The Spectrum of MORC2-Related Disorders: A Potential Link to Cockayne Syndrome

Background: Cockayne syndrome (CS) is a DNA repair disorder primarily associated with pathogenic variants in ERCC6 and ERCC8. As in other Mendelian disorders, there are a number of genetically unsolved CS cases.Methods: We ascertained five individuals with monoallelic pathogenic variants in MORC2, previously associated with three dominantly inherited phenotypes: an axonal form of Charcot-Marie-Tooth disease type 2Z; a syndrome of developmental delay, impaired growth, dysmorphic facies, and axonal neurop-athy; and a rare form of spinal muscular atrophy.Results: One of these individuals bore a strong phenotypic resemblance to CS. We then identified monoallelic pathogenic MORC2 variants in three of five genetically unsolved individuals with a clinical diagnosis of CS. In total, we identified eight individuals with MORC2-related disorder, four of whom had clinical features strongly suggestive of CS.Conclusions: Our findings indicate that some forms of MORC2-related disorder have phenotypic simi-larities to CS, including features of accelerated aging. Unlike classic DNA repair disorders, MORC2-related disorder does not appear to be associated with a defect in transcription-coupled nucleotide excision repair and follows a dominant pattern of inheritance with variants typically arising de novo. Such de novo pathogenic variants present particular challenges with regard to both initial gene discovery and diag-nostic evaluations. MORC2 should be included in diagnostic genetic test panels targeting the evaluation of microcephaly and/or suspected DNA repair disorders. Future studies of MORC2 and its protein product, coupled with further phenotypic characterization, will help to optimize the diagnosis, understanding, and therapy of the associated disorders.(c) 2023 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Automated summary

Research has found that pathogenic variants in the MORC2 gene are associated with phenotypic similarities to Cockayne syndrome (CS) and accelerated aging features. Unlike traditional DNA repair disorders, MORC2-related disorders are not associated with a defect in transcription-coupled nucleotide excision repair and follow a dominant pattern of inheritance, with variants typically arising de novo. The results suggest that MORC2 should be included in diagnostic genetic test panels for evaluating microcephaly and/or suspected DNA repair disorders.