Abstract
Chromosomal microarray analysis (CMA) has been recommended and practiced routinely in the large reference laboratories of U.S.A. as the first-tier test for the postnatal evaluation of individuals with intellectual disability, autism spectrum disorders, and/or multiple congenital anomalies. Using CMA as a diagnostic tool and without a routine setting of fluorescence in situ hybridization with labeled bacterial artificial chromosome probes (BAC-FISH) in the large reference laboratories becomes a challenge in the characterization of chromosome 9 pericentric region. This region has a very complex genomic structure and contains a variety of heterochromatic and euchromatic polymorphic variants. These variants were usually studied by G-banding, C-banding and BAC-FISH analysis. Chromosomal microarray analysis (CMA) was not recommended since it may lead to false positive results. Here, we presented a cohort of four cases, in which high-resolution CMA was used as the first-tier test or simultaneously with G-banding analysis on the proband to identify pathogenic copy number variants (CNVs) in the whole genome. CMA revealed large pathogenic CNVs from chromosome 9 in 3 cases which also revealed different G-banding patterns between the two chromosome 9 homologues. Although we demonstrated that high-resolution CMA played an important role in the identification of pathogenic copy number variants in chromosome 9 pericentric regions, the lack of BAC-FISH analysis or other useful tools renders significant challenges in the characterization of chromosome 9 pericentric regions.Trial registration: None; it is not a clinical trial, and the cases were retrospectively collected and analyzed.Electronic supplementary materialThe online version of this article (doi:10.1186/s13039-016-0272-6) contains supplementary material, which is available to authorized users.
Highlights
Chromosomal microarray analysis (CMA) has been recommended and practiced routinely in the large reference laboratories of U.S.A. as the first-tier test for the postnatal evaluation of individuals with intellectual disability, autism spectrum disorders, and/or multiple congenital anomalies
In a cohort of 334 carriers studied by using fluorescence in situ hybridization (FISH) analysis with different sets of labeled bacterial artificial chromosome (BAC) probes (BACFISH), 17 different types of heterochromatic variants of chromosome 9 have been identified [6], with pericentric inversions being the most frequent variant (50 %) followed by 9qh-variants (24 %) and 9ph-variants (11 %)
The second reviewer thought it was a large pericentric inversion, 46,XX,inv(9)(p13q32) since the band 9q31 was missing (Fig. 1a, arrow) and instead inverted to 9p13 region (Fig. 1a, arrow head), and considered that it was not a variant. Further characterization of this large pericentric inversion by concurrent highresolution CMA revealed the presence of an interstitial deletion of 14 Mb at 9q22.3–q32
Summary
Chromosomal microarray analysis (CMA) has been recommended and practiced routinely in the large reference laboratories of U.S.A. as the first-tier test for the postnatal evaluation of individuals with intellectual disability, autism spectrum disorders, and/or multiple congenital anomalies. Headings CMA as the first-tier test for the identification of pathogenic CNVs in chromosome 9 pericentric regions and its challenge. CMA has largely replaced fluorescence in situ hybridization (FISH) analysis for the identification of pathogenic copy number variants (CNVs) across the whole genome.
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