Background: We report three brothers born to consanguineous parents of Syrian descent with a novel homozygous c.324G>A (p.W108*) mutation in PTRH2 that encodes mitochondrial peptidyl-tRNA hydrolase 2. Mutations in PTRH2 have recently been identified in the autosomal recessive condition, Infantile Onset Multisystem Neurologic, Endocrine and Pancreatic Disease (IMNEPD). To our knowledge, this is the first case of IMNEPD described in a Canadian centre. Methods: Clinical phenotyping enabled a targeted approach in which all exons of PTRH2 were sequenced. We identified a novel mutation and compared our patients with those recently described. Results: We identified a homozygous nonsense mutation in PTRH2, c.324G>A (p.W108*). This G to A mutation results in a premature stop at codon 108 that produces a truncated protein, removing most of the amino acids at the enzymatic active site. This mutation is not listed in the human Gene Mutation Database Cardiff, NCBI dbSNP, 1000 Genomes, Exome Variant Server or ClinVar and is a rare variant listed in gnomAD. Conclusions: In IMNEPD, nonsense mutations in PTRH2 appear to cause severe disease with postnatal microcephaly, neurodevelopmental regression, and ataxia with additional features of seizures, peripheral neuropathy, and pancreatic dysfunction, whereas missense mutations may produce a milder phenotype. The spectrum exhibited by our patients suggests variable expressivity with PTRH2 mutations.
P.134 Infantile Onset Multisystem Neurologic, Endocrine and Pancreatic Disease: case series and review
