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Major Diseases Performed in Molecular Testing

Major Diseases Performed in Molecular Testing


It is the procedure to perform a test to increase pregnancy success by taking cells from embryo for aneuploidy screening. The PGT procedure is mostly used for the detection of single gene diseases (PGT-M: Preimplantation Genetic Test for Monogenic Diseases) or for the selection of the segregation product embryos due to balanced translocation carrier (PGT-SC: Preimplantation Genetic Test for Structural Chromosomal Abnormalities). Currently, it is recommended that both the PGT-M application and the pregnancies that will occur following PGT-A applications should be confirmed by one of the prenatal diagnostic methods (Amniocentesis or CVS).


Preimplantation genetic diagnosis applications require cell biopsy from oocyte or embryo. Polar body biopsy is performed to remove 1st and 2nd polar bodies consecutively from the egg after oocyte collection. Embryo biopsy is performed as blastomer cell biopsy on the 3rd day or trophectoderm cell biopsy on the 5th day. The first polar body is a small, non-functional cell containing a nuclear material that is the product of the first meiosis division. Since chromosome pairs are separated in the first meiosis, mutations go to the polar body and egg separately. Thus, when tested if the mutation is detected in the polar body it is understood that the oocyte is normal. In other words, polar body test provides an indirect diagnostic mechanism for oocyte. As it can be understood it only provides maternal genetic information and is used for X-linked conditions. Polar body biopsy and testing for aneuploidy screening (PGT-A) can be used for maternal age reasons or for the detection of segregation pathogens in maternal translocation carriers. It is an important limitation that it does not provide paternal information and is limited only to maternal conditions.

The biggest advantage of this method is that it enables the transfer of fresh embryos in the same cycle (usually on the 5th day). Among the weaknesses of the third day biopsy it can be listed as the high “allele drop out (ADO) rate”, high “mosaicism rate” and “lack of information about mosaicism” resulting from the use of minimal genetic material (a single cell). Also, comparative data obtained in recent years have revealed that the 3rd day biopsy is more likely to damage the embryo than the 5th day biopsy (trophectoderm biopsy) or negatively affect the implantation rate.

Day 5 (blastocyst) biopsy is beeing preferred more recently. At this stage there is a large number of cells, some of which are the inner cell mass ICM that will form the baby, and some are trophectoderm cells that will form the amniotic sac and placenta. The fact that the trophectoderm biopsy has a minimal potential damage the embryo provides this method to become more widely used. However, in this method, it is compulsory to freeze the embryo before transfer, considering that there is not enough time for post-biopsy testing and the endometrial implantation window ends. In this way, quite high pregnancy rates are achieved with freezed cycles. On the other hand, which biopsy method to choose should be determined by taking the opinion of the genetic laboratory according to the purpose of the test.



It is a method applied in both single gene diseases and chromosomal balanced carriers. When a parent has a chromosomal specific carrier PGT is safe and widely used for spouses to have a balanced  and healthy baby. Apart from chromosomal conditions, single gene disease carrier

(such as cystic fibrosis, SMA, Huntington, Marfan Syndrome, DMD, Hemophilia) is a common area to PGT usage. Undoubtedly, prenatal diagnosis with CVS or amniocentesis is an option for these spouses but PGT has taken its place as the first choice for risky spouses in today's medicine because of protecting them from medical abortion.

On the other hand, PGT methods can also be used for deletions such as translocations, duplications or some new gene arrangements (eg 22q 11.2 deletion, Angelman and Pradervilli Syndrome). In some cancer cases, PGT application is becoming widespread (in the presence of a mutation associated with family cancers such as Fankoni aplastic anemia, breast or colon). However, PGT cannot be applied for multifactorial conditions such as autism or autosomal diseases. It is possible to perform PGT for autism or autosomal conditions with known mutation; For example, when investigating Autism, Fragile X, Rett Syndrome or a metabolic disease can be detected, and in this case PGT for the detected mutation can be performed.



Some “preliminary preparations”, which are indispensable before PGT should be made. Preliminary preparations include detection of the disease-causing mutation and verification of this mutation in parents or other family members.

Work flow chart of PGT process

As the IVF procedure will be applied to the spouses that require PGT they should be informed about this issue and whether it is suitable for treatment simultaneously and whether there are any obstacles (such as over-uterine factors and spermatogenesis) should be revealed. Then mutation studies and informative marker analyzes should be completed by taking DNA samples from spouses and other family members.

These steps do not need to be done in the case of chromosomal diseases (eg balanced translocation carriage). In such diseases, PGT is performed directly at the embryo stage. The only exception to this is when some microdeletion diseases and a very small piece of chromosome are translocated. In such cases, it is necessary to test the somatic cells before PGT and make sure that the resolution of the applied method can cover the microdeletion or small part that is translocated. If it does not cover or its resolution is not sufficient, the method can be changed, for example, a specific probe and FISH method can be used, or patient-specific PCR designs can be made with molecular methods.

As a requirement of the flow chart of IVF procedures,many eggs are collected from the female partner with the “Controlled Ovarian Hyperstimulation” treatment, and these eggs are fertilized simultaneously with the sperm taken from the male and ICSI. Depending on preference of developing embryos, 3-6. Between days, one or more cells are taken by biopsy and the PGT test is performed. As a result of the tests, which embryos are healthy and which are sick or unbalanced are transferred to the mother of healthy embryos. Increasing healthy embryos are stored by freezing.


The most important stage of the process for the preimplantation genetic diagnosis of single gene diseases is DNA replication (DNA amplification) that is taken by embryo biopsy. This can be done in two ways: "Whole Genome Amplification-WGA" and "Multiplex PCR Amplification" of the Target Region of DNA. For both amplification methods there is the possibility of ADO, which leads to misdiagnosis. However, this possibility is somewhat higher when the biopsy is performed on the 3rd day instead of the 5th day or when WGA is performed instead of PCR amplification of the target region. It is best to see this in the chart below. As can be seen from the graphic, the ADO ratio is higher in blastomer biopsies than trophectoderm and again higher than multiplex nested PCR (lysis) options in all genome amplifications (Figure 30).

In the pre-test amplification of DNA, some regions may be more amplified selectively than others. This is called selective amplification (PA-Preferential Amplification).

We use “informative marker analysis” within our modern genetic applications to eliminate the potential for misdiagnosis such as ADO, PA or foreign DNA contamination. Thanks to this method, which is a kind of mini fingerprint analysis, we can select healthy embryos not only by mutation analysis but by including more than one control region. The use of polymorphic microsatellite STRs selected from the locations adjacent to the mutation site is a kind of "Fingerprint haplotype analysis" and increases the test reliability.

Although performing ICSI instead of classical IVF also reduces the possibility of erroneous diagnosis by preventing sperm DNA contamination, the STR analysis mentioned above is seen as the most effective way to keep risks under control. Recently, SNP analysis has been used instead of STR markers. With this method, practical and reliable PGT applications can be made.

The PGT procedure for single gene diseases is a very different and specific application compared to other genetic diagnostic tests. In order to perform this test reliably and effectively, a certain algorithm must be followed.

PGT applications for single gene diseases are carried out by STR analysis using polymorphic microsatellite markers adjacent to disease-causing mutations. The analysis of STRs designed adjacent to the mutation or identified, known mutations that are intended to be investigated provides almost happrint type information. By including the samples taken from spouses and other family members, it is possible to follow the disease-causing mutations and to select suitable healthy embryos.

A new technology related to PGT applications is “Karyomapping”. With this method, screening for both targeted mutation and simultaneous chromosomal aneuploidies can be performed. In this method, by using high amount of SNP (Single Nucleotide Polymorphism), the distribution of mutant and normal alleles (knowledge of which embryo and how segregated) on the one hand, and quantitative of all genome length SNPs on the other analysis, it is possible to detect aneuploidies, segmental deletions and duplications. An advantage of the caryomapping method is that there is no need for patient-specific design and preliminary preparation, so that the PGT procedure can be started in a short time. However, the most important handicap of this method is that it cannot be used in fresh mutations in cases where there are no informal index people in the family and in co-relatives.



PGT procedures for spouses (translocation, inversion carriers, etc.) with balanced chromosomal carriage. The application for aneuploidy screening is called PGT-A (preimplantation genetic diagnosis-aneuploidy screening) and will be examined in the next section.

A balanced translocation carrier expects a spouse 3 risks:

  1. Miscarriage
  2. Birth of abnormal baby
  3. Infertility


Balanced translocation carrier is the most important danger for spouses, gametes carrying segregation product in unbalanced structure. Embryos that will consist of these gametes result in either miscarriage or a baby with genetic anomaly. Infertility caused by chromosomal new formation is not only due to irregularities of sex chromosomes (such as XXY-Klineferter Syndrome and XO-Turner Syndrome). Translocations and even polymorphisms of autosome chromosomes can also cause infertility (azoospermia or ovarian reserve deficiencies). The most important reason for this is that structural balanced changes of chromosomes block meiosis division. For reciprocal or Robertsonian translocation carriers, the unbalanced gamet formation rate is 66%. So theoretically, 4 out of every 6 gametes are unbalanced and 2 are balanced. However, practical risks differ according to gender and chromosomes involved in translocation. For example, in couples where the male partner is a translocation carrier, the chance of a balanced embryo is higher than the couples that the

female partner is a carrier. Given the unbalanced gamet rates, performing PGT for balanced translocation carriage provides dramatic benefits for patients. Several different technologies can be used for PGT applications for translocation purposes. The oldest of these is the FISH administration. Others are aCGH and NGS technologies. Which method will be more suitable for the patient depends on the translocation, the patient and the characteristics of the embryos. For example, when a very small region is translocated, the resolution of NGS or aCGH may not be sufficient to detect this. In this case, there may be a possibility of skipping microdeletions or duplications.


In the case of such a risk, the FISH method using subtelomeric probes should be preferred instead of NGS or aCGH. If the number of embryos is low or the quality is low or if there are embryos that cannot go to the blastocyst the 3rd day biopsy and FISH method can be preferred. On the other hand, NGS or aCGH methods are very advantageous in PGT applications for translocation. Because these methods allow us to control not only the chromosomes involved in translocation, but all chromosomes. Thus, while catching unbalanced segregation products secondary to balanced translocation in parents, we can also detect aneuploidies that may be present in other chromosomes.


An increase in aneuploidy of other chromosomes (interchromosomal effect) is reported in translocation carriers. Therefore, using these methods increases the success even more. Another issue that NGS and aCGH methods are advantageous is that their effects on pregnancy success are higher than FISH method. As is known, a Flastomer cell is fixed in FISH analysis and allows analysis only if this nucleus is intact and regular FISH signals are received. Therefore, FISH analysis cannot be performed in cases where the nucleus breaks down and the integrity of the nucleoma is impaired. In PGT result reports, we frequently encounter these situations as “anucleolar” or “nucleus-cell not observed” and so on. However, since we target DNA within blastomer or trophecdermerm cells in NGS and aCGH methods, we naturally replicate DNA (WGA = Whole Genomic Amplification) and perform analysis by exploding the cell and nucleus. The rate of achieving results in these methods is much higher than the FISH method. A variety of methods used for PGT-A purposes.


Another advantage of NGS method in aneuploidy screening is that its potential to capture mosaics is far superior to other methods. Monitoring the mosaicism has gained great importance in aneuploidy screening and increasing the success of IVF. In recent years, the spread of blastocyst biopsy and the strengthening of analysis programs have shown that post-zygotic abnormalities and mosaicism are present at very high rates in the embryo. According to some studies, mosaicism rate in embryos is at least as high as the frequency of meiotic aneuploidy.



Alzheimer's Disease

Alzheimer's Disease (AH) is divided into two groups such as early and late onset, About 5% of AH patients were diagnosed with early-onset AH. A great majority of early-onset AH cases have taken the disease from their families as an autosomal dominant genetic mutation. In these cases, the probability of first-degree relatives of individuals with confirmed autosomal dominant AD is 50%. Individuals with this mutation have a very high risk of being diagnosed with AD at a young age. However, it should be noted that this form of AH is very rare and represents only a small proportion of all AH cases.

In addition to autosomal dominant AH which does not conform to any heredity pattern but is observed in other family members in the family history  constitutes approximately 15-25% of AH cases. This type of Alzheimer APOE is frequently observed in those with a susceptibility gene. This type of disease is mostly associated with late-onset AH. Putting aside the APOE test, the risk of the average individual to diagnose AH is 10-12%, while if a first-degree relative is diagnosed with AH, this risk increases up to 15-39%. The remaining 70-80% of the cases of AH are thought to have been sporadic, that is, without a family history. However, although family history is an important factor, studies show that cardiovascular risk factors (such as smoking, obesity, diabetes, high cholesterol and blood pressure) are important risk factors for AD. Another finding of the studies is that engaging in social and cognitive activities reduces the risk of AH and other types of dementia.



Autism and Autism Spectrum Disorders (ASD) are diseases with a complex etiology. Genetic causes include chromosomal disorders, microduplications, deletions and single gene disorders. The origin of the disease is unknown in 75% of cases. In order to determine the risk of a couple having a child with ASD in the most accurate way, it is recommended to investigate which of the possible causes of ASD, and to make the necessary genetic evaluation and to make risk calculations based on these findings. Attention Deficit and Hyperactivity Disorder (ADHD)

Attention Deficit Disorder (ADD) and Attention Deficit and Hyperactivity Disorder (ADHD) are considered as complex diseases caused by a combination of multiple genes and other non-genetic factors acting together. The relatives of patients diagnosed with ADD/ADHD due to the genetic components of ADD/ADHD, which affects approximately 3-7 % of the population, are also at higher risk of developing the same disorder. In first-degree relatives, this risk is approximately five times that of the population.


Autoimmune Diseases

Autoimmune diseases are those in which both genetic and environmental factors play a role. When an autoimmune disease occurs in a person in the family, the same or different autoimmune disease may occur in other individuals.

Cleft Lip and / or Palate

Cleft lip and cleft palate are congenital disorders that can occur together or independently. In the general population, the risk of both being together is 0.1 %, and the risk of having only the cleft is 0.04 %. If there is a cleft lip / palate presence in one sibling, the risk of this recurrence in the other sibling is 2.5-5 %. Spouses' relatives have a negative effect on the increase of this risk.

Low Foot

Low foot is a birth defect that can occur alone or as part of a genetic syndrome.


Congenital Heart Diseases

There are several types of congenital heart diseases that can manifest themselves alone or as part of another syndrome.

Epilepsy / Seizure

In general, if an individual has idiopathic general epilepsy, the risk of that person's child having clinical epileptic seizures by the age of 20 is cumulatively about 4 %.


Some sources state that 1-2 out of 1000 babies born are born with hydrocephalus. Most of them are sporadic cases. A relatively common genetic cause of hydrocephalus is "X-linked recessive Hydrocephalus". Naturally, the incidence is higher in boys and girls are carriers.

Neural Tube Defects

The most common neural tube defects (NTD) are Spina Bifida School, Spina Bifida Cystica, Encephalocele, Inencephaly, and Anencephaly. NTDs are mostly isolated and are often associated with low folic acid intake by the mother. The risk of NTD in the general population is 0.1 %.

Parkinson's Disease

Parkinson's Disease (PH) can be examined in three categories; childhood type (before the age of 20), early onset (between the ages of 20 and 50) and late onset (after the age of 50). Child-type and early-onset PH is much less rare than late-onset, often based on a specific genetic cause. Among the genetic forms of PH, there are autosomal dominant and autosomal recessive inheritance types. Depending on the heredity pattern, the risk of disease migration will vary. Late-onset PH is a multifactorial disease. Studies show that someone with a late-onset PH also has an increased risk in their first-degree relatives, and the risk of this occurrence is between 3 % and 7 % for life.

Psychiatric Disorders

Psychiatric diseases are complex disorders related to both multiple genes and non-gene factors. In general, families with a history of psychiatric illness have a greater risk of developing the same or a different psychiatric disorder than the general population. Today, unfortunately, there are no genetic tests or prenatal diagnostic methods that we can use to predict the course and severity of psychiatric diseases.


We call diseases less than 1/2000 of which are rare diseases, of which 80 % are based on genetic basis. February 28 runs the world declared as rare diseases day. More than 300.000 people and more than 6 million in our country suffer from one or more of the rare diseases.

The main common findings of rare diseases include physical and motor developmental retardation, mental retardation, sensory examination, dysmorphological findings and other important findings. Children are rare in 50 % of these diseases, and in 35 % of first-year child deaths, the cause is rare diseases.

It is very important to make detailed inquiries for the detection of rare diseases and the necessary of our road map, to draw up an anamnesis and family tree. Queries of your data are exemplary:

Is there an individual in your family with an innate disorder (such as a hole heart, cleft lip / palate, extra fingers)? What kind of disorder, if any? Did that individual have another view? Does that individual have mental problems? Has anyone in your family recurrent miscarriages?

Miscarriages occurred in the week of pregnancy? Have genetic tests or autopsy been performed on the low material? If so, was there a genetic cause of miscarriage? Does the individual have children? How many? Are they healthy?

Has anyone in your family given birth? How many? How many weeks of pregnancy did the birth occur? Have genetic tests been performed on the fetus? Is there any genetic cause for death detected? Does the individual have a baby born alive? How many, if any? Are they healthy?

Has anybody lost their child at an early age in your family? How many and how old are they? Is the cause of death determined? Did the child have a serious health problem?

Are there individuals in your family who are blind or have vision loss? When did it start? Was it a progressive loss of vision, how fast was it? How serious is the vision defect right now? Does the individual have other complaints (such as hearing loss)? If vision loss started at a young age (<40 years), was there a genetic test? What were the results? Does this individual have a brother / siblings? Are there any other affected among them? If any, is the vision loss similar? Are there any other relatives affected?

Are there any individuals who are deaf or have hearing loss in your family? Was hearing loss, if any, congenital or did it occur later? Has hearing loss progressed? Was it fast or slow? What is the level of hearing loss now? Does this individual use hearing aids?

Can he read lips or use sign language? Does this individual have other problems such as vision loss, heart problems, heterochromia (two eyes having different colors), kidney diseases? If hearing loss was congenital or early-onset (<20 years), was any genetic testing performed?

Was there a conclusion? Does this individual have a brother / siblings? Are there any hearing loss from siblings? Is hearing loss similar if any? Are there any other relatives affected?

Are there any individuals with mental disabilities or difficulties in learning in your family? How advanced is the learning disability, if any ?, Has he been educated in a private class / institution? Is there a job he is working for?

Is there an individual in your family who has epileptic seizures, a defined epilepsy disorder? How old did he have his first seizure, if any? Did the individual's seizures continue? Has he used any medication to prevent seizures? Has the cause of seizures been found? Is there a history of head trauma?

Is there any history of muscle disease in your family (diagnosed with muscular dystrophy, having to use a wheelchair at an early age, etc.)? Is there a history of injury / accident, if any? When did the symptoms start? How long was the process from the walkable situation to the need for a wheelchair? Is there a particular diagnosis made? Have any genetic tests been performed? Does the individual have a brother? If they are healthy? Are there any other relatives in this situation?

Are there any skeletal problems in your family (congenital structural skeletal disorder, multiple fractures, etc.)? When did symptoms start, if any? Is there a history of accident / injury? Have any genetic tests been performed? Are there any other relatives in this situation? Does the individual have a brother? Is it healthy?

Is there someone in your family with hypermobility / hyperflexibility in your joints and skin, with heart valve problems? Are their limbs in length proportional to their body? Does the person have a retinal rupture or myopia history? Is the person's skin soft and / or pale? Does the person bruise / bleed easily? or does it have unusual wounds? Is there a history of scoliosis or flatfoot? Does the person have a shoemaker or pigeon breast? Is there a pneumothorax or mitral valve prolapse? Are there other family members with similar problems? Is there anyone in the family who died suddenly or unexpectedly?

Is there someone in your family diagnosed with cancer at a young age (<50 years)? What cancer, if any, and how old? Are there any other relatives affected in the upper generations? What kind of cancer, if any, and how old? Has a genetic test been performed in any of the affected relatives?

Is there anyone in your family with hypermobility / hyperflexibility in your joints and skin, with heart valve problems? Are their limbs in length proportional to their body? Does the person have a retinal rupture or myopia history? Is the person's skin soft and / or pale? Does the person bruise / bleed easily? or does it have unusual wounds? Is there a history of scoliosis or flatfoot? Does the person have a shoemaker or pigeon breast? Is there a pneumothorax or mitral valve prolapse? Are there other family members with similar problems? Is there anyone in the family who died suddenly or unexpectedly?


After all these inquiries, it is necessary to choose the right test for the sick person or related family members. Test results may require another additional test, or retest some of the family members.


Alpha Thalassemia

Alpha thalassemia is an autosomal recessive blood disease in which individuals' capacity to produce functional hemoglobin (the oxygen carrying part of erythrocytes) is reduced. This disease is caused by mutations in the HBA1 and HBA2 genes that make up the alpha-globin building block of hemoglobin. In order for hemoglobin to be fully functional, both HBA1 and HBA2 genes must have two working copies. Alpha thalassemia can occur in two forms, depending on the presence of copies of these genes; HbH disease and Hb Bart Syndrome. HbH disease is a milder form of alpha thalassemia and occurs in the absence of three of the four copies. Individuals with this condition may have mild / moderate anemia, weakness, fatigue, enlarged liver and spleen, and jaundice. In some patients, bone changes may occur, such as lengthening of the upper jaw. The more serious form of alpha thalassemia is Hb Bart Syndrome. In this disease, all four copies of HBA genes do not work. Most of these babies are either still born dead or die shortly after birth. Being pregnant with a child with Hb Bart syndrome may bring risks such as hypertension to the expectant mother.


Alpha Thalassemia


The prognosis of this disease depends largely on the type of alpha thalassemia. While the prognosis of Hb Bart Syndrome is quite bad, in HbH disease, patients can reach adult ages without any treatment.


There is no cure for Hb Bart Syndrome. People with HbH Disease may not need treatment, but the hemoglobin levels and overall growth and development rates of these children should be followed. Some patients may need blood transfusions. Again, if splenomegaly reaches advanced levels in these children, splenectomy may be recommended.

Autosomal Recessive Polycystic Kidney Disease

Autosomal Recessive Polycystic Kidney Disease (ORPBH) is a serious disease that affects the kidneys and sometimes the liver. This occurs as a result of mutations that occur in the PKHD1 gene, which is normally found in both the fetal and adult kidneys. People with this disease are born with many cysts in their kidneys that disrupt renal function. These cysts can affect other organs, especially the liver. In most cases, symptoms begin to manifest themselves shortly after birth. These symptoms are; difficult breathing, cyst-filled and enlarged kidney, hepatomegaly, high blood pressure, anemia, frequent urination, pain in the lower back or sides. Even though it is rare, a person may not show any symptoms until childhood or young adulthood. In such individuals, the liver condition is more serious than the kidneys.


Although its prognosis is generally poor, survival rates have been increasing in recent years. 30% of babies born with this disease die in their first year due to respiratory problems. More than 50% develop kidney failure until the age of 10. The survival rate of babies who can survive the first year with respiratory support and kidney transplantation by the age of 10 has reached 82%. The 15-year survival rate is 67-79%, which is getting better.


Treatment in newborns is primarily aimed at stabilizing breathing by mechanical ventilation. Sometimes dialysis or surgical intervention may be needed even in childhood. When the kidneys begin to go bankrupt, regular dialysis or kidney transplants should be performed. Medical treatment is used for high blood pressure. If this is not enough, liver transplantation is among the possible solutions. Endocrine complications such as fibrosis / cirrhosis, diabetes, thyroid, parathyroid and pituitary insufficiency may occur. Among them, especially cardiac problems restrict lifespan and are responsible for 71 % of deaths. People with this disease can see over the age of 30, although their life span is shortened.

Biotinidase Deficiency

Biotinidase deficiency is an autosomal recessively inherited disease that causes skin and neurological problems when left untreated. This disease is caused by mutations in the “BTD” gene responsible for Vitamin H (biotin) recycling. Babies with this condition begin to show some symptoms in the first few months. If this deficiency progresses further, seizures, hypotonia, respiratory problems and developmental retardation can be observed. If the disease is skipped and untreated, complications such as hearing and hearing loss, movement and balance disorders, rashes, hair loss and candidiasis can occur. Partial biotinidase deficiency is the milder form of this disease, and it only progresses with hypotonia, rash and hair loss that occurs during times of stress and illness.


Its prognosis is generally good. Quick treatment and regular biotin supplementation prevent most complications. However, if vision / hearing loss or growth retardation occurred before treatment, these findings cannot be normalized even with biotin supplementation.


Treatment of this disease is based on early intervention and lifelong biotin supplementation. This treatment prevents most symptoms and improves them. Apart from this, closely monitoring the patient in terms of vision and hearing is very important for the follow-up of the treatment.


Classical CAD (Congenital Adrenal Hyperplasia)

Classic CAD has two forms; salt-losing form and simple virilization form. Classical CAD is a disease that occurs as a result of 21-hydroxylase enzyme deficiency and affects the adrenal glands where hormones are synthesized, which have many important functions in the body. This is due to mutations in the CYP21A2 gene, which is responsible for producing cortisol and aldosterone hormones. These hormones have very important functions such as maintaining the sugar and salt balance in the body.

In the absence of 21-hydroxylase enzyme, these hormones cannot be produced and precursors of these hormones begin to be converted to androgens. Symptoms of this disease occur due to the deficiency of cortisol and aldosterone, and due to the excess of the androgen hormone. In girls affected by the disease, excess of androgen causes external genital organs in the male direction (virilization), while internal genital organs remain normal. Adult female patients may also have symptoms such as irregular menstruation, acne, early pubic hair growth, fallen fertility, rapid growth, short height, excessive hair growth and male pattern baldness. In male patients, genital organs are normal, but they may also have symptoms such as rapid growth, short stature, acne, early pubic hair and low fertility.

Hormone production in CAD, which progresses with salt loss, is either very low or none, which leads to the loss of very high amounts of sodium in urine. This loss leads to vital complications such as low nutrition, weight loss, dehydration, vomiting and low blood pressure in the newborn. Hormone production is still present in CAD with simple virilization and does not cause salt loss and complications.


Its prognosis is quite good with treatment. Normal life expectancy is expected in patients diagnosed and intervened early. Although the treatment corrects the disorders caused by androgen excess and optimizes growth and development, fertility problems may not pass.


Treatment is life-long glucocorticoid replacement to replace missing hormones, minimize excess adrenal sex hormone, minimize virilization, optimize development and ensure fertility. This dosage is increased in times of stress.

Classical Galactosemia

Classical galactosemia arises when the body cannot convert galactose sugar into energy. This is due to mutations in the GALT gene, which encodes the galactose-1-phosphate uridyltransferase enzyme. The absence of this enzyme prevents the processing of galactose taken as a nutrient. It is found in many foods, including galactose sugar, dairy products, and baby food. Babies with galactosemia are healthy when they are born and show complications such as feeding difficulties, vomiting, diarrhea, jaundice and bleeding shortly after breastfeeding. Its treatment is the complete removal of galactose from the diet. If treatment is not started within the first few days, vital conditions such as liver failure and sepsis may occur. Even with treatment, problems such as mental retardation, developmental retardation, speech disorders, cataracts and muscle weakness may occur. If the affected patient is female, reproductive disorders such as ovarian failure may also be observed.



Its prognosis is very variable. Removing galactose from the diet can prevent or reduce the risk of liver problems, lethargy, vomiting, diarrhea, cataracts, and sepsis. However, developmental delays, mental retardation, speech disorders, early ovarian failure and movement disorders can remain as they are even with a galactose diet. Despite this, a shortening of the lifespan is not expected in patients who adhere to the galactose diet.



It is  is based on the removal of galactose from the diet for life. Therefore, patients with this condition should not consume milk and dairy products. Newborns should be given food without galactose. In acute attacks, antibiotics, vitamin K and other supportive treatments may be required. Speech disorders and backwardness can be eliminated with speech therapy. Eye exams should be carried out every six months until the age of three, and then once a year. In female patients, endocrinological consultation should be recommended from the age of ten. They may need hormone therapy.


Congenital Glycolysis Disorder: Type 1A


Congenital Glycosylation Disorder (KGB) is an autosomal recessive disease that shows clinical heterogeneity and affects different parts of the body. KGB Type 1A arises from mutations in the PMM2 gene, which encodes enzymes responsible for synthesizing sugars and binding them to proteins. The most serious forms of this disease lead to hydrops fetalis, which means that the baby either dies intrauterinely or shortly after birth. However, in most patients symptoms appear in childhood; these include hypotonia, developmental retardation, inability to gain weight. In patients who can complete childhood, mental problems, seizure-like attacks, and inability to walk without help are common findings. Females with this disease do not enter puberty; men have a normal puberty, but the testicles are smaller than normal.



Its prognosis is very variable. Approximately 20 % of patients die before their age. In milder cases, there may be very few findings. Nevertheless, the most common finding is mental retardation and the presence of more than one system accompanying it.



The main methods used in treatment are to support nutrition with gastrostomy tubes and special formulas, to provide hydration, to provide physical and speech therapy and to correct scoliosis by surgical intervention.Symptoms appear in childhood; these include hypotonia, developmental retardation, inability to gain weight. In patients who can complete childhood, mental problems, seizure-like attacks, and inability to walk without help are common findings. Females with this disease do not enter puberty; men have a normal puberty, but the testicles are smaller than normal.

Cystic fibrosis

Cystic Fibrosis is a disease that is inherited by autosomal recessive and affected by many systems, especially respiratory and digestive systems, due to adhesive mucus secretion. The severity and symptoms of the disease may differ among individuals. Abnormal mucus causes obstruction in the respiratory tract, causing respiratory failure and the development of bacterial infections. Over time, infections and injuries cause permanent fibrosis and scars in the lung, leading to the development of cysts. On the other hand, digestive problems are also prominent in people with cystic fibrosis. In infants born with the disease, meconium ileus develops and passage stops.

Other digestive problems occur in the pancreas, and because of the blockage of the duct by the mucus, the digestive enzymes are prevented from reaching the intestines, associated symptoms such as malnutrition and developmental retardation, as well as insulin production, and “Cystic Fibrosis Caused Diabetes Mellitus (CFRDM) occurs. Another finding related to cystic fibrosis is vas deferens agenesis and is among the most important causes of obstructive azoospermia in men.

The frequency of delivery of cystic fibrosis is about 2500-3500 births on average. The disease is caused by mutations in the CFTR gene.


Cystic Fibrosis progresses quite slowly in some cases and shortens the life span, and sometimes it is possible to encounter cases that progress almost asymptomatically. While there were early deaths due to lung complications, today the average life span has reached the age of 40 with treatment and some precautions.


Successful results are obtained with specific treatments and applications for each system. Inhaler, DNAse enzyme treatments, oxygen treatments, treatment of bacterial agents and some surgical approaches, adding pancreatic enzymes to treatment increase life expectancy and quality of life.


Familial Mediterranean Fever (FMF)

Familial Mediterranean Fever causes recurrent fever and pain attacks. This disease is caused by mutations in the MEFV gene involved in inflammation. It is an autosomal recessive disease. FMF patients complain of high fever and pain attacks caused by inflammation in the abdominal region, around the lungs and joints. Type1 FMF patients show shorter inflammation and fever attacks, while typical FMF attacks last about 3 days. The frequency of seizures can vary from 1 week to several times a year. Symptoms and severity of the disease vary among patients. The accumulation of protein plaques in various organs, especially kidneys, that is amyloidosis, is the most serious complication of the disease. The first symptom in type 2 FMF patients is amyloidosis.


The average lifespan of sick individuals with appropriate treatments is similar to the general population. The most serious consequence of FMF is the development of kidney failure due to amyloidosis.


MEFV Gene Sequence analysis: Diagnoses in 75-90 % of patients. Standard treatment of patients diagnosed with FMF is with Colchicine. FMF attacks and amyloid accumulation have been shown to be prevented in daily colchicine use. Fever and inflammatory events are treated with non-steroidal anti-inflammatory drugs.

Duchenne Muscular Dystrophy

Duchenne Muscular Dystrophy is an inherited myopathy caused by mutations in the DMD gene. The DMD gene encodes the dystrophin protein. Dystrophin in skeletal muscle is part of the sarcolemma-related protein complex, which stabilizes sarcolemia. DMD is a muscle disease that occurs with muscle damage and weakness. Although it rarely shows symptoms with hypotonia or developmental retardation in the neonatal period, it usually starts in the form of gait disturbance between 3-5 years of age in male patients. In the progressive disease, most patients up to the age of 12 are in a wheelchair. Most patients die due to loss of respiratory function and pneumonia. The emergence of disease symptoms in women depends on X inactivation. If the X chromosome carrying the mutant DMD allele is active in many cells, DMD symptoms are observed in women, but if the X carrying the normal DMD allele is predominantly active, no symptoms or little symptoms can be observed.


Carrier women have a 50 % risk of passing the mutation to their children during each pregnancy. Boys who receive the mutant allele will be ill. Girls who receive the mutant allele are carriers and may or may not develop cardiomyopathy. Even if a woman who had a child with DMD did not appear as a carrier after DNA tests, the risk of having a boy with DMD again was 7 % due to germ cell mosaicism.


In DMD gene analysis, "deletion analysis" is positive in ~ 50 % -65 % of cases, "duplication analysis" in ~ 5 % -10 % and "Sequence analysis" in ~ 20 % -35 %. Treatment of the disease is directed towards symptoms. Stem cell studies and some new treatments for this disease are promising.



Phenylalanine hydroxylase deficiency is an autosomal recessive inheritance, also known as Phenylketonuria, leading to the accumulation of toxic phenylalanine in the body. The disease occurs as a result of mutations in the PAH gene due to the failure of the phenylalanine hydroxylase enzyme to function. Dietary phenylalanine accumulates in the body in sick individuals and, if left untreated, causes mental retardation. Symptoms can be observed with mild to severe intensity. Classical Phenylketonuria is the most common form, and if left untreated, patients may experience seizures, developmental retardation, behavioral problems, and psychiatric illnesses, as well as mental retardation. In mild form, patients are less likely to develop serious mental retardation if they are not treated.


PAH Gene Sequence analysis is diagnostic in '97-99 % of cases. If the sequence analysis test is normal, the deletion / duplicon analysis will diagnose in 1-3 % of the cases. The prognosis of the disease can be corrected with treatment. Neurological and psychiatric symptoms are prevented if diet therapy is started immediately after diagnosis.


Treatment should be for life. Treatment is done with a restricted diet from phenylalanine. Sick individuals should be fed a diet containing low protein forms rich in low-protein vegetables and fruits. Keeping blood phenylalanine levels within safe limits prevents mental retardation and ensures normal development and growth.


Fragile X Syndrome

Fragile X Syndrome is a disease characterized by X-linked recessively inherited mental retardation caused by mutation in the FMR1 gene located in the q27 region of the X chromosome. Fragile X Syndrome is the most common cause of hereditary mental retardation. The disease is caused by an increase in the number of CGG repeats in the FMR1 gene. If a person is carrying a full mutation (> 200 CGG repetition), the function of the FMR1 gene is impaired and FMR protein is not synthesized, resulting in the manifestations of the disease.

Since fragile X is an inherited disease due to X and it is the only X chromosome in men, all men who carry a full mutation become ill. In contrast, since women have two X chromosomes, women who carry a full mutation due to inactivation of the X chromosome are often asymptomatic. However, these carrier women can sometimes show mild findings due to X inactivation or even show the classic Fragile X phenotype.

Behavioral anomalies such as mental retardation, autism spectrum diseases, attention deficit, anxiety disorder are observed in patients (> 200 CGG repetition). Normal individuals have fewer than 50 CGG repeats, with no risk of disease for themselves and their children. Individuals with an intermediate mutation (50-58 CGG repeat) do not show signs of Fragile X syndrome, and an increase in the full mutation as the number of repeats they carry is transferred to the next generation.

Since there is no risk of Fragile X Syndrome, these intermediate mutations can cause premutations (55-200 CGG repeat) to be transferred to the next generation, thereby increasing the full mutation as this premutation is transferred to the next generation. Premutation carriers (repeat 55-200 CGG) do not show symptoms of Fragile X, but they are at risk for Fragile X-associated Tremor / Ataxia syndrome (FXTAS) and / or Premature Ovarian Insufficiency. FXTAS is a movement disorder that occurs in late adulthood, and its symptoms are short-term memory loss, Parkinsonism, and muscle weakness in the lower extremity. This disease is observed in 16.5 % of female premutations and 75% of male premutations. Premature Ovarian Insufficiency is the onset of menopause before the age of 40, and this risk is 21 % in women who are the premutations.


The prognosis of the disease is variable. Sick men show developmental retardation and the autism spectrum can be observed. Sick girls can show different spectrum findings. The disease does not affect the average life span. There is a risk of having a sick child as the number of repetitions increases when transferring the premutation carrier women to the next generation. In male premutation carriers, there is no increase in the number of repeats when transferring to the next generation.


Detection of CGG repeat count is done by PCR or Southern Blot Method and it is diagnostic in 98-99% of cases. Methylation analysis: 100 % of patients, Deletion / duplicon analysis: <1 % Sequence analysis: Provides diagnosis in <1 %. Treatment of the disease is carried out symptomatically. Since there is a risk of premature ovarian failure and infertility in women who are carrier of premutations, while these patients receive assisted reproductive therapy (IVF treatment), the risk of child with full mutation should be taken into consideration and preimplantation genetic diagnosis should be applied to these patients.


Sickle Cell Anemia

Sickle cell anemia is an autosomal recessive disease that progresses with the disruption of the structure of the hemoglobin protein necessary for erythrocytes to absorb oxygen in the body. 2 of hemoglobin

It contains 4 protein subunits, beta globin and the other 2 alpha alpha. Sickle cell anemia occurs as a result of a specific mutation in the HBB gene. This mutation leads to the production of structurally abnormal beta-globin called HbS. This change in beta-globin structure causes the erythrocytes to become sickle. Such blood cells break down early and cause anemia. Symptoms of the disease are generally fatigue, jaundice, bone pain and growth-growth retardation. In addition, due to the sickle shape of the erythrocytes, capillary bed obstruction occurs and causes seizures. Attacks cause damage to organs that require oxygen-rich blood, especially in the lungs, kidneys, spleen and brain. Patients with sickle cell anemia have an increased risk of recurrent infections.


The average lifespan of patients is about 40-60 years. While mortality in childhood is due to infection or acute siplenomegaly, mortality in adulthood occurs due to organ failure or problems with clotting.


HBB gene Sequence Analysis: Diagnoses in 100 % of patients. Routine treatment of the disease is hydration, avoiding extreme temperatures and screening of acute problems. Pain attacks are managed by combined treatment with medication, heat and massage. Antibiotics for acute respiratory problems are treated with oxygen and painkillers. Hydroxyurea treatment prevents the erythrocytes from becoming sickle by increasing the production of Hemoglobin F. Blood transfusion is performed to prevent chronic pain attacks, pulmonary hypertension, chronic renal failure, and acute respiratory problems and stroke. If necessary, splenectomy can be performed due to the growth in the spleen. Again, gene therapy applications are promising sizes for sickle cell anemias.


Congenital Deafness

It is also called non-syndromic hearing loss and deafness associated with GJB2. Non-syndromic hearing loss and deafness is a hereditary form of hearing loss with no other findings than hearing loss. There are many genetic causes of non-syndromic hearing loss and deafness, and in most cases it results from mutations in the GJB2 gene. The GJB2 gene encodes the 26 protein of Connex, which is involved in maintaining the balance of nutrients in the inner ear. Sick individuals have hearing loss from birth. The degree of hearing loss is equal in both ears. The severity of the disease can vary from moderate to serious and usually remains stable over time.


If hearing loss is diagnosed before the age of 2, its prognosis is good. Hearing loss is typically present from birth. The degree of hearing loss varies from moderate to severe.


HBB gene Sequence Analysis: Diagnoses in 100 % of patients. Routine treatment of the disease is hydration, avoiding extreme temperatures and screening of acute problems.

Pain attacks are managed by combined treatment with medication, heat and massage. Antibiotics for acute respiratory problems are treated with oxygen and painkillers. Hydroxyurea treatment prevents the erythrocytes from becoming sickle by increasing the production of Hemoglobin F. Blood transfusion is performed to prevent chronic pain attacks, pulmonary hypertension, chronic renal failure and acute respiratory problems and stroke. If necessary, splenectomy can be performed due to the growth in the spleen. Again, gene therapy applications are promising sizes for sickle cell anemias.


Spinal Muscular Atrophy (SMA)

Spinal muscular atrophy (SMA) is an autosomal recessive inherited disease that involves the muscles. The disease is caused by mutations in the SMN1 gene. The SMN1 gene is responsible for maintaining the robustness of motor neurons. Loss of motor neurons in the spinal cord and brainstem, and, accordingly, weakness in the movements of the muscles used in movements such as walking and sitting are observed. In some cases, swallowing and respiratory muscles may also be affected.

There are different types of SMN1-associated SMA, and each is classified by the age of onset of symptoms and the severity of symptoms. Type 1 SMN1 related SMA (Werdig-Hoffman disease) is the most serious type of SMA. In babies born with type 1 SMA, the symptoms appear in the first 6 months, with the difficulty of swallowing and breathing, and these babies cannot sit without support. In SMA (Dubowitz Syndrome) associated with Type 2 SMN1, symptoms appear at 6 and 12 months. Although these individuals can sit without support, they cannot stand up and walk without support.

Type 3 SMN1-associated SMA (KugelBerg-Welander Disease) or Juvenile Type SMA is a milder form of the disease. These individuals show typical symptoms in early childhood, but they can stand up, walk without support, and maintain this condition until they are 30 or 40 years old. Type 4 SMN1-associated SMA is the mildest form of this disease and disease manifestations appear in adulthood. Muscle weakness, tremors and twitches are observed in these individuals.


The prognosis in SMA patients depends on the severity of the symptoms. In SMA Type 1 patients, the prognosis is poor, breathing and swallowing difficulties are observed in sick babies and these babies are generally lost around the age of 2 years. This period can be extended a little more with respiratory and nutritional support. In individuals with type 2 SMA, the prognosis is better than in Type 1 SMA, two thirds of patients can live up to the age of 20. The prognosis is good in individuals with Type3 SMA, they lose their walking ability and need support in their 30s and 40s. The prognosis is good in individuals with type 4 SMA, symptoms appear in adulthood and their mobility remains relatively intact.


In recent years, the active substance called Nusinersen has been used in the treatment of SMA patients. Nusinersen is an FDA approved molecule that acts by binding to the SMN2 messenger RNA: SMN2 is an antisense oligonucleotide that binds to pre-mRNA, and reduces the effects of the genetic error associated with the mutation in the SMN1 gene by increasing functional SMN protein production.


Tay-Sachs Disease

Tay-Sachs Disease is a neurodegenerative disease that is inherited autosomal recessively. This disease is caused by mutations in the HEXA gene. Accumulation of toxic metabolites in the brain and spinal cord neurons in sick individuals leads to the destruction of these cells. Disease symptoms occur in sick individuals for approximately 3-6 months and are noticeable with developmental delay and muscle weakness. 8-10. After the month, the disease progresses rapidly. Sick children have seizures, vision and hearing loss, mental retardation.


The prognosis of Tay-Sachs disease is poor. There is no cure to cure. Usually patients are lost at 2-4 years of age.


HEXA gene sequence analysis is diagnostic in 99 % of patients. The deletion/duplication analysis may be diagnostic for a small number of cases in patients with this test. Treatment in Tay-Sachs disease is mostly supportive therapy. Anti-epileptic drugs are used to prevent seizures. However, seizures are progressive and may differ. Nutrition and hydration are an important part of the treatment.


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