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

Abstract

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.

Figure 1. Custom-designed high-resolution array comparative genomic hybridization (CGH) analysis of the 9q34.11 region, including genes of interest (in scale)

Array CGH probes with absolute value log₂ patient:control ratios greater than 0.5 within the deleted region are colored for ease of visualization. The locations of the STXBP1, ENG, SPTAN1, and TOR1A genes are indicated along the top of the graph in black. Ninety-four additional RefSeq genes are depicted as horizontal gray rectangles. All data are presented according to the GRChr37/hg19 assembly.

Figure 2. Single gene deletions of STXBP1 coding sequence

Top, array comparative genomic hybridization analysis of the STXBP1, coding region in two patients from this study with partial deletions of STXBP1,. Middle, schematic representation of the two RefSeq isoforms of STXBP1,. Below, schematic representation of the deletions involving segments of the STXBP1, gene in four previously reported patients. Dashed lines represent the extent of the genomic deletion in the previous patients. Black horizontal bars represent nondeleted regions; gradient bars identify either uninformative or inconclusive areas.