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Genetics are at the core of some congenital heart defects, and a new scientific statement could help guide doctors in new information and testing techniques that not only could help patients but also their families. Mary Ella Pierpont, a pediatrician and a professor of pediatric genetics and metabolism at the University of Minnesota.

The summary covers a broad spectrum of topics and new advancements in genetic conditions, including a phenomenon called copy number variation, or CNV, when the number of copies of a particular gene varies from one person to the next. The statement also offers updated information on new molecular testing techniques and how they apply to congenital heart disease and other congenital anomalies or syndromes.

The statement discusses new prenatal gene testing techniques that have emerged in recent years to better inform doctors and parents who may be concerned about the increased risks for women who have congenital heart disease and for their baby. Wendy K.


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Chung, a statement co-author and a clinical and molecular geneticist and professor of pediatrics at Columbia University. Newer prenatal tests include non-invasive cell-free DNA testing, which is conducted by blood sample from the mother, and chromosomal microarray, or CMA, testing. Testing is done after an amniocentesis, a procedure which can carry a small risk of miscarriage.

Genetic Arrhythmias (Channelopathies) - Abstract - Congenital Heart Disease - Karger Publishers

This variant was also found in the patient's mother, who is unaffected. Due to lack of penetrance in the mother, we consider this variant to be of uncertain significance. The second candidate variant in patient 9 is c. This variant was found in the patient's unaffected father.

The family is of Hispanic origin and the frequency of this variant is 0. Patient 16 had a variant found in GDF1 , c. GA p. GDF1 is associated with heart and vasculature development. This variant was not found in ExAC, and is found at a frequency of 0. Patient 23 also had a variant found in MYH6 , c. CA p. This variant was not found in ExAc, and the Genomes Project observed this variant in 0. CT p. The nucleotide is highly conserved across species, and the amino acid substitution is conservative.

In one case 3 , we identified a possible deletion, which proved to be a false positive. In 25 nonsyndromic patients, we identified no causative variants and found two pathogenic variants in nine syndromic patients. In our study, our predefined gene list included genes known to be associated with embryonal cardiac development. We found 11 candidate VUS's in 34 patients.


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  • Genetic Arrhythmias (Channelopathies).
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  • Investigation of Copy Number Variation in Children with Conotruncal Heart Defects.

Although there are differences between the studies in the disorders and methodology and a small number of patients evaluated, these results suggest that extending variant analyses to a larger set of cardiac genes may not significantly increase the number of VUS per patient. Previous studies have observed higher yields from genetic testing for conditions with apparently familial transmission, as compared to families with one affected member.

This suggests that diagnostic yield for CHD may be higher if there are other family members affected, and if an autosomal dominant inheritance pattern is suggested.

Congenital Heart Disease: Molecular Diagnostics (Methods in Molecular Medicine)

There are several reasons why causative variants for the currently unexplained patients may not have been identified. To focus on variants that are sufficiently interpretable to be clinically reported, we limited the analysis to variants predicted to impact a protein sequence, but noncoding or miRNA variants may be contributory J. However, particularly for disorders with incomplete penetrance, the pathogenic variants could be unexpectedly common in control cohorts.

These issues could lead to undercalling or overcalling of variants, as illustrated by the deletion in NIPBL in patient 3 that failed validation. Despite an increase in understanding of the underlying genes of CHD, assignment of variant pathogenicity remains challenging. Variable intrafamilial expressivity has been previously reported for genes associated with CHD. With genetic testing technologies continually improving, and more options available for genetic examination, there are increasing choices for the clinical investigation of congenital heart disorders.

In our cohort, WGS detected what was found on the clinical gene panels, and also offered a wider examination of a larger gene set. This paper illustrates the low yield and the complexity involving the question of penetrance, both of which we think are important for clinicians as they evaluate clinical testing options and potential yields for their patients. Although our cohort is small, the patients and their cardiac defects are reflective of what a clinician would encounter.

These results suggest that our current knowledge of CHD pathogenesis and ability to interpret genomic sequencing is sufficient for finding a genetic diagnosis in a minority of patients when applied to patients with cardiac defects in the NICU and inpatient wards at a large community hospital. Most likely, the lack of identification of candidate variants in the majority of patients reflects the complex etiology of cardiac disorders, which could include multiple genetic, environmental, and other contributing factors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors.

Any queries other than missing content should be directed to the corresponding author for the article. Volume 6 , Issue 2. The full text of this article hosted at iucr. If you do not receive an email within 10 minutes, your email address may not be registered, and you may need to create a new Wiley Online Library account.

If the address matches an existing account you will receive an email with instructions to retrieve your username. Natalie S. Benjamin D. Dale L. Bodian Corresponding Author E-mail address: dale. Tools Request permission Export citation Add to favorites Track citation. Share Give access Share full text access. Share full text access. Please review our Terms and Conditions of Use and check box below to share full-text version of article.

Conclusions These findings suggest that with current knowledge of the proteins underlying CHD, genomic sequencing can identify the underlying genetic etiology in certain patients; however, this technology currently does not have a high enough yield to be of routine clinical use in the screening of pediatric congenital cardiac defects.

MYH6 c. Infant of a diabetic mother. Normal karyotype and microarray a a Quest Diagnostics. NIPBL c.

FOXL1 c. GATA4 c. NODAL c. AG p. MYH7 c.

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RH JAG1 c. GATA6 c. VUS, variant of unknown significance. Eight patients had candidate variants that were also detected in an unaffected parent and are considered variants of uncertain significance because of lack of segregation with phenotype and insufficient literature support for pathogenicity: Patient 1 was found to have the variant c. Abbasi, Y.

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Molecular Genetics and Genomic Medicine , 4 , — PubMed Google Scholar. Google Scholar. Citing Literature. Volume 6 , Issue 2 March Pages References Related Information. Close Figure Viewer. Browse All Figures Return to Figure.