(568) Lysosomal storage disorders in cases of NIHF 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 spectrum of LSD diagnosed by exome sequencing (ES) in cases of NIHF. 

Study Design:

A systematic review of ES studies for NIHF was conducted using 4 electronic databases between 1/1/2000-12/1/2021. All LSD gene variants reported in cases that met phenotypic criteria for NIHF were recorded. Variants were curated based on current American College of Medical Genetics and Genomics guidelines. Pathogenic or likely pathogenic variants were considered diagnostic and both diagnostic variants and variants of uncertain significance (VUS) were reported. NIHF phenotype was further classified as isolated or non-isolated. History of recurrence of NIHF and consanguinity were recorded.

Results:

Of 31 ES studies of NIHF, 161 cases received a genetic diagnosis by ES with 24 cases due to LSD. ES confirmed a genetic cause of LSD in 21/161 (13%) of NIHF. 21 diagnostic variants and 3 VUS were identified in 9 different LSD genes. Unavailable biochemical data did not support upgrading classification for the 3 VUS. All variants were inherited with a recurrence risk of 25%. Mucopolysaccharidosis type VII (14/24, 58%) was most common (Figure 1). Most cases (17/24, 71%) were isolated NIHF. Associated anomalies in non-isolated cases were musculoskeletal (3/8, 37.5%), renal (3/8, 37.5%), cardiac (2/8, 25%), and gastrointestinal (2/8, 25%) (Table 1). Hydrops recurrence was reported in (15/20, 75%) of cases. Consanguinity was reported in half of cases (13/24, 52%).

Conclusion:

ES diagnostic yield for NIHF in cases of LSD was 13%. Various LSD contribute to NIHF with Mucopolysaccharidosis type VII being most common. Majority of cases manifest prenatally as isolated NIHF. Pairing ES results with enzymatic studies, might aid variant interpretation. High rate of NIHF recurrence and consanguinity highlight importance of genetic counseling and testing for LSD.