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

Abstract

Non-immune hydrops fetalis (NIHF) is the abnormal accumulation of serous fluid in more than two fetal or neonatal interstitial spaces due to nonimmune causes. It is a serious condition that requires extensive medical care as it indicates severe fetal compromise. We clinically evaluated four patients from two branches of a highly consanguineous family from the UAE with NIHF using whole exome sequencing and in silico analysis. Fetal onset pleural and peritoneal effusions were detected in all four patients and were born with moderate to severe hydrops fetalis that resolved with age. Follow up showed relatively normal growth and development apart from mild ascites and haemangiomas in all affected children, recurrent hydrocele in all affected males, intestinal malabsorption in two patients, dysmorphic features in two patients, and congenital cardiac defects in three out of four patients. Molecular testing identified a homozygous eight nucleotide deletion in THSD1 gene (NM_199263:c.1163_1170delGGCCAGCC, p.Arg388Glnfs*66) as the underlying cause of this phenotype in the affected children. The novel variant cosegregates with the described phenotype in an autosomal recessive mode of inheritance and is predicted to be pathogenic as it leads to a truncated protein that lost important structural and functional domains. Thrombospondin-1 domain containing protein 1 gene THSD1 has been recently associated with of NIHF and embryonic lethality. Here, we report the novel truncating THSD1 variant, and describe new clinical features that have not been reported previously thus expanding the phenotype associate with loss-of-function mutations in THSD1 causing NIHF.

Manifestations of thrombospondin type‐1 domain‐containing protein 1 gene mutation in an extremely premature infant with nonimmune hydrops fetalis

“…In addition to NIHF at birth, our patient presented with other conditions, including congenital heart disease, dysmorphism, and hemangiomas, which are described as manifestations of other THSD1 variants. Interestingly, she had multiple (>16) cavernous hemangiomas, which was in contrast to the capillary hemangiomas described in previously reported cases involving premature infants (Abdelrahman et al, 2018).…”

“…The prognosis depends on the etiology, which is often poor with a perinatal mortality rate of 55%–98%. Recently, THSD1 mutations were identified in a few NIHF cases, in which biallelic variants were reported as the cause of NIHF in three families (Abdelrahman et al, 2018; Shamseldin et al, 2015). In addition, heterozygous THSD1 variants were found in some patients with intracranial aneurysms (Santiago‐Sim et al, 2016).…”

“…Shamseldin et al (2015) reported on four families, with three families harboring the same THSD1 variant, whereas the fourth had a different THSD1 variant. Moreover, Abdelrahman et al (2018) reported a homozygous eight‐nucleotide deletion in THSD1 (NM_199263:c.1163_1170delGGCCAGCC p.[Arg388Glnfs*66]) as the underlying cause of NIHF in one family with four alive and one deceased individuals. Most surviving patients were late preterm infants (33–35‐week‐gestation) and their phenotypes included NIHF that subsided later in life, congenital heart disease (atrial septal defect, PDA, mitral regurgitation, and/or patent foramen ovale), capillary hemangiomas, and subtle dysmorphism.…”

The utility of exome sequencing for fetal pleural effusions

“…Recent case reports of fetuses undergoing ES for pleural effusions have revealed a few genes such as EPHB4, which regulates angiogenesis. Such case reports have increased our recognition of the diverse genetic etiologies that may contribute to fetal pleural effusions. The present study has identified four novel candidate variants, through in‐depth analysis of ES.…”

Diagnostic yield from prenatal exome sequencing for non‐immune hydrops fetalis: A systematic review and meta‐analysis

“…One VUS in THSD1 (NM_018676.4:c.617G > A), was reported in four homozygous cases from consanguineous families of middle eastern descent 18,20 . No other included case series reported variants in this gene, though a homozygous loss of function variant has been reported in NIHF, 45 suggesting that this could be a population specific founder variant. PIEZO1 (NM_001142864.4:c.1792G > A), 7,29,39 RIT1 (NM_006912.6:c.268A > G), 23,24,26 and PTPN11 (NM_002834.5:c.854 T > C) 7,39 occurred de novo in three independent cases each.…”