Novel 9q34.11 gene deletions encompassing combinations of four Mendelian disease genes: STXBP1, SPTAN1, ENG, and TOR1A

Genet Med. 2012 Oct;14(10):868-76. doi: 10.1038/gim.2012.65. Epub 2012 Jun 21.


Purpose: A number of genes in the 9q34.11 region may be haploinsufficient. However, studies analyzing genotype-phenotype correlations of deletions encompassing multiple dosage-sensitive genes in the region are lacking.

Methods: We mapped breakpoints of 10 patients with 9q34.11 deletions using high-resolution 9q34-specific array comparative genomic hybridization (CGH) to determine deletion size and gene content.

Results: The 9q34.11 deletions range in size from 67 kb to 2.8 Mb. Six patients exhibit intellectual disability and share a common deleted region including STXBP1; four manifest variable epilepsy. In five subjects, deletions include SPTAN1, previously associated with early infantile epileptic encephalopathy, infantile spasms, intellectual disability, and hypomyelination. In four patients, the deletion includes endoglin (ENG), causative of hereditary hemorrhagic telangiectasia. Finally, in four patients, deletions involve TOR1A, of which molecular defects lead to early-onset primary dystonia. Ninety-four other RefSeq genes also map to the genomic intervals investigated.

Conclusion: STXBP1 haploinsufficiency results in progressive encephalopathy characterized by intellectual disability and may be accompanied by epilepsy, movement disorders, and autism. We propose that 9q34.11 genomic deletions involving ENG, TOR1A, STXBP1, and SPTAN1 are responsible for multisystemic vascular dysplasia, early-onset primary dystonia, epilepsy, and intellectual disability, therefore revealing cis-genetic effects leading to complex phenotypes.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Abnormalities, Multiple / genetics*
  • Abnormalities, Multiple / pathology
  • Antigens, CD / genetics*
  • Carrier Proteins / genetics*
  • Child
  • Chromosomes, Human, Pair 9 / genetics*
  • Comparative Genomic Hybridization
  • Endoglin
  • Female
  • Gene Deletion*
  • Haploinsufficiency
  • Humans
  • In Situ Hybridization, Fluorescence
  • Intellectual Disability / genetics
  • Intellectual Disability / pathology
  • Male
  • Microfilament Proteins / genetics*
  • Molecular Chaperones / genetics*
  • Munc18 Proteins / genetics*
  • Polymerase Chain Reaction
  • Receptors, Cell Surface / genetics*
  • Spasms, Infantile / genetics*
  • Spasms, Infantile / pathology


  • Antigens, CD
  • Carrier Proteins
  • ENG protein, human
  • Endoglin
  • Microfilament Proteins
  • Molecular Chaperones
  • Munc18 Proteins
  • Receptors, Cell Surface
  • STXBP1 protein, human
  • TOR1A protein, human
  • fodrin

Supplementary concepts

  • Infantile Epileptic-Dyskinetic Encephalopathy