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


CONCLUSIONS
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.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
Ian M
IM
Campbell
Svetlana A
SA
Yatsenko
Patricia
P
Hixson
Tyler
T
Reimschisel
Matthew
M
Thomas
William
W
Wilson
Usha
U
Dayal
James W
JW
Wheless
Amy
A
Crunk
Cynthia
C
Curry
Nicole
N
Parkinson
Leona
L
Fishman
James J
JJ
Riviello
Malgorzata J M
MJ
Nowaczyk
Susan
S
Zeesman
Jill A
JA
Rosenfeld
Bassem A
BA
Bejjani
Lisa G
LG
Shaffer
Sau Wai
SW
Cheung
James R
JR
Lupski
Pawel
P
Stankiewicz
Fernando
F
Scaglia
D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D015703:Antigens, CD / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D000071063:Endoglin; D005260:Female; D017353:Gene Deletion; D057895:Haploinsufficiency; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008607:Intellectual Disability / Q000235:genetics / Q000473:pathology; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics*; D018832:Molecular Chaperones / Q000235:genetics*; D051938:Munc18 Proteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011956:Receptors, Cell Surface / Q000235:genetics*; D013036:Spasms, Infantile / Q000235:genetics* / Q000473:pathology; D013049:Spectrin
D015703:Antigens, CD; D002352:Carrier Proteins; D000071063:Endoglin; D008840:Microfilament Proteins; D018832:Molecular Chaperones; D051938:Munc18 Proteins; D011956:Receptors, Cell Surface; D013049:Spectrin; C064206:ENG protein, human; C497937:STXBP1 protein, human; C108175:TOR1A protein, human