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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.

SUBMITTER: Guillen Sacoto MJ 

PROVIDER: S-EPMC7413887 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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

Guillen Sacoto Maria J MJ   Tchasovnikarova Iva A IA   Torti Erin E   Forster Cara C   Andrew E Hallie EH   Anselm Irina I   Baranano Kristin W KW   Briere Lauren C LC   Cohen Julie S JS   Craigen William J WJ   Cytrynbaum Cheryl C   Ekhilevitch Nina N   Elrick Matthew J MJ   Fatemi Ali A   Fraser Jamie L JL   Gallagher Renata C RC   Guerin Andrea A   Haynes Devon D   High Frances A FA   Inglese Cara N CN   Kiss Courtney C   Koenig Mary Kay MK   Krier Joel J   Lindstrom Kristin K   Marble Michael M   Meddaugh Hannah H   Moran Ellen S ES   Morel Chantal F CF   Mu Weiyi W   Muller Eric A EA   Nance Jessica J   Natowicz Marvin R MR   Numis Adam L AL   Ostrem Bridget B   Pappas John J   Stafstrom Carl E CE   Streff Haley H   Sweetser David A DA   Szybowska Marta M   Walker Melissa A MA   Wang Wei W   Weiss Karin K   Weksberg Rosanna R   Wheeler Patricia G PG   Yoon Grace G   Kingston Robert E RE   Juusola Jane J  

American journal of human genetics 20200720 2


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 w  ...[more]

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