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PMID: 20188345 Published · ppublish English Case Reports Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Identification of uncommon recurrent Potocki-Lupski syndrome-associated duplications and the distribution of rearrangement types and mechanisms in PTLS.

American journal of human genetics ·Vol. 86 ·No. 3 ·2010-03-12 ·Pages 462-70

Zhang F, Potocki L, Sampson JB, Liu P, Sanchez-Valle A, Robbins-Furman P, Navarro AD, Wheeler PG, Spence JE, Brasington CK, Withers MA, Lupski JR

Abstract

Nonallelic homologous recombination (NAHR) can mediate recurrent rearrangements in the human genome and cause genomic disorders. Smith-Magenis syndrome (SMS) and Potocki-Lupski syndrome (PTLS) are genomic disorders associated with a 3.7 Mb deletion and its reciprocal duplication in 17p11.2, respectively. In addition to these common recurrent rearrangements, an uncommon recurrent 5 Mb SMS-associated deletion has been identified. However, its reciprocal duplication predicted by the NAHR mechanism had not been identified. Here we report the molecular assays on 74 subjects with PTLS-associated duplications, 35 of whom are newly investigated. By both oligonucleotide-based comparative genomic hybridization and recombination hot spot analyses, we identified two cases of the predicted 5 Mb uncommon recurrent PTLS-associated duplication. Interestingly, the crossovers occur in proximity to a recently delineated allelic homologous recombination (AHR) hot spot-associated sequence motif, further documenting the common hot spot features shared between NAHR and AHR. An additional eight subjects with nonrecurrent PTLS duplications were identified. The smallest region of overlap (SRO) for all of the 74 PTLS duplications examined is narrowed to a 125 kb interval containing only RAI1, a gene recently further implicated in autism. Sequence complexities consistent with DNA replication-based mechanisms were identified in four of eight (50%) newly identified nonrecurrent PTLS duplications. Our findings of the uncommon recurrent PTLS-associated duplication at a relative prevalence reflecting the de novo mutation rate and the distribution of 17p11.2 duplication types in PTLS reveal insights into both the contributions of new mutations and the different underlying mechanisms that generate genomic rearrangements causing genomic disorders.

MeSH Terms
Abnormalities, Multiple/genetics Adult Base Sequence Child Child Behavior Disorders/genetics Child, Preschool Chromosomes, Human, Pair 17/genetics Comparative Genomic Hybridization Developmental Disabilities/genetics Facies Female Gene Rearrangement Genomic Instability Humans Male Models, Genetic Phenotype Recombination, Genetic Segmental Duplications, Genomic Sequence Deletion Syndrome
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Zhang Feng
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Potocki Lorraine
Sampson Jacinda B
Liu Pengfei
Sanchez-Valle Amarilis
Robbins-Furman Patricia
Navarro Alicia Delicado
Wheeler Patricia G
Spence J Edward
Brasington Campbell K
Withers Marjorie A
Lupski James R
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Article Info
Journal
American journal of human genetics
Abbr.
Am J Hum Genet
ISSN
1537-6605
DOI
10.1016/j.ajhg.2010.02.001
Published
2010-03-12
Epub
2010-00-25
Pages
462-70
Language
English
Region
United States
NLM ID
0370475
PMCID
PMC2833368
Subset
IM
Grants
NINDS NIH HHS · R01NS058529 · United States
NCRR NIH HHS · M01 RR000188 · United States
NICHD NIH HHS · P30 HD024064 · United States
NICHD NIH HHS · P30HD024064 · United States
NINDS NIH HHS · R01 NS058529 · United States
NCRR NIH HHS · M01RR00188 · United States
External Links
PubMed source DOI: 10.1016/j.ajhg.2010.02.001 PMC Full Text View journal details
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