Structures and molecular mechanisms for common 15q13.3 microduplications involving CHRNA7: benign or pathological?
We have investigated four approximately 1.6-Mb microduplications and 55 smaller 350-680-kb microduplications at 15q13.2-q13.3 involving the CHRNA7 gene that were detected by clinical microarray analysis. Applying high-resolution array-CGH, we mapped all 118 chromosomal breakpoints of these microduplications. We also sequenced 26 small microduplication breakpoints that were clustering at hotspots of nonallelic homologous recombination (NAHR). All four large microduplications likely arose by NAHR between BP4 and BP5 LCRs, and 54 small microduplications arose by NAHR between two CHRNA7-LCR copies. We identified two classes of approximately 1.6-Mb microduplications and five classes of small microduplications differing in duplication size, and show that they duplicate the entire CHRNA7. We propose that size differences among small microduplications result from preexisting heterogeneity of the common BP4-BP5 inversion. Clinical data and family histories of 11 patients with small microduplications involving CHRNA7 suggest that these microduplications might be associated with developmental delay/mental retardation, muscular hypotonia, and a variety of neuropsychiatric disorders. However, we conclude that these microduplications and their associated potential for increased dosage of the CHRNA7-encoded alpha 7 subunit of nicotinic acetylcholine receptors are of uncertain clinical significance at present. Nevertheless, if they prove to have a pathological effects, their high frequency could make them a common risk factor for many neurobehavioral disorders.
Szafranski
Przemyslaw
P
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
Schaaf
Christian P
CP
Person
Richard E
RE
Gibson
Ian B
IB
Xia
Zhilian
Z
Mahadevan
Sangeetha
S
Wiszniewska
Joanna
J
Bacino
Carlos A
CA
Lalani
Seema
S
Potocki
Lorraine
L
Kang
Sung-Hae
SH
Patel
Ankita
A
Cheung
Sau Wai
SW
Probst
Frank J
FJ
Graham
Brett H
BH
Shinawi
Marwan
M
Beaudet
Arthur L
AL
Stankiewicz
Pawel
P
D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D019457:Chromosome Breakage; D025063:Chromosome Disorders / Q000235:genetics / Q000473:pathology; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D002658:Developmental Disabilities / Q000473:pathology; D005192:Family Health; D005260:Female; D020440:Gene Duplication; D006801:Humans; D008607:Intellectual Disability / Q000473:pathology; D008297:Male; D001523:Mental Disorders / Q000473:pathology; D008969:Molecular Sequence Data; D009123:Muscle Hypotonia / Q000473:pathology; D010375:Pedigree; D011978:Receptors, Nicotinic / Q000235:genetics*; D017422:Sequence Analysis, DNA; D064569:alpha7 Nicotinic Acetylcholine Receptor
C579167:Chrna7 protein, human; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor