2. Academic Validation
  3. Rare deleterious de novo missense variants in Rnf2/Ring2 are associated with a neurodevelopmental disorder with unique clinical features

Rare deleterious de novo missense variants in Rnf2/Ring2 are associated with a neurodevelopmental disorder with unique clinical features

  • Hum Mol Genet. 2021 Jun 26;30(14):1283-1292. doi: 10.1093/hmg/ddab110.
Xi Luo 1 2,  Kelly Schoch 3,  Sharayu V Jangam 1 2,  Venkata Hemanjani Bhavana 1 2,  Hillary K Graves 1 2,  Sujay Kansagra 4,  Joan M Jasien 4,  Nicholas Stong 5,  Boris Keren 6 7,  Cyril Mignot 7 8,  Claudia Ravelli 7 9,  Undiagnosed Diseases Network,  Hugo J Bellen 1 2 10 11,  Michael F Wangler 1 2,  Vandana Shashi 3,  Shinya Yamamoto 1 2 10
Affiliations

Affiliations

  • 1 Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Houston, TX 77030, USA.
  • 2 Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
  • 3 Division of Medical Genetics, Department of Pediatrics, Duke Health, Durham, NC 27710, USA.
  • 4 Division of Pediatric Neurology, Department of Pediatrics, Duke Health, Durham, NC 27710, USA.
  • 5 Institute for Genomic Medicine, Columbia University, New York, NY 10032, USA.
  • 6 Département de Génétique, Hospitalier Pitié-Salpêtrière, APHP, Paris 75013, France.
  • 7 Sorbonne Université, Paris 75006, France.
  • 8 APHP, Sorbonne Université, Département de Génétique et Centre de Référence Déficiences Intellectuelles de Causes Rares, Groupe Hospitalier Pitié-Salpêtrière et Hôpital Trousseau, Paris 75013, France.
  • 9 Département de Neuropédiatrie, Hôpital Armand Trousseau, APHP, Paris 75012, France.
  • 10 Department of Neuroscience, BCM, Houston, TX 77030, USA.
  • 11 Howard Hughes Medical Institute, Houston, TX 77030, USA.
PMID: 33864376 DOI: 10.1093/hmg/ddab110
Abstract

The Polycomb group (PcG) gene RNF2 (RING2) encodes a catalytic subunit of the Polycomb repressive complex 1 (PRC1), an evolutionarily conserved machinery that post-translationally modifies chromatin to maintain epigenetic transcriptional repressive states of target genes including Hox genes. Here, we describe two individuals, each with rare de novo missense variants in RNF2. Their phenotypes include intrauterine growth retardation, severe intellectual disabilities, behavioral problems, seizures, feeding difficulties and dysmorphic features. Population genomics data suggest that RNF2 is highly constrained for loss-of-function (LoF) and missense variants, and both p.R70H and p.S82R variants have not been reported to date. Structural analyses of the two alleles indicate that these changes likely impact the interaction between RNF2 and BMI1, another PRC1 subunit or its substrate Histone H2A, respectively. Finally, we provide functional data in Drosophila that these two missense variants behave as LoF alleles in vivo. The evidence provide support for deleterious alleles in RNF2 being associated with a new and recognizable genetic disorder. This tentative gene-disease association in addition to the 12 previously identified disorders caused by PcG genes attests to the importance of these chromatin regulators in Mendelian disorders.

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