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Am J Med Genet A. 2018 Nov;176(11):2501-2508. doi: 10.1002/ajmg.a.40512. Epub 2018 Sep 23.

Small 4p16.3 deletions: Three additional patients and review of the literature.

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Cytogenetics Unit, IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy.
Medical Genetics Unit and Laboratory of Medical Genetics, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
Medical Genetics Unit, A.O.R.N. "G. Rummo", Benevento, Italy.
Medical Genetics, University of Catania, Catania, Italy.
Laboratory of Medical Genetics, Policlinico Tor Vergata, Rome, Italy.
Medical Genetics and Laboratory of Medical Genetics Unit, A.O. "Antonio Cardarelli", Naples, Italy.


Wolf-Hirschhorn syndrome is a well-defined disorder due to 4p16.3 deletion, characterized by distinct facial features, intellectual disability, prenatal and postnatal growth retardation, and seizures. Genotype-phenotype correlations based on differently sized deletions have been attempted, and some candidate genes have been suggested. We report on clinical characteristics of three patients with pure interstitial submicroscopic 4p16.3 deletions, ranging in size from 68 to 166 kb, involving WHSCR1 and/or part of WHSCR2, and review published cases with overlapping 4p16.3 losses. The present study highlights a major role of NSD2 gene in the pathogenesis of the WHS main features and predicts that loss-of-function mutations affecting NSD2 gene could result in microcephaly, prenatal and postnatal growth retardation, psychomotor and language delay, and craniofacial features. Absent seizures in all subjects corroborate the suggestion that this specific feature is causally linked with at least one additional causative gene. Finally, we suggest that mir-943 could play a role in the pathogenesis of CHD in some of these patients.


CHD; NSD2 gene; Wolf-Hirschhorn syndrome; mir-943

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