Compound heterozygous inheritance of two novel COQ2 variants results in familial coenzyme Q deficiency
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RESEARCH
Compound heterozygous inheritance of two novel COQ2 variants results in familial coenzyme Q deficiency Aliaa H. Abdelhakim1†, Avinash V. Dharmadhikari2†, Sara D. Ragi1, Jose Ronaldo Lima de Carvalho Jr.1,3, Christine L. Xu1, Amanda L. Thomas2, Christie M. Buchovecky2, Mahesh M. Mansukhani2, Ali B. Naini2, Jun Liao2, Vaidehi Jobanputra2, Irene H. Maumenee1 and Stephen H. Tsang1*
Abstract Background: Primary coenzyme Q10 deficiency is a rare disease that results in diverse and variable clinical manifestations. Nephropathy, myopathy and neurologic involvement are commonly associated, however retinopathy has also been observed with certain pathogenic variants of genes in the coenzyme Q biosynthesis pathway. In this report, we describe a novel presentation of the disease that includes nephropathy and retinopathy without neurological involvement, and which is the result of a compound heterozygous state arising from the inheritance of two recessive potentially pathogenic variants, previously not described. Materials and methods: Retrospective report, with complete ophthalmic examination, multimodal imaging, electroretinography, and whole exome sequencing performed on a family with three affected siblings. Results: We show that affected individuals in the described family inherited two heterozygous variants of the COQ2 gene, resulting in a frameshift variant in one allele, and a predicted deleterious missense variant in the second allele (c.288dupC,p.(Ala97Argfs*56) and c.376C > G,p.(Arg126Gly) respectively). Electroretinography results were consistent with rod-cone dystrophy in the affected individuals. All affected individuals in the family exhibited the characteristic retinopathy as well as end-stage nephropathy, without evidence of any neurological involvement. Conclusions: We identified two novel compound heterozygous variants of the COQ2 gene that result in primary coenzyme Q deficiency. Targeted sequencing of coenzyme Q biosynthetic pathway genes may be useful in diagnosing oculorenal clinical presentations syndromes not explained by more well known syndromes (e.g., Senior-Loken and Bardet-Biedl syndromes). Keywords: Coenzyme Q10, COQ2 gene, Oculorenal syndrome, Hereditary retinopathy
*Correspondence: [email protected] † Aliaa H. Abdelhakim and Avinash V. Dharmadhikari have contributed equally to this work 1 Edward S. Harkness Eye Institute, Columbia University Irving Medical Center, New York, NY, USA Full list of author information is available at the end of the article
Introduction Coenzyme Q10 (CoQ10), a key component of the oxidative phosphorylation pathway, is an essential factor in mitochondrial metabolism, and plays important roles in other cellular processes such as nucleotide synthesis, sulfide metabolism and cellular apoptosis. Endogenous defects in the biosynthesis pathway of coenzyme Q result in mitochondrial respiratory chain deficiency and associated manifestations. Involvement of the disease is systemic, and often includes neurologic manifestations
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