Rare copy number variants in isolated sporadic and syndromic atrioventricular septal defects

James R. Priest, Santhosh Girirajan, Tiffany H. Vu, Aaron Olson, Evan E. Eichler, Michael A. Portman

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Atrioventricular septal defects (AVSDs) are a frequent but not universal component of Down syndrome (DS), while AVSDs in otherwise normal individuals have no well-defined genetic basis. The contribution of copy number variation (CNV) to specific congenital heart disease (CHD) phenotypes including AVSD is unknown. We hypothesized that de novo CNVs on chromosome 21 might cause isolated sporadic AVSDs, and separately that CNVs throughout the genome might constitute an additional genetic risk factor for AVSD in patients with DS. We utilized a custom oligonucleotide arrays targeted to CNV hotspots that are flanked by large duplicated segments of high sequence identity. We assayed 29 euploid and 50 DS individuals with AVSD, and compared to general population controls. In patients with isolated-sporadic AVSD we identified two large unique deletions outside of chromosome 21 not seen in the expanded set of 8,635 controls, each overlapping with larger deletions associated with similar CHD reported in the DECIPHER database. There was a small duplication in one patient with DS and AVSD. We conclude that isolated sporadic AVSDs may be occasionally associated with large de novo genomic structural variation outside of chromosome 21. The absence of CNVs on chromosome 21 in patients with isolated sporadic AVSD suggests that sub-chromosomal duplications or deletions of greater than 150kbp on chromosome 21 do not cause sporadic AVSDs. Large CNVs do not appear to be an additive risk factor for AVSD in the DS population.

Original languageEnglish (US)
Pages (from-to)1279-1284
Number of pages6
JournalAmerican Journal of Medical Genetics, Part A
Volume158 A
Issue number6
DOIs
StatePublished - Jun 1 2012

Fingerprint

Chromosomes, Human, Pair 21
Down Syndrome
Atrioventricular Septal Defect
Genomic Structural Variation
Heart Diseases
Chromosome Duplication
Population Control
Oligonucleotide Array Sequence Analysis
Genome
Databases
Phenotype
Population

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Priest, James R. ; Girirajan, Santhosh ; Vu, Tiffany H. ; Olson, Aaron ; Eichler, Evan E. ; Portman, Michael A. / Rare copy number variants in isolated sporadic and syndromic atrioventricular septal defects. In: American Journal of Medical Genetics, Part A. 2012 ; Vol. 158 A, No. 6. pp. 1279-1284.
@article{9df2ad9021bb4fc59b98a7d552d4b174,
title = "Rare copy number variants in isolated sporadic and syndromic atrioventricular septal defects",
abstract = "Atrioventricular septal defects (AVSDs) are a frequent but not universal component of Down syndrome (DS), while AVSDs in otherwise normal individuals have no well-defined genetic basis. The contribution of copy number variation (CNV) to specific congenital heart disease (CHD) phenotypes including AVSD is unknown. We hypothesized that de novo CNVs on chromosome 21 might cause isolated sporadic AVSDs, and separately that CNVs throughout the genome might constitute an additional genetic risk factor for AVSD in patients with DS. We utilized a custom oligonucleotide arrays targeted to CNV hotspots that are flanked by large duplicated segments of high sequence identity. We assayed 29 euploid and 50 DS individuals with AVSD, and compared to general population controls. In patients with isolated-sporadic AVSD we identified two large unique deletions outside of chromosome 21 not seen in the expanded set of 8,635 controls, each overlapping with larger deletions associated with similar CHD reported in the DECIPHER database. There was a small duplication in one patient with DS and AVSD. We conclude that isolated sporadic AVSDs may be occasionally associated with large de novo genomic structural variation outside of chromosome 21. The absence of CNVs on chromosome 21 in patients with isolated sporadic AVSD suggests that sub-chromosomal duplications or deletions of greater than 150kbp on chromosome 21 do not cause sporadic AVSDs. Large CNVs do not appear to be an additive risk factor for AVSD in the DS population.",
author = "Priest, {James R.} and Santhosh Girirajan and Vu, {Tiffany H.} and Aaron Olson and Eichler, {Evan E.} and Portman, {Michael A.}",
year = "2012",
month = "6",
day = "1",
doi = "10.1002/ajmg.a.35315",
language = "English (US)",
volume = "158 A",
pages = "1279--1284",
journal = "American Journal of Medical Genetics, Part A",
issn = "1552-4825",
publisher = "Wiley-Liss Inc.",
number = "6",

}

Rare copy number variants in isolated sporadic and syndromic atrioventricular septal defects. / Priest, James R.; Girirajan, Santhosh; Vu, Tiffany H.; Olson, Aaron; Eichler, Evan E.; Portman, Michael A.

In: American Journal of Medical Genetics, Part A, Vol. 158 A, No. 6, 01.06.2012, p. 1279-1284.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Rare copy number variants in isolated sporadic and syndromic atrioventricular septal defects

AU - Priest, James R.

AU - Girirajan, Santhosh

AU - Vu, Tiffany H.

AU - Olson, Aaron

AU - Eichler, Evan E.

AU - Portman, Michael A.

PY - 2012/6/1

Y1 - 2012/6/1

N2 - Atrioventricular septal defects (AVSDs) are a frequent but not universal component of Down syndrome (DS), while AVSDs in otherwise normal individuals have no well-defined genetic basis. The contribution of copy number variation (CNV) to specific congenital heart disease (CHD) phenotypes including AVSD is unknown. We hypothesized that de novo CNVs on chromosome 21 might cause isolated sporadic AVSDs, and separately that CNVs throughout the genome might constitute an additional genetic risk factor for AVSD in patients with DS. We utilized a custom oligonucleotide arrays targeted to CNV hotspots that are flanked by large duplicated segments of high sequence identity. We assayed 29 euploid and 50 DS individuals with AVSD, and compared to general population controls. In patients with isolated-sporadic AVSD we identified two large unique deletions outside of chromosome 21 not seen in the expanded set of 8,635 controls, each overlapping with larger deletions associated with similar CHD reported in the DECIPHER database. There was a small duplication in one patient with DS and AVSD. We conclude that isolated sporadic AVSDs may be occasionally associated with large de novo genomic structural variation outside of chromosome 21. The absence of CNVs on chromosome 21 in patients with isolated sporadic AVSD suggests that sub-chromosomal duplications or deletions of greater than 150kbp on chromosome 21 do not cause sporadic AVSDs. Large CNVs do not appear to be an additive risk factor for AVSD in the DS population.

AB - Atrioventricular septal defects (AVSDs) are a frequent but not universal component of Down syndrome (DS), while AVSDs in otherwise normal individuals have no well-defined genetic basis. The contribution of copy number variation (CNV) to specific congenital heart disease (CHD) phenotypes including AVSD is unknown. We hypothesized that de novo CNVs on chromosome 21 might cause isolated sporadic AVSDs, and separately that CNVs throughout the genome might constitute an additional genetic risk factor for AVSD in patients with DS. We utilized a custom oligonucleotide arrays targeted to CNV hotspots that are flanked by large duplicated segments of high sequence identity. We assayed 29 euploid and 50 DS individuals with AVSD, and compared to general population controls. In patients with isolated-sporadic AVSD we identified two large unique deletions outside of chromosome 21 not seen in the expanded set of 8,635 controls, each overlapping with larger deletions associated with similar CHD reported in the DECIPHER database. There was a small duplication in one patient with DS and AVSD. We conclude that isolated sporadic AVSDs may be occasionally associated with large de novo genomic structural variation outside of chromosome 21. The absence of CNVs on chromosome 21 in patients with isolated sporadic AVSD suggests that sub-chromosomal duplications or deletions of greater than 150kbp on chromosome 21 do not cause sporadic AVSDs. Large CNVs do not appear to be an additive risk factor for AVSD in the DS population.

UR - http://www.scopus.com/inward/record.url?scp=84861223064&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84861223064&partnerID=8YFLogxK

U2 - 10.1002/ajmg.a.35315

DO - 10.1002/ajmg.a.35315

M3 - Article

C2 - 22529060

AN - SCOPUS:84861223064

VL - 158 A

SP - 1279

EP - 1284

JO - American Journal of Medical Genetics, Part A

JF - American Journal of Medical Genetics, Part A

SN - 1552-4825

IS - 6

ER -