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.
Mitochondrial diseases comprise a heterogeneous group of disorders due to dysfunction of mitochondrial respiratory chain caused by mutations in both mitochondrial and nuclear genes. EARS2 encodes mitochondrial glutamyl t-RNA synthetase responsible for attaching glutamate to its cognate mitochondrial t-RNA. Hence, EARS2 is critical for protein translation in mitochondria. Homozygous or compound heterozygous EARS2 pathogenic variants are associated with a neurological disorder characterized by leukoencephalopathy with thalamus and brain stem involvement and high lactate (LTBL) [1]. Patients with EARS2-related mitochondrial disease become symptomatic in infancy with characteristic MRI findings of diffuse white matter changes and symmetrical signal abnormalities in the thalamus and brain stem. Their clinical presentations fall into two groups-severe and mild. Patients in the severe group present before 6 months of age with marked neurological regression followed by clinical stagnation. Patients in the mild group present later in infancy with neurological regression, but they regain some milestones and follow a stable clinical *
Multiple acyl‐CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder of fatty acid, amino acid, and choline metabolism. We describe a patient identified through newborn screening in which the diagnosis of MADD was confirmed based on metabolic profiling, but clinical molecular sequencing of ETFA, ETFB, and ETFDH was normal. In order to identify the genetic etiology of MADD, we performed whole genome sequencing and identified a novel homozygous promoter variant in ETFA (c.‐85G > A). Subsequent studies showed decreased ETFA protein expression in lymphoblasts. A promoter luciferase assay confirmed decreased activity of the mutant promoter. In both assays, the variant displayed considerable residual activity, therefore we speculate that our patient may have a late onset form of MADD (Type III). Our findings may be helpful in establishing a molecular diagnosis in other MADD patients with a characteristic biochemical profile but apparently normal molecular studies.
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