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. 2024 Sep 9:15:1458953.
doi: 10.3389/fgene.2024.1458953. eCollection 2024.

De novo and inherited micro-CNV at 16p13.11 in 21 Chinese patients with defective cardiac left-right patterning

Kun Yu #  1 , Weicheng Chen #  2 , Yan Chen #  3 , Libing Shen  4 , Boxuan Wu  3 , Yuan Zhang  5 , Xiangyu Zhou  3
Affiliations

De novo and inherited micro-CNV at 16p13.11 in 21 Chinese patients with defective cardiac left-right patterning

Kun Yu et al. Front Genet. .

Abstract

Objective: Copy number changes at Chromosomal 16p13.11 have been implicated in a variety of human diseases including congenital cardiac abnormalities. The clinical correlation of copy number variants (CNVs) in this region with developmental abnormalities remains controversial as most of the patients inherit the duplication from an unaffected parent.

Methods: We performed CNV analysis on 164 patients with defective left-right (LR) patterning based on whole genome-exome sequencing (WG-ES) followed by multiplex ligation-dependent probe amplification (MLPA) validation. Most cases were accompanied with complex congenital heart disease (CHD).

Results: CNVs at 16p13.11 were identified in a total of 21 cases, accounting for 12.80% (21/164) evaluated cases. We observed a marked overrepresentation of chromosome 16p13.11 duplications in cases when compared with healthy controls according to literature reports (15/164, 9.14% versus 0.09% in controls). Notably, in two independent family trios, de novo 16p13.11 micro-duplications were identified in two patients with laterality defects and CHD. Moreover, 16p13.11 micro-duplication was segregated with the disease in a family trio containing 2 affected individuals. Notably, five coding genes, NOMO1, PKD1P3, NPIPA1, PDXDC1, and NTAN1, were potentially affected by micro-CNV at 16p13.11 in these patients.

Conclusion: Our study provides new family-trio based evidences to support 16p13.11 micro-duplications predispose individuals to defective cardiac left-right patterning and laterality disorder.

Keywords: 16p13.11; ciliopathy; congenital heart disease; copy number variation; deletion; duplication; laterality disorder; left-right patterning.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
De novo 16p13.11 duplication in a monozygotic twin (A) Pedigrees of Family-1 (F1) indicating the affected individuals and the distribution of 16p13.11 duplication. (B) Chest X-ray and CT-scan show isolated dextrocardia in the proband (F1-II-1) (upper), and color ultrasound scans reveal an atrial septal defect (ASD), and a pulmonary artery sling in the patient (bottom). RA, right atrium; LA, left atrium; RV, left ventricle; LPA, left pulmonary artery; PA, pulmonary artery. (C) CNV analysis based on WGS data identified de novo 16p13.11 micro-duplication (chr16: 14.98–15.13, 150 kb, GRCh37.p13) in both sibilings when compared to the parents, independently.
FIGURE 2
FIGURE 2
Inherited 16p13.11 duplication segregated with the disease in Family-2. (A) Pedigrees of Family-2 (F2) indicating the affected individuals and the distribution of 16p13.11 duplication. (B) Representative images of chest X-ray and CT scan shows the mirror-image arrangement of the abdominal organs in both patients (F2-I-2 and F2-II-1), R, right. (C) CNV analysis based on WGS data identified 16p13.11 micro-duplication (chr16: 14.98–15.13, GRCh37.p13) in both patients when compared to the unaffected individual, respectively. (D) Human Protein Atlas database showing PDXDC1 is widely expressed in various human tissues and has highest levels in testis. (E) Sanger sequencing on PDXDC1 variant (p.L428V) in the patients and unaffected members. (F) Sequencing alignment of missense variants p.L428V in different species as indicated. (C) elegans, caenorhabditis elegans.
FIGURE 3
FIGURE 3
De novo 16p13.11 duplication potentially modulates the cardiac phenotype. (A) Pedigrees of Family-2 (F3) indicating the affected individuals and the distribution of 16p13.11 duplication in two siblings with different ciliopathies. (B) CNV analysis based on WES data identified micro-duplication at 16p13.11 in the brother (F3-II-1) but not in the sister (F3-II-2). (C) MLPA confirmation of the gain of copy in PDXDC1, located in the 16p13.11 region, that identified from CNV analysis in the F3-II-1 when compared with F3-II-2. Three independent probes were designed for each targeted gene as indicated. GAPDH served as the internal reference. Dosage quotient (DQ) values = 1.501 (1.3<DQ < 1.65, heterozygous duplication) (D) Genome-wide CNV analysis also identified 16p13.11 deletion in the patient with defective LR patterning when compared with health Ctrl (right panel). Left panel served as a internal Ctrl. (E) The diagram of 16p13.11 duplications (red) and deletions (green) in 21 patients. The scale is in megabases. The region that is spanned by all CNVs containing five coding genes, NOMO1, PKD1P3, NPIPA1, PDXDC1 and NTAN1, as indicated.
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