European Journal of Human Genetics · 8 authors, 4 centres
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This case report describes two siblings with a homozygous loss-of-function variant in the RNH1 gene, presenting with congenital cataracts, global developmental delay, myopathy, and episodes of infection-induced psychomotor deterioration, seizures, and anemia. Functional studies on patient fibroblasts showed increased sensitivity to RNase A, suggesting a mechanism for the multi-organ disease.
This study reports two affected siblings from a family of seven, presenting with a novel multi-organ disorder. Clinical features included congenital cataracts, global developmental delay, myopathy, and episodic psychomotor deterioration, seizures, and macrocytic anemia triggered by infections. Genetic analysis identified a homozygous splice-site variant in RNH1 (c.615-2A>C) that caused skipping of exon 7 and total loss of RNH1 protein. Functional analysis of patient-derived fibroblasts demonstrated increased cytotoxicity when exposed to extracellular RNase A, a defect rescued by RNH1 expression. The findings establish a link between human RNH1 deficiency and a developmental disease with infection-induced exacerbations, potentially due to susceptibility to extracellular RNases or inflammasome dysregulation.
