De novo CTBP1 variant is associated with decreased mitochondrial respiratory chain activities

Abstract

Objective: To determine the genetic etiology of a young woman presenting an early-onset, progressive neurodegenerative disorder with evidence of decreased mitochondrial complex I and IV activities in skeletal muscle suggestive of a mitochondrial disorder. Methods: A case report including diagnostic workup, whole-exome sequencing of the affected patient, filtering, and prioritization of candidate variants assuming a suspected autosomal recessive mitochondrial disorder and segregation studies. Results: After excluding candidate variants for an autosomal recessive mitochondrial disorder, reevaluation of rare and novel heterozygous variants identified a recently reported, recurrent pathogenic heterozygous CTBP1 missense change (c.991C>T, p.Arg331Trp), which was confirmed to have arisen de novo. Conclusions: We report the fifth known patient harboring a recurrent pathogenic de novo c.991C>T p.(Arg331Trp) CTBP1 variant, who was initially suspected to have an autosomal recessive mitochondrial disorder. Inheritance of suspected early-onset mitochondrial disease could wrongly be assumed to be autosomal recessive. Hence, this warrants continued reevaluation of rare and novel heterozygous variants in patients with apparently unsolved suspected mitochondrial disease investigated using next-generation sequencing.