellar hypoplasia ([PMID:36720536]). No common founder alleles have been described specifically for the perinatal lethal form. Variant spectrum across all Gaucher phenotypes shows frequent nonsense, frameshift, splice-site and severe missense mutations leading to null or near-null enzyme activity.
Mechanistically, perinatal lethal Gaucher disease arises from near-complete loss of glucocerebrosidase activity, resulting in massive glucosylceramide accumulation. In vitro expression studies of severe GBA1 alleles demonstrate <1% residual activity and impaired lysosomal trafficking, while enzymatic assays in patient cells show absent activity ([PMID:31192173]). Animal and cellular models of GBA1 knockout recapitulate hydrops, skin barrier defects and neuronal apoptosis.
The convergence of multiple unrelated perinatal lethal cases with biallelic severe GBA1 variants, consistent autosomal recessive segregation, and extensive functional data demonstrating loss-of-function supports a Moderate clinical validity for GBA1–perinatal lethal Gaucher disease. Additional evidence from broader Gaucher disease cohorts exceeds the ClinGen scoring framework but reinforces the pathogenic mechanism.
Key Take-home: Biallelic severe GBA1 loss-of-function variants cause perinatal lethal Gaucher disease, warranting early genetic testing for rapid diagnosis and informed reproductive counseling.
Gene–Disease AssociationModerateThree unrelated perinatal lethal cases with biallelic GBA1 variants and concordant loss-of-function data Genetic EvidenceModerate3 probands with AR inheritance and trans parental segregation Functional EvidenceModerateIn vitro and in vivo models show <1% activity and ER retention recapitulating severe phenotype |