Infant male with TARP syndrome: Review of clinical features, prognosis, and commonalities with previously reported patients

Abstract

TARP syndrome (talipes equinovarus, atrial septal defect, Robin sequence, and persistent left superior vena cava) is a rare X-linked condition. As more patients are identified through genetic testing, it is increasingly clear that the original TARP acronym does not fully describe the complete phenotypic spectrum of this syndrome. The presented patient had genetically confirmed TARP syndrome and demonstrated new findings of hydronephrosis and hemodynamically significant hypertrophic obstructive cardiomyopathy. The patient also had physical findings common with previously reported individuals with TARP syndrome in the literature but not described by the TARP acronym. These features include central nervous system dysfunction, renal abnormalities, cardiac lesions other than atrial septal defect or persistent left superior vena cava, and distal limb defects other than talipes equinovarus. By adding to the known spectrum of the TARP phenotype, this report will aid clinicians as they care for patients with this rare condition.

A novel missense variant in RBM10 can cause a mild form of TARP syndrome with developmental delay and dysmorphic features

“…Additionally, we identified that the p.Pro322Leu variant affected the protein stability of RBM10 with a much shorter half-life and a remarkably reduced expression level of the mutant protein (Figure 2A) (Table 1 and Table S3). [3][4][5][6][7][8] It also demonstrated that nearly a third of the cases lived longer than 3 years. There were no specific clinical findings that determine early lethality, but it is likely their mortality was reflective of the degree of disease involvement of vital organs, such as heart and lung.…”

“…Review of the previously reported 16 cases indicated that the clinical expressivity of TARP syndrome is variable and not all patients have the tetrad of classical features (Table 1 and Table S3). 3‐8 It also demonstrated that nearly a third of the cases lived longer than 3 years. There were no specific clinical findings that determine early lethality, but it is likely their mortality was reflective of the degree of disease involvement of vital organs, such as heart and lung.…”

“…Truncating hemizygous variants in this X chromosome gene have been reported to cause TARP syndrome in males (OMIM #311900), which is characterized by the clinical tetrad of talipes equinovarus, atrial septal defect, Robin sequence, and persistent left superior vena cava 2 . Additionally, severe developmental delay, growth retardation, neurological impairments, characteristic craniofacial appearance, skeletal/limb defects, and respiratory complications have been observed and many patients die very early during infancy 3‐8 . There have been no symptomatic carrier females previously identified 3,4,7 …”

Phenotypic spectrum of the RBM10‐mediated intellectual disability and congenital malformation syndrome beyond classic TARP syndrome features

“…Pathogenic RBM10 loss of function variants cause an X‐linked disorder that is described as TARP syndrome (Talipes equinovarus, Atrial septal defect, Robin sequence, and Persistent left superior vena cava; OMIM 311900). The causal gene defect was described in 2010, where pathogenic variants were shown to be either de novo, inherited from a heterozygous female carrier or due to maternal mosaicism, with so far no known effect in carrier females 1‐12 . RBM10 is predominantly involved in RNA regulation of hundreds of genes, through alternative splicing, transcription regulation, and histone modification 5,13 .…”

“…RBM10 is predominantly involved in RNA regulation of hundreds of genes, through alternative splicing, transcription regulation, and histone modification 5,13 . So far, 13 families encompassing 24 patients with RBM10 pathogenic variants have been described in literature 1‐12 . Due to improvement of genetic techniques, identification of genetic syndromes does not remain limited to hallmark phenotypic features allowing to diagnose patients more rapidly with an atypical presentation.…”