Abstract
Pathogenic variants of the aconitase 2 gene (ACO2) are responsible for a broad clinical spectrum involving optic nerve degeneration, ranging from isolated optic neuropathy with recessive or dominant inheritance, to complex neurodegenerative syndromes with recessive transmission. We created the first public locus-specific database (LSDB) dedicated to ACO2 within the “Global Variome shared LOVD” using exclusively the Human Phenotype Ontology (HPO), a standard vocabulary for describing phenotypic abnormalities. All the variants and clinical cases listed in the literature were incorporated into the database, from which we produced a dataset. We followed a rational and comprehensive approach based on the HPO thesaurus, demonstrating that ACO2 patients should not be classified separately between isolated and syndromic cases. Our data highlight that certain syndromic patients do not have optic neuropathy and provide support for the classification of the recurrent pathogenic variants c.220C>G and c.336C>G as likely pathogenic. Overall, our data records demonstrate that the clinical spectrum of ACO2 should be considered as a continuum of symptoms and refines the classification of some common variants.
Highlights
Background & SummaryAconitate hydratase (ACO2; EC# 4.2.1.3) is a ubiquitous human mitochondrial monomeric enzyme composed of 780 amino acids
Biallelic pathogenic variants of this gene have been associated with infantile cerebellar-retinal degeneration (ICRD; MIM# 614599), a severe neurodegenerative disorder with optic neuropathy beginning in childhood and including retinal dystrophy, cerebellar ataxia, seizure, strabismus, axial hypotonia and athetosis[3]
A recent review of the literature has listed a total of 26 individuals reported from 15 families with the syndromic form since 2012, while only seven individuals from four families have been reported with the recessive form of isolated optic neuropathy[6]
Summary
Aconitate hydratase (ACO2; EC# 4.2.1.3) is a ubiquitous human mitochondrial monomeric enzyme composed of 780 amino acids It catalyses the second reaction of the citric acid cycle by isomerising citrate to isocitrate[1]. Isolated optic neuropathies have been associated with ACO2 pathogenic variants, either with recessive (locus OPA9; MIM# 616289)[4] or dominant inheritance, as recently reported[5]. Www.nature.com/scientificdata we recently developed such a database to list the genetic variants and clinical presentations of OPA1-related disorders, the major cause of dominant optic neuropathies with either isolated (80%; MIM# 165500) or syndromic (20%; MIM# 125250) presentations, and with some rare biallelic cases affected by early severe syndromes (MIM# 605390)[10]. We describe the construction of this ACO2 dataset, listing all the patients referenced in the literature, and drawing statistical information on gene variants and clinical diversity
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