A splice variant in ATAD3A expands the clinical and genetic spectrum of Harel-Yoon syndrome

ATAD3A is a mitochondrial AAA + ATPase protein localized between the inner and outer mitochondrial membrane(1); its role includes the stabilization of mitochondrial DNA, the regulation of mitochondrial fission/fusion, and the regulation of cholesterol homeostasis.(1,2) Harel-Yoon syndrome (HYS) can result from biallelic deletions in the ATAD3 gene cluster (containing ATAD3A, ATAD3B, and ATAD3C) and is associated with cerebellar and brainstem atrophy, hypotonia, encephalopathy, and death in the first days and weeks of life.(3,4) A less severe presentation has been reported in those with biallelic missense variants.(4,5) This attenuated form of HYS presents with developmental delay, cataracts, seizures, and optic and cerebellar atrophy with individuals living into adulthood.(4,5) The findings are consistent with a genotype-phenotype correlation based on the variant type.(6,7)