How Did DNA Testing Children Begin?

The story behind the first maternity and used for legal purposes.
This year marks the 20th anniversary of a remarkable discovery which forever changed the legal profession. In 1985, Alec Jeffreys (now Sir Alec), a young genetics professor at Leicester University, discovered DNA fingerprinting--the technique which allows for unambiguous human identification as well as relationship identification between different people. Since then, has emerged as a powerful tool in both civil and criminal justice systems. DNA testing can not only reveal whether two or more individuals are related but can also determine the nature of this relationship. Today, it is possible to identify people by a single hair, as well as obtain information about their gender, ethnic background, and nearly their exact age.


In non-criminal legal practice, DNA testing is used primarily for immigration and child support cases. In 2004, more than 7,000 DNA tests were conducted in the UK for these purposes. When no reliable documentary evidence is available, DNA testing can assist in determining varying degrees of relatedness between individuals, as well as their ethnic background.
The landmark immigration case Sarbah vs. Home Office (1985) was the first to use DNA testing to prove a mother-son relationship between Christiana Sarbah and her son Andrew.
The case started in 1983 when Andrew, then 13, arrived in England after a long stay in Ghana with Christiana's estranged husband. Immigration officials held him at Heathrow Airport, claiming his passport was forged, or that a substitution had been made. Only after intervention by a local MP was Andrew allowed to stay at his family's home in London.



Various genetic-determining tests showed that Christiana and Andrew were almost certainly related; however, it was impossible to determine whether Christiana was his mother or merely an aunt (Christiana has several sisters in Ghana). The photographic evidence and depositions were rejected at an immigration hearing, but deportation was delayed pending an appeal.
Around the same time, an article in The Guardian reported the discovery of DNA fingerprinting by Prof. Alec Jeffreys and his team at the University of Leicester. After reading about their work, the legal team dealing with the case approached Prof. Jeffreys, and he agreed to take on the case. In order to prove that Christiana was Andrew's mother, a DNA test was performed on blood samples from Christiana, Andrew, an unrelated individual, and Christiana's three undisputed children: David, Joyce, and Diana.



Using a recently discovered DNA probe, a DNA fingerprint was produced which confirmed that Christiana was indeed Andrew's biological mother, and that David, Joyce and Diana were his siblings. Based on this evidence, the case was dropped by the Home Office and massive press coverage ensued. The discovery of DNA fingerprinting had huge implication for the non-criminal legal system and led to an overhaul of the UK's Immigration legislation. Current UK immigration legislation accepts results of DNA testing as the ultimate proof or relationship between a child and his or her relatives. Accordingly, DNA test results will normally (although not invariably) provide conclusive evidence as to whether a child is related, as claimed, to one or both of his alleged parents.



Before January 1991, it was up to the applicant to decide whether or not to obtain DNA evidence in support of his or her application or appeal. In January 1991, a government scheme was introduced, which enables entry clearance officers (ECO) to offer to arrange DNA tests in cases where they are not satisfied that persons seeking admission as children are related to their UK sponsor.

Treatment of genetic diseases in a real world 6: Maturity Onset of Diabetes in the young (MODY)

WHAT IS MATURITY-ONSET DIABETES OF THE YOUNG (MODY)?
Maturity-Onset Diabetes of the Young or MODY affects 1-2% of people with diabetes, although it often goes unrecognised.
The 3 main features of MODY are:
Diabetes often develops before the age of 25
Diabetes runs in families from one generation to the next
Diabetes may be treated by diet or tablets and does not always need insulin treatment
WHY DOES MODY RUN IN FAMILIES?
MODY runs in families because of a change in a single gene which is passed on by affected parents to their children. We call this Autosomal Dominant Inheritance. All children of an affected parent with MODY have a 50% chance of inheriting the affected gene and developing MODY themselves.
WHY IS IT IMPORTANT TO RECOGNISE IT?
There are different types of MODY. By finding out which type of MODY a person has the most appropriate treatment for them can be determined.
Knowing the type of MODY a person has also means we can advise them about how their diabetes will progress in the future.
As it runs in families, it is important to advise other family members of their risk of inheriting it.
WHAT DIFFERENT TYPES OF MODY HAVE BEEN IDENTIFIED?
MODY is caused by a change in a single gene. 6 genes have been identified that account for 87% of UK MODY:
HNF1-a
Treatment for patients with HNF1-a
Patients with HNF-1a MODY are extremely sensitive to the blood sugar lowering effects of a group of drugs called sulphonylureas (SU). This is an example of pharmacogenetics in diabetes – a persons genes influencing response to treatment. SUs include drugs like Gliclazide, Glipizide, Glibenclamide, Tolbutamide. SUs work to stimulate the pancreas to produce insulin. Preliminary findings are that SU sensitivity in HNF-1a MODY is due to two factors: Firstly, an increased pancreatic response to SUs, and secondly an increased sensitivity to insulin compared with Type 2 diabetes.
Glucokinase
HNF1-b (including Renal Cysts and Diabetes (RCAD)
HNF4-a
IPF1
Neuro D1
Changes in these different genes lead to different types of MODY. There are still more genes to identify as 13% of MODY is not yet accounted for.
http://www.projects.ex.ac.uk/diabetesgenes/mody/ATHtalk.PPT

Thalassemia is a genetic disorders that are characterized with chronic anemia. The disease is cause from the gene that control hemoglobin production. Hemoglobins are proteins that are the major components of red blood cell. Human carries mutation of thalassemia genes may be asymptomatic or have mild anmia, or severe until they died before birth.
In Thailand, a south east Asian country, there are more than 30 percent having one mutated hemoglobin genes. We call this group as carrier. They will be healthy and asymptomatic, but they can inherited their mutated gene to their offsprings. If their couples are also the same type carriers, their off springs have chance to have mutated genes both from thier parents that will produce diseases. The number of thalassemia patients in Thailad is about 600000.
And each year, couples at risk (both are carriers) give thalassemic baby for more than 10000 annually.
Ther are two common type of thalassemia in Thailand: alpha-thalassemia and beta-thalassemia.
In general, everyone are inherited the genetic materials half from their father and the rest from their mother. Thalassemia is a disease transfered in recessive fashion, which means that you must have mutated genes from both parents to have disease. Besides, the mutation must be on the same gene. For example, alpha-thalassemia gene mutation should pair with alpha-thalassemia gene mutation to produce alpha-thalassemia patients. Who have one mutated gene of beta-type and onother mutated gene of alpha-type are healthy.
Thalassemia is the result of decreasing production of hemoglobin leading to unbalanced between each type of hemoglobin. In normal, two chain of alpha hemoglobin will be paired with two chains of beta hemoglobin. In the non-balancing situation, the excess hemoglobin will be aggregated and cause changing of red cell shape and vulnerability. red cell will be survived less, be easily destroy. These all lead to chronic anemia. Organ that produce red blood cell i.e. bone marrow, liver, and spleen have to be expanded for increasing production rate, so we will see these patients have a big and tall skull, fragile bone, big liver, big spleen. In severe cases, this occured early in thier life, and inevitable cause of death in their toddler. Milder case will be survived to their teen with regular blood transfusion. The drawbcak of blood transfusion is the iron stored in the blood cell will be accumulated in patient's heart, liver, skin, pancreas, and so on lead to malfunction of that organs that are fatal if lefted untreated. Nowadays, in the most severe type that will be dead before birth, we have technology to test the fetus and termination before birth or have complication will be done if test positive. In severe birth infants, we can treated with bone marrow transplantation, but this is a very expensive methods and there is a high death rate from this procedure and not everyone can performed these due to unmatched tissues. Milder case will receive regular blood transfusion to prevent abnormal growth and bone change, and iron-chelator will be given to prevent long term complication for iron-excess. Prevention is more appropriate practice, and prenatal screening method is the one of most success genetic project in our country. In the future , next four or five generation, we will have less thalassemia patients.

Common situation in genetic counseling

Today, a medical student asked me about her relative was pregnant and she found that her baby had thalassemia from the prenatal screening. Her doctor gave her a chance to terminate the pregnancy. This student shown me the genotype: Hb Malay (Mutation at codon 19)/ Hb E. This is called compound heterozygotes, in contrary to double hetrozygotes that have mutation on different genes. To answer this question, we should know about the severity of phenotypes, effect to mother.Fortunately, thalassemia is one of the most common and the most throughly study genetic diseases, so we have some information to cope with that. But genotype-phenotype correlation is not an easy issue, there are many factors beyond the mutation itself to correctly predict that. Like these situations, Hb Maly/Hb E infants are not severe (thalassemia intermedia), but the characteristics are widely range from asymptomatic, need some blood transfusion or more frequent need of blood transfusion until required iron chelating therapy or splenectomy in mid-life. There is no specific curative treatment for this group, while beta thallassemia major is so severe and will be died in first two or three years of life, so high mortality-procedure dependent like bone marrow transplantation is accepted.
So the best recommendation for this situation is give all the informations needed to make a good decision for those counselee i.e. severity of baby, effect for pregnancy, treatment plan for baby, side effect of termination, choices, etc. And let the families making their own decision because they have to know what is the best way for their future life. Don't use our standard, believes, social issues to force or coercion them.

Let's share experience about genetic disorders

This is a story of a families suffered from hereditary non polyposis colon cancer that was left undiagnoses for a long period.
The index patient is a 68 yr old women. She came to thyroid clinic as a regular basis to reevaluate her neck mass that was diagnosis later as benign hyroid nodule for about 2 years. Last time, my resident asked her about her family, and this resident found that this is a very interesting family. She was diagnosed transitional cell carcinoma of left kidneys and was undergone success total nephrectomy for 20 years. She also had undergone hysterectmy (cut out the womb) that was diagnosed benign smooth muscle tumor. Her brother was suffered from small intestinal adenocardinoma in his 40 years. She had 5 offsprings, two males and three females. Her son was healthy, her daughters are diagnosed ovarian cancer and colon cancer each. Left only one daughter in her 40 normal.
So this family had four members suffered from cancers which can be group to fit for hereditary non polyposis colon cancer syndrome, which is a cancer predisposing syndrome. Member who carried the abnormal gene have about 70% risk to developed colon cancer and a substantial risks to develop other tumors such as kidneys, ovaries, small intestines like this family.
The family memebers were arranged to see me. I gave them a new information that they never heard before. Surveillance colonoscopy (only the index patient go for virtual CT colonoscopy), pelvic ultrasound, serum tumor marker screening are recommended for patients and who are at 50% risk to carrier the mutated gene.
Genetic testing of this syndrome is very exhaustive, due to different genes (up to 4 or more) can be the cause of the syndrome, very large gene and many other limited factors, so this genetic test are not adopted as routine practice in our country.
The family member said " We feel that we are lucky to know this information. For more than 20 years, we see our relatives diagnosed with cancer and we cannot do anything. Now we know that genetics play important part and we can surveillance as a regular basis to find it and to manage it promptly. We are happier that we were."

Pain in the back, blood in the urine

Have anyone heard about ADPKD (autosomal dominant polycystic kidney disease), one of the most common genetic disorders in the world?
It is the disease of the kidneys, the pea-shape pairs organs, weight about 10 ounces each, in the back of the body on each side of your backbone. They filter your blood and produce urine to remove waste that we produce every day. They also regulates your blood chemicals and acid-base status. The other functions of them is regulation of blood cell production response to body need, produce active vitamin D for helping in calcium absorption to strengthening your bones. If they are severe damage or nearly loss of their function from any causes, so called kidney failure, you will become weakness, loss of energy, shortness of breath, nausea/vomiting, swelling, and even leading to death if kidney replacement such as dialysis, or kidney transplantation is performed. But if they loss only part of their functions, you may not have any symptoms. The most common causes of kidney failure are diabetes and hypertension, which affect adult and elderly and immune-mediated kidney dieases and ADPKD are the more common causes of kidney failure in teenage or young adults.
ADPKD is a kidney diseases characteristics with multiple, various in sizes, growing in both kidneys. The diseases are inherited from parents in a dominant fashion, that means when only one affected father or mother can produced offsprings with ADPKD ( risk is 50%). The defected gene is in every cells of the child since their birth, but usually cysts are gradual develop in their tens or twenties. The patients may come to medical attention by many presentations such as back pain, blood in urine, hypertension, mass in your belly, infection of urinary tract or accidental finding on other health problem unrelated to the disease.
The cysts will grow until they compress normal kidney tissues and this will lead to kidney failure in their 40s-50s. The patients will died if dialysis, or kidney transplantation is not given in time.
The dianosis can be made by perform the imaging study of the kidneys such as ultraasound or CT in patietns suspected to be ADPKD (previous lists of symptoms and family members affected with the same problems) or in family members of ADPKD. Molecular testing can be performed in some families to diagnosis presymptomatic and precyst formation family members.
Treatment of pain, infection and hypertension may alleviate the symptoms and slow down the groth rate of cysts. Due to its serious complications and they are quite common as high as 1 in 1000 birth, this is one of the most active research area to find the drugs to stop progression of diseases.
And we are nearly at that times to treat genetic diseases with simple drugs.
See more information of ADPKD in PKD foundation websites

Down Syndrome

Introduction
Human cells normally contain 23 pairs of chromosomes. Chromosomes are the parts of body cells that carry inherited information - the characteristics that are passed to you from your mother and father.
A chromosomal disorder means there is a change in the normal number of chromosomes. This can mean that physical and mental development is impaired and can result in learning difficulties and health problems.
Downs Syndrome is the most common chromosomal disorder and one of the most common causes of learning difficulties.
Named after the first person that described it, Dr J L Down, the condition affects one in every 1,000 people. Some are more severely affected than others.
Around 600 babies with Downs Syndrome are born in the UK every year. It occurs in all ethnic groups and affects slightly more boys than girls.
Symptoms
People with Downs Syndrome have lots of different characteristics.
There are thought to be up to 120 features of Downs Syndrome but many children have no more than six or seven of them.
Physical features:

Babies with Downs Syndrome usually weigh less than average at birth and are usually shorter than average as adults.

Children with Downs Syndrome often have a rounded face, with a flat profile (the face looks flat when you view it from the side). The back of the head is slightly flattened (this is called brachycephaly) and the eyes tend to slant upwards.

There are small folds of skin that run vertically between the inner corner of the eye and the bridge of the nose (epicanthic folds) and this can give the impression of crossed eyes (squint). There may be white or yellow speckling around the rim of the iris (coloured part of the eye). These are called Brushfield spots.

Children with Downs Syndrome often have straight, soft hair. As children they may have an extra fold of skin over the back of the neck and as adults, short broad necks.
People with Downs Syndrome often have smaller than average mouths with a bigger than average tongue that may stick out.

The hands may be broad with short fingers; the little finger may only have one joint instead of two and be slightly curved. The feet are often stubby with a wide space between the first and second toes.

Many people with Downs Syndrome have poor muscle tone (hypotonia). This muscular floppiness occurs in the limbs and neck and usually improves with age.

Children with Downs Syndrome learn new skills more slowly than other children and generally develop at a slower rate, meeting their developmental milestones such as walking or talking later. They may progress in stops and starts and may not fully catch up with other children their age. Often, a child with Downs Syndrome will not start to use language until his or her third year and may use some sign language before talking.

With treatment and support, the average life expectancy of someone with Downs Syndrome is about 60 years.

Marfan Syndrome

[Compiled by GenePool] [May 2006] [ Author : June-Anne Gold- Specialist Registrar Clinical Genetics]
The Least You Need to Know
1.It can present at any age – (rarely as a severe neonatal form.)
2.Any one of the systems may make you think of the diagnosis. o Eyes- myopia/lens dislocation/detached retinao Heart- dilatation, dissection or rupture of the aortao Lungs- spontaneous pneumothorax.o Skeleton- tall and thin, long limbs and fingers and toes, spinal curvature.
3.Sudden early death due to cardiac cause in family history.
4.Definitive diagnosis may be made by a cardiologist, but referral to a clinical genetics centre is advisable in order to counsel the whole family.

Mother aged more than 35

Is is safe to be pregnant after 35?
While advances in medical care can help women over age 35 have safer pregnancies than in the past, health complications for this age group are higher than for younger women. If you have decided to delay having a child, you should understand the risks associated with this so you can take precautions to minimize risks and improve your chances for a healthy pregnancy and child.


Do I Have a Greater Risk of Having a Child With a Birth Defect if I'm Over 35?
The risk of giving birth to a child with a birth defect does increase as the mother's age increases. This is probably due to abnormal division of the egg, called nondisjunction. The traditional age at which a woman is considered to be at high risk for chromosomal abnormalities is 35. Approximately 1 in 1,400 babies born from women in their 20's have Down syndrome; it increases to 1 in 100 babies born with Down syndrome from women in their 40's.

Benefits, limitations and risks of genetic testing

Benefits
1. test results may lead to institution of timely and effective treatment or management.
2. test results may predict disease rognosis
3. test results may influence personal and reproductive decision-making
4. testing can predict eventual disease in the absence of disease symptoms
5. psychological benefits
. ability to btain societal benefits or support after confirmation of a diagnosis

Limitation
1. There may be no clinical test available
2. There may be no interventions to treat or prevent the condition
3. testing may be available at only few select labs or genetic centers
4. test interpretation may depend on other family members being tested.
5. some conditions are caused by many different mutations in a single gene (allelic heterogeneity), not all of which are detected by a particular test
6. There is the possibility that a given condition is caused by mutations in more than one gene (locus heterogeneity).
7. A negative test result does not necessarily eliminate the disorder in the differential diagnosis
8. A postive test result does not guarantee that the patient will develop the condition.
9.testing may yield indeterminate rsults
10. Tests or screens may have low sensitivity or specificity.

Risks
1. Test result may identify other at-risk family members without their consent.
2. Test results ay affect family integrity, dynamics and relationships
3. Testing can predict eventual disease in the absence of disease symptoms.
4. Testing may yield indeterminate results.
5. Genetic information is potentially stigmatization
6. Genetic information can potentially lead to discrimination.
7. Test results may cause psychological effects, including anger guilt, decreased self-worth or depression.

What is the genetic test?

A genetic test is a test that involves the analysis of chromosomes, genes and/or gene products (e.g. proteins or enzymes) to determine whether a genetic alteration related to a specific disease or condition is present.



(Secretary's Advisory Committee on Genetic Testing, 2002.)



What is the difference between genetic screening and genetic testing?
Genetic screening is used when your patient:
-Has no signs or symptoms
-Has no clinically significant family history
-Belongs to a certain population (such as a racial or ethnic group) that may be at greater risk for certain disorders or traits.
Genetic screening is not diagnostic; further testing is needed to confirm, make or predict the diagnosis of a condition. Examples of genetic screening are: newborn screening for phenylketonuria and carrier screening for Tay-Sachs disease and (although not currently the standard of care) population screening for hereditary hemochromatosis.



Genetic testing is used when your patient has:
-Clinically significant signs and/or symptoms
-A clinically significant family history
-Positive genetic screen results
Genetic testing can diagnose or predict the likelihood of a genetic condition. Examples of genetic testing are: diagnostic testing for Fragile X syndrome in a child with mental retardation, prenatal diagnostic testing for Down syndrome by amniocentesis, and presymptomatic testing for Huntington disease in an individual with a family history of HD.

Genetic Testing

Genetic Testing
1. Biochemical Testing - metabolites
2. Molecular Testing - DNA, RNA
3. Cytogenetic Testing - chromosome
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