Whole exome sequencing identifies a homozygous POLG2 missense variant in an adult patient presenting with optic atrophy, movement disorders, premature ovarian failure and mitochondrial DNA depletion

• Published in: European journal of medical genetics Vol. 63; no. 4; p. 103821
• Main Authors: Dosekova, Petra, Dubiel, Andrzej, Karlowicz, Anna, Zietkiewicz, Szymon, Rydzanicz, Malgorzata, Habalova, Viera, Pienkowski, Victor Murcia, Skirkova, Miriam, Han, Vladimir, Mosejova, Alexandra, Gdovinova, Zuzana, Kaliszewska, Magdalena, Tońska, Katarzyna, Szymanski, Michal R., Skorvanek, Matej, Ploski, Rafal
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Masson SAS 01.04.2020
• Subjects: Adult; Ataxia; Chorea; DNA, Mitochondrial - genetics; DNA-Directed DNA Polymerase - genetics; Female; Homozygous; Humans; Mitochondrial DNA depletion; Movement Disorders - genetics; Mutation, Missense; Optic atrophy; Optic Atrophy - genetics; POLG2; Polyneuropathies - genetics; Polyneuropathy; Polγ; Premature ovarian failure; Primary Ovarian Insufficiency - genetics; Polγ; Mitochondrial DNA depletion; Optic atrophy; POLG2; Chorea; Premature ovarian failure; Ataxia; Polyneuropathy; Homozygous
• ISSN: 1769-7212; 1878-0849
• DOI: 10.1016/j.ejmg.2019.103821

POLG2 associated disorders belong to the group of mitochondrial DNA (mtDNA) diseases and present with a heterogeneous clinical spectrum, various age of onset, and disease severity. We report a 39-year old female presenting with childhood-onset and progressive neuroophthalmic manifestation with optic atrophy, mixed polyneuropathy, spinal and cerebellar ataxia and generalized chorea associated with mtDNA depletion. Whole-exome sequencing identified an ultra-rare homozygous missense mutation located at Chr17: 062474101-C > A (p.Asp433Tyr) in nuclear POLG2 gene encoding PolγB, an accessory subunits of mitochondrial polymerase γ responsible for mtDNA replication. The healthy parents and 2 sisters of the patient were heterozygous for the variant. To our best knowledge, this is the first case of homozygous variant in the POLG2 gene resulting in mitochondrial depletion syndrome in an adult patient and its clinical manifestations extend the clinical spectrum of POLG2 associated diseases.