Exome sequencing reveals a novel splice site variant in HUWE1 gene in patients with suspected Say-Meyer syndrome

Eur J Med Genet. 2020 Jan;63(1):103635. doi: 10.1016/j.ejmg.2019.02.007. Epub 2019 Feb 21.


Say-Meyer syndrome is a rare and clinically heterogeneous syndrome characterized by trigonocephaly, short stature, developmental delay and hypotelorism. Nine patients with this syndrome have been reported thus far although no causative gene has yet been identified. Here, we report two siblings with clinical phenotypes of Say-Meyer syndrome with moderate to severe intellectual disability and autism spectrum disorder. Cytogenetics and array-based comparative genomic hybridization did not reveal any chromosome abnormalities or copy number alterations. Exome sequencing of the patients revealed a novel X-linked recessive splice acceptor site variant c.145-2A > G in intron 5 of HUWE1 gene in both affected siblings. RT-PCR and sequencing revealed the use of an alternate cryptic splice acceptor site downstream, which led to deletion of six nucleotides resulting loss of two amino acids p.(Cys49-Glu50del) in HUWE1 protein. Deletion of these two amino acids, which are located in a highly conserved region, is predicted to be deleterious and quite likely to affect the function of HUWE1 protein. This is the first report of a potential candidate gene mutation for Say-Meyer syndrome, which was initially described four decades ago.

Keywords: Calvarial sutures; Cranial sutures; Craniosynostosis; Developmental delay; Metopic suture.

MeSH terms

  • Abnormalities, Multiple / genetics*
  • Abnormalities, Multiple / pathology
  • Adolescent
  • Autism Spectrum Disorder / genetics*
  • Autism Spectrum Disorder / pathology
  • Child
  • Child, Preschool
  • Comparative Genomic Hybridization
  • Cranial Sutures / diagnostic imaging
  • Cranial Sutures / pathology
  • Craniofacial Abnormalities / genetics*
  • Craniofacial Abnormalities / pathology
  • Exome / genetics
  • Female
  • Growth Disorders / genetics*
  • Growth Disorders / pathology
  • Humans
  • Intellectual Disability / genetics*
  • Intellectual Disability / pathology
  • Male
  • Protein Isoforms / genetics
  • RNA Splice Sites / genetics
  • Tumor Suppressor Proteins / genetics*
  • Ubiquitin-Protein Ligases / genetics*
  • Whole Exome Sequencing


  • Protein Isoforms
  • RNA Splice Sites
  • Tumor Suppressor Proteins
  • HUWE1 protein, human
  • Ubiquitin-Protein Ligases

Supplementary concepts

  • Say Meyer syndrome