Abstract
BackgroundWolf-Hirschhorn syndrome is a well-characterized genomic disorder caused by 4p16.3 deletions. Wolf-Hirschhorn syndrome patients exhibit characteristic facial dysmorphism, growth retardation, developmental delay, intellectual disability and seizure disorders. Recently, NSD2 gene located within the 165 kb Wolf-Hirschhorn syndrome critical region was identified as the key causal gene responsible for most if not all phenotypes of Wolf-Hirschhorn syndrome. So far, eight NSD2 loss of function variants have been reported in patients from different parts of the world, all were de novo variants.MethodsIn our study, we performed whole exome sequencing for two patients from one family. We also reviewed more NSD2 mutation cases in pervious literature.ResultsA novel loss of function NSD2 variant, c.1577dupG (p.Asn527Lysfs*14), was identified in a Chinese family in the proband and her father both affected with intellectual disability. After reviewing more NSD2 mutation cases in pervious literature, we found none of them had facial features that can be recognized as Wolf-Hirschhorn syndrome. In addition, we have given our proband growth hormone and followed up with this family for 7.5 years.ConclusionsHere we reported the first familial NSD2 variant and the long-term effect of growth hormone therapy for patients. Our results suggested NSD2 mutation might cause a distinct intellectual disability and short stature syndrome.
Highlights
Wolf-Hirschhorn syndrome is a well-characterized genomic disorder caused by 4p16.3 deletions
Patients with deletions involving the 165 kb Wolf-Hirschhorn syndrome (WHS) critical region usually exhibit these typical features of WHS [4], but individuals with LOF mutations of Nuclear receptor-binding set domain protein 2 gene (NSD2) often do not present with the full WHS facial features [1, 3, 9]
Both patients presented with main features reported in previous NSD2 patients who presented with overlapping features of WHS
Summary
Wolf-Hirschhorn syndrome is a well-characterized genomic disorder caused by 4p16.3 deletions. WolfHirschhorn syndrome patients exhibit characteristic facial dysmorphism, growth retardation, developmental delay, intellectual disability and seizure disorders. Despite its great phenotypic variability, the minimal diagnostic criteria for WHS are defined by typical facial features, prenatal/ postnatal growth retardation, developmental delay/intellectual disability (ID) and seizures [1, 2]. A 165 kb Wolf-Hirschhorn syndrome critical region (WHSCR) at 4p16.3, which was commonly deleted by all WHS patients, was first described in 1997 by Wright et al [4]. Within this critical region, the NSD2 gene, known as WHSC1 (Wolf–Hirschhorn Syndrome Candidate 1 gene), had been recognized as one of the key candidate genes for the contiguous gene deletion syndrome. We evaluated the effectiveness of a longterm growth hormone therapy for the proband based on a 7.5-year follow-up study
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