THSD1 – Non-immune Hydrops Fetalis

Non-immune hydrops fetalis (NIHF) is characterized by abnormal accumulation of serous fluid in two or more fetal compartments without maternal alloimmunization, often portending poor perinatal outcome. Recent genetic studies have implicated bi-allelic loss-of-function variants in THSD1 in a spectrum from lethal hydrops to resolving edema.

In a multi-patient study, whole exome sequencing in a consanguineous family from the UAE identified four affected children with fetal pleural and peritoneal effusions. All harbored a homozygous eight-nucleotide deletion in THSD1 (c.1163_1170delGGCCAGCC (p.Arg388GlnfsTer66)) segregating in autosomal recessive fashion with NIHF; postnatal follow-up demonstrated gradual fluid resolution and near-normal development ([PMID:30055085]).

A subsequent case report described two successive pregnancies in a separate family, both presenting with NIHF and carrying a homozygous truncating THSD1 variant (p.Glu298Ter). These fetuses similarly showed spontaneous postpartum resolution of hydrops ([PMID:37993095]).

All reported pathogenic alleles are predicted to truncate THSD1, consistent with a loss-of-function mechanism. Segregation across three unrelated families and absence of other etiologies supports an autosomal recessive inheritance model with complete penetrance of the hydrops phenotype in utero.

Direct functional assays in hydrops models are currently lacking, but the recurrence of bi-allelic truncating variants and the consistent clinical course across unrelated kindreds provide strong genetic evidence. No conflicting reports have been published to date.

Collectively, these data establish a strong gene-disease association between THSD1 and NIHF. THSD1 sequencing should be considered in unexplained cases of familial non-immune hydrops, enabling diagnosis, genetic counseling, and management guidance.

References

• American Journal of Medical Genetics Part A • 2018 • A recessive truncating variant in thrombospondin-1 domain containing protein 1 gene THSD1 is the underlying cause of nonimmune hydrops fetalis, congenital cardiac defects, and haemangiomas in four patients from a consanguineous family. PMID:30055085
• European Journal of Medical Genetics • 2023 • Resolving fetal hydrops - A rare entity. PMID:37993095

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