AOPEP variants as a novel cause of recessive dystonia: Generalized dystonia and dystonia-parkinsonism. (April 2022) - Garavaglia, Barbara
Abstract: Introduction: The genetic basis of autosomal-recessive dystonia remains poorly understood. Our objective was to report identification of additional individuals with variants in AOPEP, a recently described gene for recessively inherited dystonic disorders (OMIM:619565 ). Methods: Ongoing analysis on a high-throughput genetic platform and international case-recruitment efforts were undertaken. Results: Novel biallelic, likely pathogenic loss-of-function alleles were identified in two pedigrees of different ethnic background. Two members of a consanguineous Iranian family shared a homozygous c.1917-1G>A essential splice-site variant and featured presentations of adolescence-onset generalized dystonia. An individual of Chinese descent, homozygous for the nonsense variant c.1909G>T (p.Glu637*), displayed childhood-onset generalized dystonia combined with later-manifesting parkinsonism. One additional Iranian patient with adolescence-onset generalized dystonia carried an ultrarare, likely protein-damaging homozygous missense variant (c.1201C>T [p.Arg401Trp]). Conclusions: These findings support the implication of AOPEP in recessive forms of generalized dystonia and dystonia-parkinsonism. Biallelic AOPEP variants represent a worldwide cause of dystonic movement-disorder phenotypes and should be considered in dystonia molecular testing approaches. Highlights: Recessively inherited dystonia syndromes are underreported. We confirm AOPEP biallelic variants as a new cause of recessive dystonia. The AOPEP -related condition includes generalized dystonia and dystonia-parkinsonism. In addition to loss-of-function mutations, rare AOPEP missense variants may also be disease-causing.