Expanding the phenotype of PURA-related neurodevelopmental disorder: a close differential diagnosis of infantile hypotonia with psychomotor retardation and characteristic facies.

Purine-rich element-binding protein A (PURA) encodes Pur-alpha, a transcriptional activator protein is crucial for normal brain development. Pathogenic variants in PURA are known to cause mental retardation, autosomal dominant 31, characterized by psychomotor delay, absent or poor speech, hypotonia, feeding difficulties, seizures or 'seizure-like' movements, and dysmorphism. PURA-related neurodevelopmental disorder (PURA-related NDD) result either from heterozygous pathogenic sequence variants in PURA or microdeletions spanning PURA. Singleton whole-exome sequencing (WES) was performed for the proband after a clinical diagnosis of infantile hypotonia with psychomotor retardation and characteristic facies (IHPRF) was made. The pathogenic variant was validated by Sanger sequencing in the proband and parents. Comparison of PURA-related NDD and IHPRF was carried out. WES identified a novel, de-novo stop-gain variant c.178G>T in PURA. In addition to typical phenotype, subject also had hypersensitivity to various stimuli which was not reported in PURA-related NDD. Significant phenotypic overlap was observed in subjects with PURA-related NDD and IHPRF especially with IHPRF2, caused by biallelic pathogenic variants in UNC80. This study expands the phenotypic and mutational spectrum of PURA-related NDD. We propose PURA-related NDD to be considered as a close differential diagnosis of IHPRF.