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Deficiencies in NER typically result in a group of heterogeneous distinct disorders ranging from the mild UV sensitive syndrome to the cancer\u2010prone xeroderma pigmentosum and the neurodevelopmental\/progeroid conditions trichothiodystrophy, Cockayne syndrome and cerebro\u2010oculo\u2010facio\u2010skeletal\u2010syndrome. A complicated genetic scenario underlines these disorders with the same gene linked to different clinical entities as well as different genes associated with the same disease. Overlap syndromes with combined hallmark features of different NER disorders can occur and sporadic presentations showing extra features of the hematological disorder Fanconi Anemia or neurological manifestations mimicking Hungtinton disease\u2010like syndromes have been described. Here, we discuss the multiple functions of the five major pleiotropic NER genes (<jats:italic>ERCC3\/XPB, ERCC2\/XPD<\/jats:italic>, <jats:italic>ERCC5\/XPG<\/jats:italic>, <jats:italic>ERCC1<\/jats:italic> and <jats:italic>ERCC4\/XPF<\/jats:italic>) and their relevance in phenotypic complexity. We provide an update of mutational spectra and examine genotype\u2010phenotype relationships. Finally, the molecular defects that could explain the puzzling overlap syndromes are discussed.<\/jats:p>","DOI":"10.1111\/cge.13545","type":"journal-article","created":{"date-parts":[[2019,3,28]],"date-time":"2019-03-28T13:52:36Z","timestamp":1553781156000},"page":"12-24","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":53,"title":["Heterogeneity and overlaps in nucleotide excision repair disorders"],"prefix":"10.1111","volume":"97","author":[{"given":"Debora","family":"Ferri","sequence":"first","affiliation":[{"name":"Istituto di Genetica Molecolare (IGM) Consiglio Nazionale delle Ricerche  Pavia Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donata","family":"Orioli","sequence":"additional","affiliation":[{"name":"Istituto di Genetica Molecolare (IGM) Consiglio Nazionale delle Ricerche  Pavia 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