Deep sequencing detects paternal mosaicism of a novel pathogenic DNM1L variant underlying
encephalopathy due to defective mitochondrial peroxisomal fission in proband
2TOVANA Health, TOVANA Health, USA
3Precision Medicine Insights, Precision Medicine Insights, USA
4Genetics Institute, Soroka Medical Center, Israel
5Medical Center, University of Mississippi, Israel
Dynamin 1-like protein, encoded by DNM1L, is known as a critical regulator of mitochondrial fission or
division. Biallelic pathogenic variants in DNM1L cause encephalopathy due to defective mitochondrial and
peroxisomal fission-1 (EMPF1), with variability in phenotype and age of onset. EMPF1 is a severe,
sometimes lethal condition accompanied by delayed psychomotor development or neurodevelopmental
regression, dystonia or hypotonia, and refractory seizures consistent with epileptic encephalopathy. We
now report a proband affected by early onset neurodevelopmental delay and regression, one-sided
hypotonia, involuntary movements, optic atrophy, hereditary alpha tryptasemia (HaT) immunological
dysfunction, carrying two likely pathogenic compound heterozygous novel DNM1L variants: c.270C>G
(p.Asn90Lys) and c.1393G>A (p.Val465Ile). Segregation analysis using Sanger sequencing revealed
maternal carrier status of the c.1393G>A variant, but no parental source of the c.270C>G variant.
Suspicion of low-level mosaicism of the father was entertained. Deep sequencing of multiple tissue types
collected from the proband’s father demonstrated his mosaic carrier status (7% in saliva, 12% in dermal
fibroblast tissue, 5% in blood WBC). The findings emphasize the importance of follow-up studies using
deep sequencing in cases with a high index of suspicion for a genetic diagnosis despite inconsistent results
in segregation analysis, allowing the establishment of parental mosaicism.