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Identification of candidate genes for congenital heart defects on proximal chromosome 8p.

ABSTRACT: With the application of advanced molecular cytogenetic techniques, the number of patients identified as having abnormal chromosome 8p has increased progressively. Individuals with terminal 8p deletion have been extensively described in previous studies. The manifestations usually include cardiac anomalies, developmental delay/mental retardation, craniofacial abnormalities, and multiple other minor anomalies. However, some patients with proximal deletion also presented with similar phenotypic features. Here we describe a female child with an 18.5-Mb deletion at 8p11.23-p22 that include the cardiac-associated loci NKX2-6 and NRG1. Further mutation screening of these two candidate genes in 143 atrial septal defect patients, two heterozygous mutations NKX2-6 (c.1A?>?T) and NRG1 (c.1652G?>?A) were identified. The mutations were described for the first time in patients with congenital heart disease (CHD). The c.1A?>?T NKX2-6 generated a protein truncated by 45 amino acids with a decreased level of mRNA expression, whereas the NRG1 mutation had no significant effect on protein functions. Our findings suggest that 8p21-8p12 may be another critical region for 8p-associated CHD, and some cardiac malformations might be due to NKX2-6 haploinsufficiency. This study also links the NKX2-6 mutation to ASD for the first time, providing novel insight into the molecular underpinning of this common form of CHD.

SUBMITTER: Li T

PROVIDER: S-EPMC5093561 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Identification of candidate genes for congenital heart defects on proximal chromosome 8p.

Li Tingting T Liu Chunjie C Xu Yuejuan Y Guo Qianqian Q Chen Sun S Sun Kun K Xu Rang R

Scientific reports 20161103

With the application of advanced molecular cytogenetic techniques, the number of patients identified as having abnormal chromosome 8p has increased progressively. Individuals with terminal 8p deletion have been extensively described in previous studies. The manifestations usually include cardiac anomalies, developmental delay/mental retardation, craniofacial abnormalities, and multiple other minor anomalies. However, some patients with proximal deletion also presented with similar phenotypic fea ...[more]

PMID: 27808268

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Project description:BackgroundHeterotaxy (Htx) syndrome comprises a class of congenital disorders resulting from malformations in left-right body patterning. Approximately 90% of patients with heterotaxy have serious congenital heart diseases; as a result, the survival rate and outcomes of Htx patients are not satisfactory. However, the underlying etiology and mechanisms in the majority of Htx cases remain unknown. The aim of this study was to investigate the function of rare copy number variants (CNVs) in the pathogenesis of Htx.MethodsWe collected 63 sporadic Htx patients with congenital heart defects and identified rare CNVs using an Affymetrix CytoScan HD microarray and real-time polymerase chain reaction. Potential candidate genes associated with the rare CNVs were selected by referring to previous literature related to left-right development. The expression patterns and function of candidate genes were further analyzed by whole mount in situ hybridization, morpholino knockdown, clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9)-mediated mutation, and over-expressing methods with zebrafish models.ResultsNineteen rare CNVs were identified for the first time in patients with Htx. These CNVs include 5 heterozygous genic deletions, 4 internal genic duplications, and 10 complete duplications of at least one gene. Further analyses of the 19 rare CNVs identified six novel potential candidate genes (NUMB, PACRG, TCTN2, DANH10, RNF115, and TTC40) linked to left-right patterning. These candidate genes exhibited early expression patterns in zebrafish embryos. Functional testing revealed that downregulation and over-expression of five candidate genes (numb, pacrg, tctn2, dnah10, and rnf115) in zebrafish resulted in disruption of cardiac looping and abnormal expression of lefty2 or pitx2, molecular markers of left-right patterning.ConclusionsOur findings show that Htx with congenital heart defects in some sporadic patients may be attributed to rare CNVs. Furthermore, DNAH10 and RNF115 are Htx candidate genes involved in left-right patterning which have not previously been reported in either humans or animals. Our results also advance understanding of the genetic components of Htx.

Dataset Information

Identification of candidate genes for congenital heart defects on proximal chromosome 8p.

Publications

Identification of candidate genes for congenital heart defects on proximal chromosome 8p.

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