*3.2.3.2. Florescence in situ hybridization (FISH)*

More advanced cytogenetic techniques such as FISH and chromosome microarray are required to diagnose more subtle structural abnormalities, such as microdeletions, tiny duplications and/or subtle translocations. This technology can be used to detect small deletions and duplications in chromosomes that cannot be detected with standard analysis as it looks specifically at the one area of the chromosome. A final FISH analysis will report on how many chromosomes of a certain type are present, in addition confirm suspected rearrangements. FISH technology uses probes of DNA that have been labeled with a fluorescent dye, that bind to complementary parts of a DNA, when it is heated. These probes are able to attach to their complementary DNA sequence [127]. The classic examples that uses this technology is the diagnosis of DiGeorge Syndrome with 22q11 deletion and William Syndrome with 7q11.23 deletion. The drawback of fluorescence in situ hybridization (FISH) lies in its targeted approach to detect chromosomal defects, rather than a genome-wide screening method like microarrays [128].

## *3.2.3.3. Chromosome microarray*

Chromosomal microarray (CMA) testing looks for extra (duplicated) or missing (deleted) chromosomal segments, sometimes called copy number variants (CNVs). It refers to a microchip-based testing platform that allows high-volume, automated analysis of many pieces of DNA at once. CMA chips use labels or probes that bond to specific chromosome regions [129]. The resolution of conventional karyotype analysis is limited to 5 Mb or larger genomic imbalances. Chromosome Microarray Analysis (CMA) is a routine technique in clinical molecular testing nowadays, which contains two types of arrays: oligonucleotide arrays and Single Nucleotide Polymorphism arrays (SNP arrays). Computer analysis is used to compare a patient's genetic material to that of a reference sample. A difference between a patient's DNA and the reference sample is called a variant. These include chromosomal microdeletions and micro-duplications that are too small, abnormalities of chromosome number like the trisomies. In addition other variants include unbalanced rearrangements of chromosome structure such as translocations and triploidies.

treatment option for some inherited disorders. The application of PGD can be used in some conditions present at birth, in addition to prevent carrier states that may or may not present later on in life. Holt-Oram syndrome (HOS) was the first heart disease in which PDG was used successfully [125, 132]. The features of HOS include ASD and cardiac conduction disorder, which has a variable penetrance. Currently there is no treatment prospect as it may manifest later on in life. Clinical manifestations may be extremely variable, and may not be present at birth, or present subtly as a sinus bradycardia, as the only clinical sign. So PGD may provide a treatment option to prevent offspring with this genetic diagnosis [117, 125, 132].

The identification of genetic cause in congenital heart disease can prove to be very beneficial. Firstly is allows for the physician to be confident of the diagnosis and explain the mechanism

syndrome, it allows for the care team to look for other associated anomalies in other organ system. A genetic basis for disease may also necessitate evaluation into other family members [22, 117]. This will help further characterize the extent of the disease in the family and monitor risks and assess ability to pass on to future offspring [117]. Patients and families need to be made aware of both the numeric risk, as in Marfan and William Syndrome, an affected person has a 50% risk. However when the cardiac malformation has variable expressivity, predicting

Since approximately, 75% of congenital heart diseases have no identifiable cause or underlying condition, the notion of formal genetic evaluation may appear unwarranted [123]. However with the development and feasibility of genetic evaluations improving, more and more cardiac malformation are being linked to underlying genetic anomalies. Therefore the need to look for a genetic link become more crucial, as more patient with congenital heart disease live into adult age, it is very important that families understand their recurrence risk [120–122]. Unfortunately genetic counseling is not an integral or compulsory part of the treatment plan for families at many centers. Too many times, parents are exhausted from the complex interventional procedures and surgeries and its subsequent complications, the need for such counseling is forgotten and pushed aside [22, 117]. There are likely to be approximately 400 genes involved in the causation of congenital heart disease, many of which are yet to be identified [119]. Therefore the role of genetic counselors, with specialized skills in cardiovascular genetics is of utmost importance in the adult patient with congenital heart disease. Such genetic counselors play a crucial role in providing accurate recurrence risk, facilitating appropriate genetic testing, interpreting of results and appropriate subspecialty referrals. Phenotypic heterogeneity and incomplete penetrance complicate our understanding of the genesis of congenital heart disease. However it seems more likely than ever that our gaps in understanding the causes of congenital heart disease are primarily genetic and that

When the cardiac malformation is part of a genetic

Congenital Heart Disease: Genetic Aspect and Prenatal and Postnatal Counseling

http://dx.doi.org/10.5772/intechopen.72486

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*3.2.5. Impact on patients and families*

of disease and other prognostic factors.1

severity becomes extremely difficult [118].

the mechanism are multifactorial [117].

**4. Conclusion**

Both the arrays could detect genome-wide CNVs. Moreover, SNP arrays can detect mosaicism, triploid, loss of heterozygosity and uniparental disomy. In 2010, the American College of Medical Genetics issued practice guidelines for CMA, and pointed out that CMA was recommended as a first-tier test for postnatal patients with multiple congenital anomalies, intellectual disabilities/developmental delay (ID/DD) and autism spectrum disorders [127, 129]. Recently, CMA has been successfully applied to detect CNVs in patients with CHD, which confirmed the relationship between chromosome microdeletion/microduplication and CHD [128].

#### *3.2.3.4. Whole exome sequencing*

Whole exome sequencing is part of next-generation sequencing. With this technology, it is now possible to sequence large amounts of DNA that provide genetic code for making proteins, which are called exons. All the exons in a genome are referred to as the exome, hence this method of sequencing them is known as whole exome sequencing, which allows for the identification of variations in the protein-coding region. It is known that most mutations that cause disease states, occur in these regions. Therefore, the use of this technology allows an efficient way to detect possible disease-causing mutations [130]. Whole exome sequencing has been successfully applied to patients with CHD. Many de novo mutations involved in cardiac related genes to the developing heart have been detected. [22, 130, 131]. This finding helped better elucidate understanding of overall CHD and its developmental pathways. However, more research needs to be done to determine a causal relation and best therapeutic interventions in these cohort of patient studied [130].

#### *3.2.4. Preimplantation genetic diagnosis*

In the current era of in vitro fertilization, preimplantation genetic diagnosis is possible. PGD provides chromosomal and mutational analysis of blastocyst that results from in vitro fertilization before implantation [22]. In assisted reproductive technology, PGD is becoming a treatment option for some inherited disorders. The application of PGD can be used in some conditions present at birth, in addition to prevent carrier states that may or may not present later on in life. Holt-Oram syndrome (HOS) was the first heart disease in which PDG was used successfully [125, 132]. The features of HOS include ASD and cardiac conduction disorder, which has a variable penetrance. Currently there is no treatment prospect as it may manifest later on in life. Clinical manifestations may be extremely variable, and may not be present at birth, or present subtly as a sinus bradycardia, as the only clinical sign. So PGD may provide a treatment option to prevent offspring with this genetic diagnosis [117, 125, 132].
