title: Recurrent deletions and reciprocal duplications of 10q11.21q11.23 including CHAT and SLC18A3 are likely mediated by complex low-copy repeats.
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.
authors.affiliation: Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA. pawels@bcm.edu
authors.forename: Paweł
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authors.lastname: Stankiewicz
authors.forename: Shashikant
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authors.lastname: Kulkarni
authors.forename: Avinash V
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authors.lastname: Dharmadhikari
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authors.lastname: Saunders
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authors.lastname: Scaglia
authors.forename: Florence
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authors.forename: Jacqueline
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authors.lastname: Hoover
authors.forename: Livija
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authors.lastname: Medne
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authors.lastname: Bonnemann
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authors.lastname: Moeschler
authors.forename: Stephanie E
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authors.lastname: Vallee
authors.forename: Sumit
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authors.lastname: Parikh
authors.forename: Polly
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authors.lastname: Irwin
authors.forename: Victoria P
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authors.lastname: Dalzell
authors.forename: Wendy E
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authors.lastname: Smith
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authors.lastname: Flannery
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Lovell
authors.forename: Gary A
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authors.lastname: Bellus
authors.forename: Kathryn
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authors.lastname: Golden-Grant
authors.forename: Jerome L
authors.initials: JL
authors.lastname: Gorski
authors.forename: Jennifer L
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authors.lastname: Kussmann
authors.forename: Tracy L
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authors.lastname: McGregor
authors.forename: Rizwan
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authors.lastname: Hamid
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authors.lastname: Pfotenhauer
authors.forename: Blake C
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authors.lastname: Ballif
authors.forename: Chad A
authors.initials: CA
authors.lastname: Shaw
authors.forename: Sung-Hae L
authors.initials: SH
authors.lastname: Kang
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Bacino
authors.forename: Ankita
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authors.lastname: Patel
authors.forename: Jill A
authors.initials: JA
authors.lastname: Rosenfeld
authors.forename: Sau Wai
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authors.lastname: Cheung
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mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D002874:Chromosome Mapping; D002879:Chromosomes, Human, Pair 10; D056915:DNA Copy Number Variations; D002658:Developmental Disabilities / Q000150:complications / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D059765:Homologous Recombination; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D008607:Intellectual Disability / Q000150:complications / Q000235:genetics; D008297:Male; D009414:Nerve Growth Factors / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D019683:Penetrance; D056916:Segmental Duplications, Genomic / Q000235:genetics*; D017384:Sequence Deletion; D050494:Vesicular Acetylcholine Transport Proteins / Q000235:genetics*
chemical_list: C072167:CAT development factor; D009414:Nerve Growth Factors; C493459:SLC18A3 protein, human; D050494:Vesicular Acetylcholine Transport Proteins