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

Abstract

RBM10, is an RNA binding protein that is important for development by regulating the expression of multiple genes. RBM10 is on the X chromosome, and nonsense and frameshift RBM10 variants cause TARP syndrome in males. In a 4-year-old male, we identified a novel maternally inherited missense RBM10 variant in the RRM2 RNA binding domain, c.965C>T, p.Pro322Leu. His clinical features included intellectual disability, developmental delay, growth restriction, hypotonia, and craniofacial malformations. These features were much milder than those described in previously reported cases of TARP syndrome. By in vitro assays, we found that the mutant p.Pro322Leu RBM10 protein retained its specific RNA binding capacity, while gaining a low-affinity nonspecific RNA binding. It was normally localized to the nucleus, but its expression level was significantly reduced with a significantly short half-life. These results indicated that the p.Pro322Leu missense variant causes a developmental disorder in humans through a unique loss-of-function mechanism.

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

“…We report two novel cases with loss of function RBM10 variants that further demonstrate the wide phenotypic spectrum of RBM10 pathogenic variants 1‐12 . Reviewing all 25 reported cases with RBM10 loss of function variants, we suggest for the first time recurrent clinical features important for diagnosis and provide possible evidence for a genotype–phenotype correlation for RBM10 variants.…”

“…As such, pathogenic variants in exon 4, present in lower abundance, have been reported in two patients with relatively milder phenotypes (Reference 8 and case 1). Recently, for one RBM10 missense variant only partial reduction in RBM10 protein and retained normal RNA binding function was shown, probably explaining the milder phenotype in this patient and possibly for missense variants in general 11 . To further explore the genotype–phenotype correlation, additional studies with more patients and mutations are needed.…”

“…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.…”

“…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 .…”

A Frameshift RBM10 Variant Associated With TARP Syndrome

“…RBM10 has been shown to regulate alternative splicing of pre-mRNA of NUMB , FAS , Dlg4 , SMN2 and Even its own pre-mRNA resulting in alternative splicing-coupled nonsense-mediated mRNA decay (AS-NMD) ( Loiselle and Sutherland, 2018 ). Disease mutations include missense and frameshift mutations that lead to abnormal or truncated proteins ( Højland et al, 2018 ; Imagawa et al, 2020 ). The identification of RMB10 variants could help to clarify its clinical variabilities and shed light on the pathogenesis of TARP syndrome.…”