@article{6ccfee233fc746289f9c998de10247d7,
title = "De Novo Variants in the ATPase Module of MORC2 Cause a Neurodevelopmental Disorder with Growth Retardation and Variable Craniofacial Dysmorphism",
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 neurological findings and medical concerns expands the spectrum of genetic disorders resulting from pathogenic variants in MORC2.",
keywords = "CMT2Z, Leigh-like disease, MORC2, developmental delay, intellectual disability, microcephaly",
author = "{Undiagnosed Diseases Network} and {Guillen Sacoto}, {Maria J.} and Tchasovnikarova, {Iva A.} and Erin Torti and Cara Forster and Andrew, {E. Hallie} and Irina Anselm and Baranano, {Kristin W.} and Briere, {Lauren C.} and Cohen, {Julie S.} and Craigen, {William J.} and Cheryl Cytrynbaum and Nina Ekhilevitch and Elrick, {Matthew J.} and Ali Fatemi and Fraser, {Jamie L.} and Gallagher, {Renata C.} and Andrea Guerin and Devon Haynes and High, {Frances A.} and Inglese, {Cara N.} and Courtney Kiss and Koenig, {Mary Kay} and Joel Krier and Kristin Lindstrom and Michael Marble and Hannah Meddaugh and Moran, {Ellen S.} and Morel, {Chantal F.} and Weiyi Mu and Muller, {Eric A.} and Jessica Nance and Natowicz, {Marvin R.} and Numis, {Adam L.} and Bridget Ostrem and John Pappas and Stafstrom, {Carl E.} and Haley Streff and Sweetser, {David A.} and Marta Szybowska and Walker, {Melissa A.} and Wei Wang and Karin Weiss and Rosanna Weksberg and Wheeler, {Patricia G.} and Grace Yoon and Kingston, {Robert E.} and Jane Juusola",
note = "Funding Information: I.A.T. is a postdoctoral fellow of the Damon Runyon Cancer Research Foundation. Research reported in this manuscript was supported by the NIH Common Fund through the Office of Strategic Coordination, Office of the NIH Director under award number U01HG007690 . The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funding Information: I.A.T. is a postdoctoral fellow of the Damon Runyon Cancer Research Foundation. Research reported in this manuscript was supported by the NIH Common Fund through the Office of Strategic Coordination, Office of the NIH Director under award number U01HG007690. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: {\textcopyright} 2020 American Society of Human Genetics",
year = "2020",
month = aug,
day = "6",
doi = "10.1016/j.ajhg.2020.06.013",
language = "English (US)",
volume = "107",
pages = "352--363",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "2",
}