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

Abstract

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 neuropathy; 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 similarities 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 diagnostic 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.

Keywords: Cockayne syndrome; DNA repair; MORC2; Microcephaly.

FIGURE 1

(A-C) Images of the face, hands, and feet from participant 3 showing enophthalmos, mouth with incompetent lips, prominent teeth, emerging retrognathia, livedo reticularis, and poor peripheral circulation. (D-F) Images of the face, hands, and feet from participant 4, sibling of participant 3, showing similar features. (G-I) Images of the face, hands, and feet from participant 5 showed marked enophthalmos, retrognathia, fixed distal contractures in the feet with overlapping toes, and pes cavus suggestive of a peripheral neuropathy. Families consented for photography of all individuals shown. The color version of this figure is available in the online edition.

FIGURE 2

(A) A schematic diagram of the MORC2 protein domain structure. The ATPase module is at the N terminus including the GHKL, CC1, and S5 domains. (B) An inset of the diagram from (A) demonstrating the locations of the pathogenic variants in the current cohort. All pathogenic variants localize to the ATPase module. The color version of this figure is available in the online edition.

FIGURE 3

(A) A graph indicating the frequencies of noted symptoms in our participants shows similar patterns to data from a classic prior study of CS. (B) A graph indicating the distribution of CS likelihood scores using a published scoring system. (C) A graph indicating the distribution of CS severity scores based on clinical criteria, using a published scoring system, with CS type III data from that publication shown for comparison. Note that a lower score indicates increased severity. The color version of this figure is available in the online edition.