Prenatal diagnosis of a homozygous variant of SUMF1 in a fetus with hydrops fetalis using chorionic villus sampling
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https://doi.org/10.15625/vjbt-21946Keywords:
Chorionic villus sampling, exome sequencing, nonimmune hydrops fetalis, multiple sulfatase deficiency, prenatal diagnosis, SUMF1 gene.Abstract
Nonimmune hydrops fetalis (NIHF) is a severe prenatal condition with a broad etiological spectrum, including chromosomal abnormalities, structural malformations, congenital infections, and inherited metabolic disorders. Early identification of the underlying cause is essential for accurate prognosis, clinical decision-making, and genetic counseling. Here, we report the prenatal diagnosis of a fetus presenting with early-onset NIHF caused by a homozygous missense variant in the SUMF1 gene, detected through first-trimester chorionic villus sampling (CVS). A 27-year-old gravida 5 woman with a history of two previous pregnancies affected by unexplained hydrops fetalis was referred at 12 weeks and 3 days of gestation. Ultrasound examination revealed markedly increased nuchal translucency, generalized hydrops fetalis, and absence of the nasal bone. Given the recurrent phenotype and early gestational presentation, invasive prenatal diagnosis was performed using CVS. Clinical exome sequencing identified a homozygous SUMF1 variant (NM_182760.4: c.538T>A, p.Trp180Arg), which is absent from population databases and has been reported only once in ClinVar as a variant of uncertain significance. Subsequent Sanger sequencing confirmed heterozygous carrier status in both parents and the unaffected sibling, consistent with autosomal recessive inheritance. SUMF1 encodes the sulfatase-modifying factor 1, a critical enzyme required for post-translational activation of all sulfatases. Biallelic pathogenic variants in SUMF1 cause multiple sulfatase deficiency, an ultra-rare lysosomal storage disorder that may present prenatally with hydrops fetalis. The severe and recurrent fetal phenotype observed in this family strongly supports the pathogenic relevance of the identified variant. This case highlights the diagnostic value of early invasive prenatal testing, particularly CVS combined with next-generation sequencing, in pregnancies complicated by early-onset or recurrent NIHF. Early molecular diagnosis enables timely counseling, informed reproductive decision-making, and appropriate planning for future pregnancies.
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Bellini C., and Hennekam R. C. (2012). Non-immune hydrops fetalis: a short review of etiology and pathophysiology. American Journal of Medical Genetics - Part A, 158A(3), 597-605. https://doi.org/10.1002/ajmg.a.34438
ClinVar. Retrieved from https://www.ncbi.nlm.nih.gov/ clinvar/variation/VCV002186489.1. Retrieved Oct. 31, 2024, from National Center for Biotechnology Information Cosma M. P., Pepe S., Annunziata I., Newbold R. F., Grompe M., Parenti G., et al. (2003). The multiple sulfatase deficiency gene encodes an essential and limiting factor for the activity of sulfatases. Cell, 113(4), 445-456. http://doi.org/10.1016/s0092-8674(03)00348-9
Dong C., Wei P., Jian X., Gibbs R., Boerwinkle E., Wang K., et al. (2015). Comparison and integration of deleteriousness prediction methods for nonsynonymous SNVs in whole exome sequencing studies. Human Molecular Genetics, 24(8), 2125-2137. https://doi.org/10.1093/hmg/ddu733
Eto Y., Gomibuchi I., Umezawa F., and Tsuda T. (1987). Pathochemistry, pathogenesis and enzyme replacement in multiple-sulfatase deficiency. Enzyme, 38(1-4), 273-279. https://doi.org/10.1159/000469216
Fraldi A., Biffi A., Lombardi A., Visigalli I., Pepe S., Settembre C., et al. (2007). SUMF1 enhances sulfatase activities in vivo in five sulfatase deficiencies. Biochemical Journal, 403(2), 305-312. https://doi.org/10.1042/BJ20061783
Liu X., Jian X., and Boerwinkle E. (2011). dbNSFP: a lightweight database of human nonsynonymous SNPs and their functional predictions. Human Mutation, 32(8), 894-899. https://doi.org/10.1002/humu.21517
Liu X., Wu C., Li C., and Boerwinkle E. (2016). dbNSFP v3.0: A one-stop database of functional predictions and annotations for human nonsynonymous and splice-site SNVs. Human Mutation, 37(3), 235-241. https://doi.org/10.1002/humu.22932
Martins A. T., Francisco C., Correia H., and Cohen A. (2020). Chorionic villus sampling: 10 years of experience in a University referral center. Journal of Gynecology Obstetrics and Human Reproduction, 49(5), 101715. https://doi.org/10.1016/j.jogoh.2020.101715
Mujezinovic F., and Alfirevic Z. (2007). Procedure-related complications of amniocentesis and chorionic villous sampling: a systematic review. Obstetrics and gynecology, 110(3), 687-694. https://doi.org/10.1097/01.AOG.0000278820.54029.e3
Practice Bulletin No. 162 Summary: Prenatal Diagnostic Testing for Genetic Disorders. (2016). Obstetrics and gynecology, 127(5), 976-978. https://doi.org/10.1097/AOG.0000000000001438
Richards S., Aziz N., Bale S., Bick D., Das S., Gastier-Foster J., et al. (2015). Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genetics in Medicine, 17(5), 405-424. https://doi.org/10.1038/gim.2015.30
Sabourdy F., Mourey L., Le Trionnaire E., Bednarek N., Caillaud C., Chaix Y., et al. (2015). Natural disease history and characterisation of SUMF1 molecular defects in ten unrelated patients with multiple sulfatase deficiency. Orphanet Journal of Rare Diseases, 10, 31. https://doi.org/10.1186/s13023-015-0244-7
Schlotawa L., Dierks T., Christoph S., Cloppenburg E., Ohlenbusch A., Korenke G. C., et al. (2019). Severe neonatal multiple sulfatase deficiency presenting with hydrops fetalis in a preterm birth patient. JIMD Reports, 49(1), 48-52. https://doi.org/10.1002/jmd2.12074
Wapner R. J. (1997). Chorionic villus sampling. Obstetrics and Gynecology Clinics of North America, 24(1), 83-110. https://doi.org/10.1016/s0889-8545(05)70291-6
Whybra C., Mengel E., Russo A., Bahlmann F., Kampmann C., Beck M., et al. (2012). Lysosomal storage disorder in non-immunological hydrops fetalis (NIHF): more common than assumed? Report of four cases with transient NIHF and a review of the literature. Orphanet Journal of Rare Diseases, 7, 86. https://doi.org/10.1186/1750-1172-7-86
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