Clinical implementation of chromosomal microarray analysis: summary of 2513 postnatal cases.
BACKGROUND
Array Comparative Genomic Hybridization (a-CGH) is a powerful molecular cytogenetic tool to detect genomic imbalances and study disease mechanism and pathogenesis. We report our experience with the clinical implementation of this high resolution human genome analysis, referred to as Chromosomal Microarray Analysis (CMA).


RESULTS
CMA was performed clinically on 2513 postnatal samples from patients referred with a variety of clinical phenotypes. The initial 775 samples were studied using CMA array version 4 and the remaining 1738 samples were analyzed with CMA version 5 containing expanded genomic coverage. Overall, CMA identified clinically relevant genomic imbalances in 8.5% of patients: 7.6% using V4 and 8.9% using V5. Among 117 cases referred for additional investigation of a known cytogenetically detectable rearrangement, CMA identified the majority (92.5%) of the genomic imbalances. Importantly, abnormal CMA findings were observed in 5.2% of patients (98/1872) with normal karyotypes/FISH results, and V5, with expanded genomic coverage, enabled a higher detection rate in this category than V4. For cases without cytogenetic results available, 8.0% (42/524) abnormal CMA results were detected; again, V5 demonstrated an increased ability to detect abnormality. Improved diagnostic potential of CMA is illustrated by 90 cases identified with 51 cryptic microdeletions and 39 predicted apparent reciprocal microduplications in 13 specific chromosomal regions associated with 11 known genomic disorders. In addition, CMA identified copy number variations (CNVs) of uncertain significance in 262 probands; however, parental studies usually facilitated clinical interpretation. Of these, 217 were interpreted as familial variants and 11 were determined to be de novo; the remaining 34 await parental studies to resolve the clinical significance.


CONCLUSIONS
This large set of clinical results demonstrates the significantly improved sensitivity of CMA for the detection of clinically relevant genomic imbalances and highlights the need for comprehensive genetic counseling to facilitate accurate clinical correlation and interpretation.
Lu
Xinyan
X
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
Shaw
Chad A
CA
Patel
Ankita
A
Li
Jiangzhen
J
Cooper
M Lance
ML
Wells
William R
WR
Sullivan
Cathy M
CM
Sahoo
Trilochan
T
Yatsenko
Svetlana A
SA
Bacino
Carlos A
CA
Stankiewicz
Pawel
P
Ou
Zhishu
Z
Chinault
A Craig
AC
Beaudet
Arthur L
AL
Lupski
James R
JR
Cheung
Sau W
SW
Ward
Patricia A
PA
D022981:Allelic Imbalance / Q000235:genetics; D002877:Chromosomes, Human / Q000235:genetics*; D055028:Comparative Genomic Hybridization / Q000379:methods*; D014644:Genetic Variation; D015894:Genome, Human; D006801:Humans; D007231:Infant, Newborn; D007621:Karyotyping; D046228:Microarray Analysis / Q000379:methods; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010641:Phenotype; D012016:Reference Values