Lysosomal storage disorders in nonimmune hydrops fetalis diagnosed by exome sequencing.

Lysosomal storage disorders (LSD) are a group of inherited metabolic diseases that contribute to nonimmune hydrops fetalis (NIHF). Our objective was to review the pooled exome sequencing (ES) diagnostic yield of LSD in NIHF cases. We expanded our previous meta-analysis and updated our search strategy of prenatal ES studies from 1/1/2000 to 8/1/2024. Cases with LSD gene variants were reviewed. Variants were curated based on the current American College of Medical Genetics and Genomics and ClinGen guidelines. Forty-one ES studies met our inclusion criteria. A total of 207/558 NIHF cases yielded a positive diagnosis by ES. LSD cases represented 27/558 (5%) of all clinically diagnosed NIHF cases that had ES. Rate of LSD among NIHF cases with positive genetic diagnosis by ES was 27/207 (13%). The 27 diagnostic variants and 4 additional variants of uncertain significance (VUS) were identified in 9 different LSD genes. All variants were inherited with a recurrence risk of 25%. Mucopolysaccharidosis type VII (MPS VII) was most prevalent (14/27, 52%). Also, the 4 cases with VUS were identified in the GUSB gene. Most cases (21/31, 68%) were isolated NIHF. Hydrops recurrence when reported was present in 75% (15/20) of cases. Consanguinity was reported in 57% (12/21) of cases. In conclusion, 5% of all NIHF cases received a genetic diagnosis of LSD by ES. Thirteen percent of NIHF cases that received a genetic diagnosis by ES were attributable to LSD, with MPS VII being the most prevalent condition. Pairing ES results with enzymatic studies can aid variant interpretation and could have potentially upgraded some of the 4 VUS cases, leading to a higher LSD diagnostic yield. Most cases of LSD presenting as NIHF manifest prenatally as isolated NIHF. High rate of NIHF recurrence and consanguinity highlight importance of genetic counseling and testing for LSD.