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Chromosome microarray testing for patients with congenital heart defects reveals novel disease causing loci and high diagnostic yield.

Geng J, Picker J, Zheng Z, Zhang X, Wang J, Hisama F, Brown DW, Mullen MP, Harris D, Stoler J, Seman A, Miller DT, Fu Q, Roberts AE, Shen Y - BMC Genomics (2014)

Bottom Line: Four recurrent genomic loci (4q terminal region, 15q11.2, 16p12.2 and Yp11.2) were more significantly enriched in cases than in controls.The high clinical diagnostic yield of CMA in this study provides supportive evidence for CMA as the first-line genetic diagnostic tool for CHD patients.The CNVs detected in our study suggest a number of CHD candidate genes that warrant further investigation.

View Article: PubMed Central - PubMed

Affiliation: Department of Laboratory Medicine, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China. qihuafu@hotmail.com.

ABSTRACT

Background: Congenital heart defects (CHD), as the most common congenital anomaly, have been reported to be frequently associated with pathogenic copy number variants (CNVs). Currently, patients with CHD are routinely offered chromosomal microarray (CMA) testing, but the diagnostic yield of CMA on CHD patients has not been extensively evaluated based on a large patient cohort. In this study, we retrospectively assessed the detected CNVs in a total of 514 CHD cases (a 422-case clinical cohort from Boston Children's Hospital (BCH) and a 92-case research cohort from Shanghai Children's Medical Center (SCMC)) and conducted a genotype-phenotype analysis. Furthermore, genes encompassed in pathogenic/likely pathogenic CNVs were prioritized by integrating several tools and public data sources for novel CHD candidate gene identification.

Results: Based on the BCH cohort, the overall diagnostic yield of CMA testing for CHD patients was 12.8(pathogenic CNVs)-18.5% (pathogenic and likely pathogenic CNVs). The diagnostic yield of CMA for syndromic CHD was 14.1-20.6% (excluding aneuploidy cases), whereas the diagnostic yield for isolated CHD was 4.3-9.3%. Four recurrent genomic loci (4q terminal region, 15q11.2, 16p12.2 and Yp11.2) were more significantly enriched in cases than in controls. These regions are considered as novel CHD loci. We further identified 20 genes as the most likely novel CHD candidate genes through gene prioritization analysis.

Conclusion: The high clinical diagnostic yield of CMA in this study provides supportive evidence for CMA as the first-line genetic diagnostic tool for CHD patients. The CNVs detected in our study suggest a number of CHD candidate genes that warrant further investigation.

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Distribution of the 89 sub-chromosomal genomic imbalances detected in this study among patients with CHD. Chromosomal loci 22q11.21 and 8p23.1 were two known pathogenic CNV hotspots in CHD patients. This study also identified deletions at loci 4q terminal, 15q11.2, 16p12.1 and Yp11.2 as potential pathogenic hotspots.
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Fig1: Distribution of the 89 sub-chromosomal genomic imbalances detected in this study among patients with CHD. Chromosomal loci 22q11.21 and 8p23.1 were two known pathogenic CNV hotspots in CHD patients. This study also identified deletions at loci 4q terminal, 15q11.2, 16p12.1 and Yp11.2 as potential pathogenic hotspots.

Mentions: A genome-wide CNV analysis for a total of 502 CHD cases (410 from BCH cohort and 92 from SCMC cohort; Additional file1: Figure S1) led to the detection of 209 (183 in BCH cohort and 26 in SCMC cohort) non-polymorphic CNVs. As a result, a total of 89 CNVs at 57 unique chromosome loci were considered to be of known or possible clinical relevance in this study. They were widely distributed on different chromosomes (Figure 1). We observed 32 recurrent (n ≥ 3) CNVs distributed at six chromosomal loci (Additional file1: Table S1, S2) which include 12 imbalances (nine deletions and three duplications) at 22q11.2 and five aberrations (three deletions and two duplications) at the 8p23.1 involving the GATA4 gene, both loci are known to be associated with syndromic or isolated CHD. In this study, we also identified five patients with 4q terminal deletions which range from 4, 600 kb to 19, 300 kb in size (Figure 2A). Similar deletions were not detected in 9170 control cases (Table 3), and are not reported in DGV (http://dgv.tcag.ca/ accessed March, 2014). 4q terminal deletion is known to cause 4q- syndrome where 50% of affected individuals have CHD, and a cardiovascular critical region has been narrowed down to 4q32.2–q34.3[25]. The smallest overlapping region (SOR) among our 4q terminal deletion cases was about 4.6 Mb in size at 4q35.1-qter. This SOR didn’t overlap with the previously defined critical region (Figure 2A). Thus our study potentially maps a novel CHD critical region at the 4q terminus. There were 24 Refseq genes at this interval, although no known CHD genes existed, we propose several possible candidate genes in discussion.Figure 1


Chromosome microarray testing for patients with congenital heart defects reveals novel disease causing loci and high diagnostic yield.

Geng J, Picker J, Zheng Z, Zhang X, Wang J, Hisama F, Brown DW, Mullen MP, Harris D, Stoler J, Seman A, Miller DT, Fu Q, Roberts AE, Shen Y - BMC Genomics (2014)

Distribution of the 89 sub-chromosomal genomic imbalances detected in this study among patients with CHD. Chromosomal loci 22q11.21 and 8p23.1 were two known pathogenic CNV hotspots in CHD patients. This study also identified deletions at loci 4q terminal, 15q11.2, 16p12.1 and Yp11.2 as potential pathogenic hotspots.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4378009&req=5

Fig1: Distribution of the 89 sub-chromosomal genomic imbalances detected in this study among patients with CHD. Chromosomal loci 22q11.21 and 8p23.1 were two known pathogenic CNV hotspots in CHD patients. This study also identified deletions at loci 4q terminal, 15q11.2, 16p12.1 and Yp11.2 as potential pathogenic hotspots.
Mentions: A genome-wide CNV analysis for a total of 502 CHD cases (410 from BCH cohort and 92 from SCMC cohort; Additional file1: Figure S1) led to the detection of 209 (183 in BCH cohort and 26 in SCMC cohort) non-polymorphic CNVs. As a result, a total of 89 CNVs at 57 unique chromosome loci were considered to be of known or possible clinical relevance in this study. They were widely distributed on different chromosomes (Figure 1). We observed 32 recurrent (n ≥ 3) CNVs distributed at six chromosomal loci (Additional file1: Table S1, S2) which include 12 imbalances (nine deletions and three duplications) at 22q11.2 and five aberrations (three deletions and two duplications) at the 8p23.1 involving the GATA4 gene, both loci are known to be associated with syndromic or isolated CHD. In this study, we also identified five patients with 4q terminal deletions which range from 4, 600 kb to 19, 300 kb in size (Figure 2A). Similar deletions were not detected in 9170 control cases (Table 3), and are not reported in DGV (http://dgv.tcag.ca/ accessed March, 2014). 4q terminal deletion is known to cause 4q- syndrome where 50% of affected individuals have CHD, and a cardiovascular critical region has been narrowed down to 4q32.2–q34.3[25]. The smallest overlapping region (SOR) among our 4q terminal deletion cases was about 4.6 Mb in size at 4q35.1-qter. This SOR didn’t overlap with the previously defined critical region (Figure 2A). Thus our study potentially maps a novel CHD critical region at the 4q terminus. There were 24 Refseq genes at this interval, although no known CHD genes existed, we propose several possible candidate genes in discussion.Figure 1

Bottom Line: Four recurrent genomic loci (4q terminal region, 15q11.2, 16p12.2 and Yp11.2) were more significantly enriched in cases than in controls.The high clinical diagnostic yield of CMA in this study provides supportive evidence for CMA as the first-line genetic diagnostic tool for CHD patients.The CNVs detected in our study suggest a number of CHD candidate genes that warrant further investigation.

View Article: PubMed Central - PubMed

Affiliation: Department of Laboratory Medicine, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China. qihuafu@hotmail.com.

ABSTRACT

Background: Congenital heart defects (CHD), as the most common congenital anomaly, have been reported to be frequently associated with pathogenic copy number variants (CNVs). Currently, patients with CHD are routinely offered chromosomal microarray (CMA) testing, but the diagnostic yield of CMA on CHD patients has not been extensively evaluated based on a large patient cohort. In this study, we retrospectively assessed the detected CNVs in a total of 514 CHD cases (a 422-case clinical cohort from Boston Children's Hospital (BCH) and a 92-case research cohort from Shanghai Children's Medical Center (SCMC)) and conducted a genotype-phenotype analysis. Furthermore, genes encompassed in pathogenic/likely pathogenic CNVs were prioritized by integrating several tools and public data sources for novel CHD candidate gene identification.

Results: Based on the BCH cohort, the overall diagnostic yield of CMA testing for CHD patients was 12.8(pathogenic CNVs)-18.5% (pathogenic and likely pathogenic CNVs). The diagnostic yield of CMA for syndromic CHD was 14.1-20.6% (excluding aneuploidy cases), whereas the diagnostic yield for isolated CHD was 4.3-9.3%. Four recurrent genomic loci (4q terminal region, 15q11.2, 16p12.2 and Yp11.2) were more significantly enriched in cases than in controls. These regions are considered as novel CHD loci. We further identified 20 genes as the most likely novel CHD candidate genes through gene prioritization analysis.

Conclusion: The high clinical diagnostic yield of CMA in this study provides supportive evidence for CMA as the first-line genetic diagnostic tool for CHD patients. The CNVs detected in our study suggest a number of CHD candidate genes that warrant further investigation.

Show MeSH
Related in: MedlinePlus