Long-Read Genome Sequencing Establishes Biallelic Pathogenic Variants in DNM1 With Distinct Functional Effects as the...

Heterozygous de novo and inherited biallelic pathogenic variants in DNM1 have been reported in association with autosomal dominant (AD) and autosomal recessive (AR) developmental and epileptic encephalopathy, respectively, due to aberrant dynamin function or expression, with each inheritance pattern associated with a different mechanism of disease. We report an instance of DNM1-related early infantile developmental and epileptic encephalopathy due to compound heterozygous pathogenic variants with different functional effects: the de novo dominant negative-associated c.194C>A (p.Thr65Asn), and the maternally inherited loss of function-associated c.850C>T (p.Gln284*). We describe this patient's severe clinical presentation and disease progression as compared to those previously reported with either AD or AR DNM1-related disease. We hypothesize about the interactions and outcomes of the two variants at the molecular level following review of in vitro and in vivo functional data and demonstrate the utility of long-read genome sequencing for phasing the variants and confirming this individual's molecular diagnosis.