Deletions involving genes WHSC1 and LETM1 may be necessary, but are not sufficient to cause Wolf–Hirschhorn Syndrome

Abstract

Wolf-Hirschhorn syndrome (WHS) is a complex genetic disorder caused by the loss of genomic material from the short arm of chromosome 4. Genotype-phenotype correlation studies indicated that the loss of genes within 4p16.3 is necessary for expression of the core features of the phenotype. Within this region, haploinsufficiency of the genes WHSC1 and LETM1 is thought to be a major contributor to the pathogenesis of WHS. We present clinical findings for three patients with relatively small (o400 kb) de novo interstitial deletions that overlap WHSC1 and LETM1. 3D facial analysis was performed for two of these patients. Based on our findings, we propose that hemizygosity of WHSC1 and LETM1 is associated with a clinical phenotype characterized by growth deficiency, feeding difficulties, and motor and speech delays. The deletion of additional genes nearby WHSC1 and LETM1 does not result in a marked increase in the severity of clinical features, arguing against their haploinsufficiency. The absence of seizures and typical WHS craniofacial findings in our cohort suggest that deletion of distinct or additional 4p16.3 genes is necessary for expression of these features. Altogether, these results show that although loss-offunction for WHSC1 and/or LETM1 contributes to some of the features of WHS, deletion of additional genes is required for the full expression of the phenotype, providing further support that WHS is a contiguous gene deletion disorder.

Epigenetics of hematopoiesis and hematological malignancies

“…NSD1 and NSD2 have each been linked to human developmental overgrowth syndromes. The NSD2 gene is among a group of genes deleted in Wolf-Hirschhorn syndrome, and loss of NSD2 is thought to be responsible for a subset of the clinical features characteristic of this syndrome (Andersen et al 2014). Deletion or loss-of-function mutations involving NSD1 results in Sotos syndrome, an autosomal dominant overgrowth syndrome characterized by a distinctive facial appearance, delayed development, and learning disabilities (Douglas et al 2003;Turkmen et al 2003).…”

Досвід Діагностики Та Спостереження Дитини Із Синдромом Вольфа — Хіршхорна

“…Сьогодні рекомендують таких фахівців, які по-винні спостерігати дитину: клінічний генетик, пе-діатр, невролог, кардіолог, офтальмолог, ортопед, логопед, отоларинголог, уролог [1,4].…”

“…1,2 , Ìàöþðà Î.È. 1,2 , Áóëàê Ã.Â. 1 Îïûò äèàãíîñòèêè è íàáëþäåíèÿ ðåáåíêà ñ ñèíäðîìîì Âîëüôà -Õèðøõîðíà Резюме.…”

“…1,2 , Áóëàê Ã.Â. 1 Îïûò äèàãíîñòèêè è íàáëþäåíèÿ ðåáåíêà ñ ñèíäðîìîì Âîëüôà -Õèðøõîðíà Резюме. В статье представлены современные данные о причинах возникновения, особенностях течения, прин-ципах диагностики и симптоматического лечения детей с синдромом Вольфа -Хиршхорна.…”

Wolf-Hirschhorn Syndrome with Epibulbar Dermoid: An Unusual Association in a Patient with 4p Deletion and Functional Xp Disomy

“…Among the candidate genes already described for WHS, these authors considered LETM1 likely to be pathogenetically involved in seizures. Andersen et al [2014] suggested that hemizygosity of WHSC1 and LETM1 could be a major contributor to the pathogenesis of WHS. However, not all patients with deletions overlapping both WHSC1 and LETM1 express the full WHS phenotype, and deletions elsewhere in 4p16.3 have been identified in patients with features overlapping WHS.…”