Following are the important points which should be considered by the every medical practitioner.
1. For Taking a Family History:
(i) If a person is seeking medical advice about a specific problem, ask specifically whether relatives have a similar problem.
(ii) When asking about brothers and sisters, inquire whether there was ever a sibling who has died, some people will only remember to mention their living sibs.
(iii) Inquire about neonatal deaths and miscarriages.
(iv) Be alert to sib ships in which not all sibs share the same two parents and to adopted sibs.
(v) Ask about consanguinity.
(vi) Ask about the ethnic origin of different branches of the family.
(vii) Where possible, try to obtain documentation (i.e., medical records) for important points of family history; often family members will conclude that a relative has a disorder believed to “run in the family” based on superficial information that may be inaccurate.
2. For Linkage based Molecular Diagnosis:
(i) Linkage testing requires a family study.
(ii) Multiple family members must be available and willing to provide samples for DNA testing, even if they themselves will not directly benefit.
(iii) It is necessary to have at least one affected family members available for testing.
(iv) Polymorphic gene loci must be mapped near the disease locus of interest.
(v) Not all families will be “informative” for a given set of polymorphic “marker” genes.
(vi) Linkage testing therefore should be initiated well in advance of anticipated diagnostic use.
(vii) Genetic recombination can lead to incorrect diagnoses.
(viii) Genetic heterogeneity, in which mutations in various different gene loci can yield the same phenotype, can lead to diagnostic errors.
(ix) The possibility of genetic heterogeneity must therefore be considered in providing genetic counseling.
3. For Chromosomal Analysis:
(i) Clinical features suggestive of syndrome known to be associated with chromosomal anomaly.
(ii) Presence of two or more congenital malformations not corresponding with known single gene disorder.
(iii) Impairment of cognitive development along with.
(a) One of more congenital anomalies.
(b) Distinctive abnormal physical features.
(c) History of two or more first trimester miscarriages in mother.
(4) Couple with two or more first trimester miscarriages.
4. For Source of Tissue Sample for Genetic Analysis:
(i) The standard tissue for cytogenetic analysis is the peripheral blood.
(ii) Cultured skin fibroblasts can also be analysed (becaused some abnormal mosaic karyotypes are found in skin cells but not lymphocytes).
5. For Counseling of Multifactorial Disorders:
(i) The possibility of an underlying single gene or chromosomal disorder must be considered.
(ii) Recurrence risks represent averages. Actual risks may differ in different populations. Also in a given family, the actual risk may be substantially higher or lower than this average.
(iii) Recurrence risk increases with proximity of relationship with the pro-band and with the number of affected individuals in the family.
(iv) There may be gender differences in risks.
6. For Mitochondrial Disorders:
(i) Either nuclear or mitochondrial genes may give rise to disorders of energy metabolism, and both autosomal and maternal inheritance patterns must be considered.
(ii) Look for examples of mild expression of a disorder of energy metabolism in the family history, including early onset sensorineural hearing loss, migraine headaches and unexplained dementia or epilepsy.
(iii) A mitochondrial mutation will be passed to all of the offspring of a carrier female; however it is impossible to predict levels of severity in an offspring; some may be severely affected and others not visibly affected at all.
(iv) When performing testing for a mitochondrial DNA mutation it is often necessary to sample multiple tissues, since heteroplasmy may result in some tissues having little or no representation of mutant mitochondria.
7. For Common Malignancies:
(i) Physicians need to be vigilant for signs in the family history that indicate an increased risk.
(ii) Three or more first or second degree relatives affected on the same side of the family.
(iii) Young age of onset in one relative (< 45 years of age).
(iv) Known family history of a predisposing mutation.
(v) Relative with multiple primary tumours.
(vi) The benefits of surveillance techniques such as colonoscopy or mammography in reducing the risks of cancer and improving out-comes have not been firmly established.
(vii) Even extreme measures, such as mastectomy, do not guarantee full protection, since other tissues may also be targets of tumour suppressor gene, such as ovaries.
(viii) Psychological harm may result from testing, as well as risks of being denied insurance of employment.
(ix) In general, children should not be screened for late-onset disorders unless clear and immediate medical benefits can be anticipated.
[It has become clear that a significant proportion of more common malignancies are also due to the action of tumor suppressor genes]
8. For Developmental Abnormality:
Major classes of developmental anomalies are:
(i) Malformations:
It is the result of abnormal development of tissues. Developmental mechanisms somehow are interfered with, and the tissue does not form properly.
(ii) Deformations:
It is defined as the distortion of a normally formed tissue by extrinsic pressure. An example is asymmetry of the skull due to pressure from a benign uterine tumor called a fibroid.
(iii) Disruptions:
It is damage of a normally formed tissue. For example, a tear in the amniotic cavity can trap a limb, amputating part of the extremity.
[It is interesting to note that disruptions tend to be asymmetric whereas malformations are more often but not always symmetric.]
It should be remembered that of the three above mentioned developmental anomalies, the most important is the malformations because various types of malformations are seen.
It can be classified into following three major class:
(i) Syndromes:
These are the sets of congenital defects that are the consequence of some defined ultimate cause, e.g. Down Syndrome. Syndromes can result from chromosomal defeats, from exposure to teratogenic agents during the time of pregnancy, etc.
(ii) Sequence:
It is generally arises as the consequence of a single primary event, for example underdevelopment of lower jaw causing other anomalies (like cleft palate) that comprise the sequence are secondary effects of the primary malformations. It is known as Pierre-Robin sequence in developmental biology.
(iii) Associations:
It has been observed that particular sets of congenital anomalies tend to occur together more often than expected due to chance. The causes are unknown but probably due to many associations of heterogeneous nature.
9. For Carrier Screening:
If offers an opportunity to identify couples at risk before this time, allowing them to use following information in their planning:
(i) Choosing not have children
(ii) Artificial insemination or egg donation
(iii) Prenatal diagnosis and termination of affected pregnancy
(iv) Prenatal diagnosis and planning for care of the affected child.
Screening options are tailored to the disorders for which members of a couple are at risk. Following are the carrier frequency in different ethnic groups.