De Novo Variants in the ATPase Module of MORC2 Cause a Neurodevelopmental Disorder with Growth Retardation and Variable Craniofacial Dysmorphism.

American Journal of Human Genetics
Maria J Guillen SacotoJane Juusola

Abstract

MORC2 encodes an ATPase that plays a role in chromatin remodeling, DNA repair, and transcriptional regulation. Heterozygous variants in MORC2 have been reported in individuals with autosomal-dominant Charcot-Marie-Tooth disease type 2Z and spinal muscular atrophy, and the onset of symptoms ranges from infancy to the second decade of life. Here, we present a cohort of 20 individuals referred for exome sequencing who harbor pathogenic variants in the ATPase module of MORC2. Individuals presented with a similar phenotype consisting of developmental delay, intellectual disability, growth retardation, microcephaly, and variable craniofacial dysmorphism. Weakness, hyporeflexia, and electrophysiologic abnormalities suggestive of neuropathy were frequently observed but were not the predominant feature. Five of 18 individuals for whom brain imaging was available had lesions reminiscent of those observed in Leigh syndrome, and five of six individuals who had dilated eye exams had retinal pigmentary abnormalities. Functional assays revealed that these MORC2 variants result in hyperactivation of epigenetic silencing by the HUSH complex, supporting their pathogenicity. The described set of morphological, growth, developmental, and neurologi...Continue Reading

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Citations

Apr 14, 2021·Genome Medicine·Zheng Yie YapWan Hee Yoon
Apr 13, 2021·Journal of the Peripheral Nervous System : JPNS·Dragan VujovicSteven S Scherer
Apr 18, 2021·Human Molecular Genetics·Angela MartinelliSilvia Paracchini
May 23, 2021·American Journal of Human Genetics·Holger HengelLudger Schöls
May 12, 2021·Human Mutation·Sarah E SeeseElena V Semina
Jul 1, 2021·European Journal of Neurology : the Official Journal of the European Federation of Neurological Societies·Rafael SiveraTeresa Sevilla

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