Genetic testing

Def: Genetic testing identifies changes in chromosomes, genes, or proteins.

Importance:  can confirm or rule out a suspected genetic condition or help determine a person’s chance of developing or passing on a genetic disorder.

More than 1,000 genetic tests are currently in use, and more are being developed.

Knowledge of the test result could lead to emotional and social problems in the child, altering both relationships within a family and expectation for the future in a variety of areas such as education, employment, and relationships.

For many types of genetic analysis, a negative test result must be interpreted with caution in case it is a false negative, i.e a genetic abnormality is actually present but was not detected by the test.

Pathological significance of detected genetic alteration may be unclear due to missense mutation and variable expression.

When preforming genetic testing, it is important to be aware that the diagnosis of a genetic disease will not only have implications for the affected individual but may have ramifications for the other family members, who may be at risk of being affected or of being carriers for the condition.

Several methods can be used for genetic testing:

·       Molecular genetic tests (or gene tests): study single genes or short lengths of DNA to identify variations or mutations that lead to a genetic disorder, it depends on base sequences on chromosome.

ü  Southern blot analysis

ü  The polymerase chain reaction (PCR)

ü  DNA sequencing

ü  Next generation sequencing (NextGen).

·       Cytogenetics: concerned with how the chromosomes relate to cell behavior, particularly to their behavior during mitosis and meiosis include: Karyotyping

·       Molecular cytogenetics: involves the combination of molecular biology and cytogenetics

ü  Fluorescent in situ hybridization (FISH)

ü Comparative genomic hybridization (CGH).

ü Array comparative genomic hybridization (also microarray-based comparative genomic hybridization, matrix CGH, array CGH, aCGH)

·       Biochemical genetic tests study the amount or activity level of proteins; abnormalities in either can indicate changes to the DNA that result in a genetic disorder.

The chromosomes could be sampled from:

˗   Peripheral blood lymphocytes                                     - Bone marrow cells

˗   Skin fibroblast                                                              - Solid tissue cells

˗   Amniotic fluid cells

Medical applications (indications of genetic testing, karyotyping, chromosomal culture, analysis) :

1.     Multiple congenital anomalies:

Birth defects > one developmental regions of the body

A.    Confirmation of a clinical diagnosis

B.    Estimate recurrence risk of future sibling

2.     Dysmorphic features or well-defined syndrome e.g down syndrome

3.     Unexplained Mental retardation (chromosomal abnormalities are responsible for 1/3  50% of MR which is due to genetic factor)   

4.     Pubertal failure

5.     Ambiguous genitalia

Provide diagnosis e.g turner, klinfilter

If Normal karyotyping → other endocrinal disorders

6.     Infertility: at least 5% of infertile men are killfilter.

7.     Recurrent spontaneous Abortions and miscarriage:

≥ 2 spontaneous abortions

At least 15% of all pregnancies end in spontaneous miscarriage

50% of these cases is due to chromosomal abnormalities of which

ü  >50% → due to autosomal trisomies e.g 22 , 16

ü  20% → due to Turner

ü  20% → due to Triploidy , tetraploidy         

ü  10% → Others

8.     Unexplained stillbirths:

ü Chromosomal abnormalities account for 5% of all stillbirth & 5% of neonatal death.

ü Trisomy 18 is the most common abnormality in still birth.

9.     primary amenorrhea

10. Short stature of unknown cause

11. Parents of individuals with chromosomal abnormalities

12. Prenatal diagnosis

13. Malignancy &chromosomal breakage syndromes:

Certain types of malignancy e.g leukemia, retinoblastoma, wilms tumour are associated with specific chromosomal abnormalities. 

Not done for well-defined syndrome caused by something other than chromosomal abnormalities e.g rubella syndrome.

Genetic tests can be thought of as diagnostic, predictive or for carrier status. Informed verbal, and increasingly written, consent (or assent) should be obtained before genetic testing.

Predictive (Presymptomatic) testing:

Children may be referred because they are at increased risk of developing a genetic disorder in childhood or adult life (i.e the individual is clinically normal now).

n  If the condition is likely to manifest in childhood (e.g. Duchenne muscular dystrophy) or if there are useful medical interventions available in childhood (e.g. screening by colonoscopy for colorectal tumours in children at risk of familial adenomatosis polyposis coli), then genetic testing is appropriate in childhood.

n  If the child is at risk of a late-onset and untreatable disorder (e.g. Huntington disease), then deferring genetic testing until the child becomes an adult, or at least sufficiently mature to be actively involved in seeking the test and can make the decision for himself/herself, is usually preferred.

n  If the child is not at risk of developing the condition but may be a carrier at risk of transmitting the disorder to their future children, then there is also a good case for deferring testing until the young person can participate actively in the decision. There may be less at stake with these reproductive carrier tests than with predictive tests for untreatable disorders, but there are still good grounds for caution and for careful discussion before proceeding with such tests.

These difficult issues are often best handled through a process of genetic counselling supporting open and sustained communication within the family and especially between parents and children.

Predictive testing is not usually offered without a formal process of genetic counselling over more than one consultation with time built in for reflection. Written consent for predictive testing is required by most laboratories.

So, Presymptomatic testing of disorders which manifest in adult life should not be performed until the individual can consent on their own behalf unless there is clear clinical benefit from testing earlier.