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Recurrent deletions and reciprocal duplications of 10q11.21q11.23 including CHAT and SLC18A3 are likely mediated by complex low-copy repeats

Authors :
Jill A. Rosenfeld
Marwan Shinawi
Scott Saunders
Livija Medne
Shashikant Kulkarni
Avinash V. Dharmadhikari
Carsten G. Bönnemann
Suneeta Madan-Khetarpal
Pawel Stankiewicz
Samarth Bhatt
Stephanie E. Vallee
Fernando Scaglia
Marshall L. Summar
Zhilian Xia
Carlos A. Bacino
Ann Martin
Brendan Lee
Alexander Asamoah
Jacques S. Beckmann
Wendy E. Smith
Sau Wai Cheung
Sumit Parikh
Rizwan Hamid
Tracy L. McGregor
Amber N. Pursley
Jean P. Pfotenhauer
Kathryn Platky
Lisa G. Shaffer
Chad A. Shaw
Ankita Patel
Polly Irwin
Paul S. Simons
Dorothy K. Grange
Sung-Hae L. Kang
Gary Bellus
Victoria P. Dalzell
John B. Moeschler
Jennifer Kussmann
Srirangan Sampath
Danielle Martinet
Alex R. Paciorkowski
Michael J. Noetzel
Carolyn Lovell
Susan Sparks
Blake C. Ballif
Kathryn Golden-Grant
Florence Fellmann
David B. Flannery
Jacqueline M. Hoover
Tamim H. Shaikh
M. Lance Cooper
Valerie Banks
Jerome L. Gorski
Source :
Human Mutation, vol. 33, no. 1, pp. 165-179
Publication Year :
2012

Abstract

We report 24 unrelated individuals with deletions and 17 additional cases with duplications at 10q11.21q21.1 identified by chromosomal microarray analysis. The rearrangements range in size from 0.3 to 12 Mb. Nineteen of the deletions and eight duplications are flanked by large, directly oriented segmental duplications of >98% sequence identity, suggesting that nonallelic homologous recombination (NAHR) caused these genomic rearrangements. Nine individuals with deletions and five with duplications have additional copy number changes. Detailed clinical evaluation of 20 patients with deletions revealed variable clinical features, with developmental delay (DD) and/or intellectual disability (ID) as the only features common to a majority of individuals. We suggest that some of the other features present in more than one patient with deletion, including hypotonia, sleep apnea, chronic constipation, gastroesophageal and vesicoureteral refluxes, epilepsy, ataxia, dysphagia, nystagmus, and ptosis may result from deletion of the CHAT gene, encoding choline acetyltransferase, and the SLC18A3 gene, mapping in the first intron of CHAT and encoding vesicular acetylcholine transporter. The phenotypic diversity and presence of the deletion in apparently normal carrier parents suggest that subjects carrying 10q11.21q11.23 deletions may exhibit variable phenotypic expressivity and incomplete penetrance influenced by additional genetic and nongenetic modifiers.

Details

Language :
English
Database :
OpenAIRE
Journal :
Human Mutation, vol. 33, no. 1, pp. 165-179
Accession number :
edsair.doi.dedup.....e7c5ff84f9bf9a002bde387a5c6e38cf