{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T16:55:16Z","timestamp":1776012916618,"version":"3.50.1"},"posted":{"date-parts":[[2024,2,7]]},"group-title":"Genetic and Genomic Medicine","reference-count":23,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,2,7]]},"abstract":"<jats:title>Abstract\/Summary<\/jats:title>\n                <jats:p>\n                  Genes encoding long non-coding RNAs (lncRNAs) comprise a large fraction of the human genome, yet haploinsufficiency of a lncRNA has not been shown to cause a Mendelian disease.\n                  <jats:italic>CHASERR<\/jats:italic>\n                  is a highly conserved human lncRNA adjacent to\n                  <jats:italic>CHD2\u2013<\/jats:italic>\n                  a coding gene in which\n                  <jats:italic>de novo<\/jats:italic>\n                  loss-of-function variants cause developmental and epileptic encephalopathy. Here we report three unrelated individuals each harboring an ultra-rare heterozygous\n                  <jats:italic>de novo<\/jats:italic>\n                  deletion in the\n                  <jats:italic>CHASERR<\/jats:italic>\n                  locus. We report similarities in severe developmental delay, facial dysmorphisms, and cerebral dysmyelination in these individuals, distinguishing them from the phenotypic spectrum of\n                  <jats:italic>CHD2<\/jats:italic>\n                  haploinsufficiency. We demonstrate reduced\n                  <jats:italic>CHASERR<\/jats:italic>\n                  mRNA expression and corresponding increased\n                  <jats:italic>CHD2<\/jats:italic>\n                  mRNA and protein in whole blood and patient-derived cell lines\u2013specifically increased expression of the\n                  <jats:italic>CHD2<\/jats:italic>\n                  allele in\n                  <jats:italic>cis<\/jats:italic>\n                  with the\n                  <jats:italic>CHASERR<\/jats:italic>\n                  deletion, as predicted from a prior mouse model of\n                  <jats:italic>Chaserr<\/jats:italic>\n                  haploinsufficiency. We show for the first time that\n                  <jats:italic>de novo<\/jats:italic>\n                  structural variants facilitated by Alu-mediated non-allelic homologous recombination led to deletion of a non-coding element (the lncRNA\n                  <jats:italic>CHASERR<\/jats:italic>\n                  ) to cause a rare syndromic neurodevelopmental disorder. We also demonstrate that\n                  <jats:italic>CHD2<\/jats:italic>\n                  has bidirectional dosage sensitivity in human disease. This work highlights the need to carefully evaluate other lncRNAs, particularly those upstream of genes associated with Mendelian disorders.\n                <\/jats:p>","DOI":"10.1101\/2024.01.31.24301497","type":"posted-content","created":{"date-parts":[[2024,2,7]],"date-time":"2024-02-07T19:04:15Z","timestamp":1707332655000},"source":"Crossref","is-referenced-by-count":6,"title":["Novel syndromic neurodevelopmental disorder caused by de novo deletion of\n                  <i>CHASERR<\/i>\n                  , a long noncoding RNA"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8709-9351","authenticated-orcid":false,"given":"Vijay S.","family":"Ganesh","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1774-0286","authenticated-orcid":false,"given":"Kevin","family":"Riquin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0538-0981","authenticated-orcid":false,"given":"Nicolas","family":"Chatron","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9572-8384","authenticated-orcid":false,"given":"Kay-Marie","family":"Lamar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miriam C.","family":"Aziz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8813-2053","authenticated-orcid":false,"given":"Pauline","family":"Monin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melanie","family":"O\u2019Leary","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0480-1924","authenticated-orcid":false,"given":"Julia K.","family":"Goodrich","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6212-5736","authenticated-orcid":false,"given":"Kiran 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