English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Zendy Plus

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Zendy Tools

Zendy Open

Objective  Hypothalamic hamartoma ( HH ) is a congenital anomalous brain tumor. Although most  HH s are found without any other systemic features,  HH  is observed in syndromic disorders such as Pallister–Hall syndrome ( PHS ) and oral‐facial‐digital syndrome ( OFD ). Here, we explore the possible involvement of somatic mutations in  HH .    Methods  We analyzed paired blood and hamartoma samples from 18 individuals, including three with digital anomalies, by whole‐exome sequencing. Detected somatic mutations were validated by Sanger sequencing and deep sequencing of target amplicons. The effect of   GLI 3  mutations on its transcriptional properties was evaluated by luciferase assays using reporters containing eight copies of the  GLI ‐binding site and a mutated control sequence disrupting  GLI  binding.    Results  We found hamartoma‐specific somatic truncation mutations in   GLI 3  and   OFD 1 , known regulators of sonic hedgehog (Shh) signaling, in two and three individuals, respectively. Deep sequencing of amplicons covering the mutations showed mutant allele rates of 7–54%. Somatic mutations in   OFD 1  at Xp22 were found only in male individuals. Potential pathogenic somatic mutations in   UBR 5  and   ZNF 263  were also identified in each individual. Germline nonsense mutations in   GLI 3  and   OFD 1  were identified in each individual with  PHS  and  OFD  type I in our series, respectively. The truncated  GLI 3 showed stronger repressor activity than the wild‐type protein. We did not detect somatic mutations in the remaining 9 individuals.    Interpretation  Our data indicate that a spectrum of human disorders can be caused by lesion‐specific somatic mutations, and suggest that impaired Shh signaling is one of the pathomechanisms of  HH .

Somatic mutations in GLI 3 and OFD 1 involved in sonic hedgehog signaling cause hypothalamic hamartoma