Missense mutations in kinesin family member 5A (KIF5A) cause spastic paraplegia 10. We report two patients with de novo stop-loss frameshift variants in KIF5A resulting in a novel phenotype that includes severe infantile onset myoclonus, hypotonia, optic nerve abnormalities, dysphagia, apnea, and early developmental arrest. We propose that alteration and elongation of the carboxy-terminus of the protein has a dominant-negative effect causing mitochondrial dysfunction in the setting of an abnormal kinesin “motor”. These results highlight the role of expanded testing and whole exome sequencing in critically ill infants and emphasize the importance of accurate test interpretation.

Digital droplet PCR is a sensitive molecular tool that enables low-level variant detection of PIK3CA in various tissue types, providing an alternative diagnostic method. Furthermore, urine cfDNA is a candidate biomarker for nephroblastomatosis in PROS, which may be useful to refine screening guidelines for tumor risk in these patients.

No abstract