Genomic imbalances in neonates with birth defects: high detection rates by using chromosomal microarray analysis.
OBJECTIVE
Our aim was to determine the frequency of genomic imbalances in neonates with birth defects by using targeted array-based comparative genomic hybridization, also known as chromosomal microarray analysis.


METHODS
Between March 2006 and September 2007, 638 neonates with various birth defects were referred for chromosomal microarray analysis. Three consecutive chromosomal microarray analysis versions were used: bacterial artificial chromosome-based versions V5 and V6 and bacterial artificial chromosome emulated oligonucleotide-based version V6 Oligo. Each version had targeted but increasingly extensive genomic coverage and interrogated>150 disease loci with enhanced coverage in genomic rearrangement-prone pericentromeric and subtelomeric regions.


RESULTS
Overall, 109 (17.1%) patients were identified with clinically significant abnormalities with detection rates of 13.7%, 16.6%, and 19.9% on V5, V6, and V6 Oligo, respectively. The majority of these abnormalities would not be defined by using karyotype analysis. The clinically significant detection rates by use of chromosomal microarray analysis for various clinical indications were 66.7% for "possible chromosomal abnormality"+/-"others" (other clinical indications), 33.3% for ambiguous genitalia+/-others, 27.1% for dysmorphic features+multiple congenital anomalies+/-others, 24.6% for dysmorphic features+/-others, 21.8% for congenital heart disease+/-others, 17.9% for multiple congenital anomalies+/-others, and 9.5% for the patients referred for others that were different from the groups defined. In all, 16 (2.5%) patients had chromosomal aneuploidies, and 81 (12.7%) patients had segmental aneusomies including common microdeletion or microduplication syndromes and other genomic disorders. Chromosomal mosaicism was found in 12 (1.9%) neonates.


CONCLUSIONS
Chromosomal microarray analysis is a valuable clinical diagnostic tool that allows precise and rapid identification of genomic imbalances and mosaic abnormalities as the cause of birth defects in neonates. Chromosomal microarray analysis allows for timely molecular diagnoses and detects many more clinically relevant genomic abnormalities than conventional cytogenetic studies, enabling more informed decision-making and management and appropriate assessment of recurrence risk.
Lu
Xin-Yan
XY
Baylor College of Medicine, Department of Molecular and Human Genetics, One Baylor Plaza, NAB 2015, Houston, TX 77030, USA.
Phung
Mai T
MT
Shaw
Chad A
CA
Pham
Kim
K
Neil
Sarah E
SE
Patel
Ankita
A
Sahoo
Trilochan
T
Bacino
Carlos A
CA
Stankiewicz
Pawel
P
Kang
Sung-Hae Lee
SH
Lalani
Seema
S
Chinault
A Craig
AC
Lupski
James R
JR
Cheung
Sau W
SW
Beaudet
Arthur L
AL
D000015:Abnormalities, Multiple / Q000175:diagnosis / Q000235:genetics; D002869:Chromosome Aberrations; D015331:Cohort Studies; D055028:Comparative Genomic Hybridization; D000013:Congenital Abnormalities / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D042822:Genomic Instability / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007231:Infant, Newborn; D008297:Male; D009030:Mosaicism; D020411:Oligonucleotide Array Sequence Analysis; D012680:Sensitivity and Specificity