{
  "abstract": "Heterozygous variants in RNU4-2, a small nuclear RNA (snRNA) component of the major spliceosome, have recently been shown to cause ReNU syndrome, a highly prevalent neurodevelopmental disorder (NDD). Recessive spliceosomopathies have only been described in the minor spliceosome snRNAs RNU12 and RNU4ATAC. Here, we describe a novel recessive NDD caused by biallelic variants in RNU4-2. Through international collaborations, we identify a cohort of 35 individuals and obtain detailed clinical information for 26 individuals. The disorder is characterised by global developmental delay (26/26, 100%), pronounced speech delay (absent speech in 15/26, 58%), hypotonia (20/24, 83%), and seizures (16/26, 62%). We observe a striking phenotype of progressive microcystic lesions in the periventricular white matter in 10/13 individuals (77%) with brain MRIs. Pathogenic variants cluster outside of the ReNU syndrome ‘critical regions’, within the Stem II region, k-turn region, and Sm protein binding site of RNU4-2. These variants are absent from UK Biobank in the homozygous (N=490,541) or compound heterozygous (N=200,011) states. In a saturation genome editing assay of RNU4-2, variants are significantly depleted for 5/7 (71%) homozygous genotypes and 9/13 (69%) compound heterozygous genotypes (at least one allele). In summary, this novel disorder expands the clinical and genetic spectrum of RNU4-2-related disease.",
  "authors": [
    {
      "affiliations": [
        "Manchester Centre for Genomic Medicine, Manchester, UK"
      ],
      "name": "Alexander Blakes"
    },
    {
      "affiliations": [
        "Centre for Population Genomics, Sydney, Australia",
        "Centre for Population Genomics, Melbourne, Australia"
      ],
      "name": "R Rius"
    },
    {
      "affiliations": [
        "Big Data Institute, University of Oxford, Oxford, UK"
      ],
      "name": "Y Chen"
    },
    {
      "affiliations": [
        "Manchester Centre for Genomic Medicine, Manchester, UK"
      ],
      "name": "RNU4-2 Recessive Consortium"
    },
    {
      "affiliations": [
        "Manchester Centre for Genomic Medicine, Manchester, UK"
      ],
      "name": "S Banka"
    },
    {
      "affiliations": [
        "The Genome Function Laboratory, The Francis Crick Institute, London, UK"
      ],
      "name": "G Findlay"
    },
    {
      "affiliations": [
        "Centre for Population Genomics, Sydney, Australia",
        "Centre for Population Genomics, Melbourne, Australia"
      ],
      "name": "D MacArthur"
    },
    {
      "affiliations": [
        "Centre for Population Genomics, Sydney, Australia",
        "Centre for Population Genomics, Melbourne, Australia"
      ],
      "name": "C Simons"
    },
    {
      "affiliations": [
        "Big Data Institute, University of Oxford, Oxford, UK",
        "Centre for Human Genetics, University of Oxford, Oxford, UK",
        "Broad Center for Mendelian Genomics, Cambridge, MA, USA"
      ],
      "name": "N Whiffin"
    }
  ],
  "title": "O1 Biallelic variants in the non-coding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes",
  "uid": "7d324212-dcef-5bbb-bc59-27c6fc239473"
}