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Review
. 2025 Jul 10;20(1):351.
doi: 10.1186/s13023-025-03851-9.

Lysosomal storage disorders in nonimmune hydrops fetalis diagnosed by exome sequencing

Mona M Makhamreh  1 , Kavya Shivashankar  2 , Stephanie M Rice  3 , Sascha Wodoslawsky  4 , Christina Grant  5 , Rodney McLaren Jr  3 , Seth I Berger  5 , Huda B Al-Kouatly  6
Affiliations
Review

Lysosomal storage disorders in nonimmune hydrops fetalis diagnosed by exome sequencing

Mona M Makhamreh et al. Orphanet J Rare Dis. .

Abstract

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.

Keywords: Exome; Hydrops fetalis; Lysosomal storage disorders.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interest: The authors declare that they have no competing interests. PROSPERO registration number: CRD42022369438. Previous presentation: Accepted as a poster presentation at the Society of Maternal Fetal Medicine 43rd Annual Pregnancy Meeting, San Francisco, February 2023.

Figures

Fig. 1
Fig. 1
Types of LSD associated with NIHF diagnosed by ES
Fig. 2
Fig. 2
a Forest plot demonstrating ES diagnostic yield for LSD in NIHF. b Forest plot demonstrating proportion of LSD among all NIHF cases with positive ES diagnosis
Fig. 2
Fig. 2
a Forest plot demonstrating ES diagnostic yield for LSD in NIHF. b Forest plot demonstrating proportion of LSD among all NIHF cases with positive ES diagnosis
Fig. 3
Fig. 3
a Funnel plot of standard error by logit transformed proportion of ES diagnostic yield to evaluate publication bias for LSD in NIHF. b Funnel plot of standard error by logit transformed proportion of LSD to evaluate publication bias for NIHF cases with positive ES diagnosis
Fig. 4
Fig. 4
Diagnostic workflow for NIHF cases suspicious for LSD
See this image and copyright information in PMC

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References

    1. Norton ME, Chauhan SP, Dashe JS. Society for maternal-fetal medicine (SMFM) clinical guideline #7: nonimmune hydrops fetalis. Am J Obstet Gynecol. 2015;212(2):127–39. - PubMed
    1. Sparks TN, Thao K, Lianoglou BR, Boe NM, Bruce KG, Datkhaeva I, et al. Nonimmune hydrops fetalis: identifying the underlying genetic etiology. Genet Med. 2019;21(6):1339–44. - PMC - PubMed
    1. Whybra C, Källén K, Hansson SR, Gunnarsson R. Non-immune hydrops fetalis was rare in Sweden during 1997–2015, but cases were associated with complications and poor prognosis. Acta Paediatr. 2020;109(12):2570–7. 10.1111/apa.15260. - PubMed
    1. Santolaya J, Alley D, Jaffe R, Warsof SL. Antenatal classification of hydrops fetalis. Obstet Gynecol. 1992;79(2):256–9. - PubMed
    1. Al-Kouatly HB, Shivashankar K, Mossayebi MH, Makhamreh M, Critchlow E, Gao Z, Fasehun LK, Alkuraya FS, Ryan EE, Hegde M, Wodoslawsky S, Hughes J, Berger SI. Diagnostic yield from prenatal exome sequencing for non-immune hydrops fetalis: a systematic review and meta-analysis. Clin Genet. 2023;103(5):503–12. 10.1111/cge.14309. - PubMed

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