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

作者：Campbell Ian M; Yatsenko Svetlana A; Hixson Patricia; Reimschisel Tyler; Thomas Matthew; Wilson William; Dayal Usha; Wheless James W; Crunk Amy; Curry Cynthia; Parkinson Nicole; Fishman Leona; Riviello James J; Nowaczyk Malgorzata J M; Zeesman Susan; Rosenfeld Jill A; Bejjani Bassem A; Shaffer Lisa G; Cheung Sau Wai; Lupski James R; Stankiewicz Pawel; Scaglia Fernando^*

来源：Genetics in Medicine, 2012, 14(10): 868-876.

DOI：10.1038/gim.2012.65

• cis-genetics
• dystonia
• early infantile epileptic encephalopathy
• hereditary hemorrhagic telangiectasia
• intellectual disability

Purpose: A number of genes in the 9q34.11 region may be haplo-insufficient. However, studies analyzing genotype phenotype correlations of deletions encompassing multiple dosage-sensitive genes in the region are lacking. %26lt;br%26gt;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. %26lt;br%26gt;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. %26lt;br%26gt;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.

• 出版日期2012-10