Beta Thalassemia
Beta thalassemia is an autosomal recessive disorder caused by the absence orreduction of beta-globin chain synthesis, resulting in microcytic hypochromic
anemia, an abnormal peripheral blood smear with nucleated red blood cells, andreduced amounts of hemoglobin A. For clinical purposes, beta thalassemia isdivided into thalassemia major, thalassemia intermedia, and thalassemia minor.
Thalassemia major is characterized by ineffective erythropoiesis andextramedullary hematopoiesis and is transfusion dependent. Thalassemia major
manifests within the first year of life. Individuals with thalassemia intermedia
present with symptoms later and have milder anemia that only rarely requires
transfusion. Thalassemia minor is asymptomatic.
Indications for genetic testing:
1.
2.
3.
4.

Confirmation of clinical diagnosis
Carrier testing for at-risk family members
Genetic counseling
Prenatal diagnosis for known familial mutation

Congenital Adrenal Hyperplasia
Congenital adrenal hyperplasia (21-hydroxylase insufficiency) is an autosomal
recessively inherited disease in case of which cortisol and aldosterone synthesis in
adrenal glands is disturbed. The disease manifests clinically during neonatal age
causing virilisation and life-threatening salt-loss syndrome. Virilisation in girls
manifests as enlargement of clitoris; in severe cases it may be difficult to identify
the neonate’s sex. In boys the virilisation is not easily diagnosable, but in them thedisease may manifest during the first weeks after birth as adrenal crisis, expressedas hyponatraemia, hyperkalaemia and metabolic acidosis.
The congenital adrenal hyperplasia is caused by mutations in the CYP21A2 gene.
The incidence of congenital adrenal hyperplasia is about 1 per 15,000 neonates.
Indications for genetic testing:
1. Confirmation of clinical diagnosis
2. Carrier testing for at-risk family members
3. Genetic counseling
4. Prenatal diagnosis

Cystic Fibrosis – CF
Cystic fibrosis (CF) is an autosomal recessive, multisystem disease. CF is
characterized by recurrent lung infections, malabsorption, malnutrition, and maleinfertility. Cystic fibrosis is caused by thick and sticky mucus due to disturbances ofsalt homeostasis in cells.

CF is caused by mutations in the CFTR gene encoding cystic fibrosis
transmembrane conductance regulator protein. The CFTR protein functions as achloride channel expressed on epithelial cell membranes and controls theregulation of other transport pathways.
Indications for genetic testing:
1. Confirmation of clinical diagnosis
2. Carrier testing for family members of CF patients
3. Genetic counseling
4. Prenatal diagnosis for known familial mutation

FGFR2 gene mutation analysis
Fibroblast growth factors (FGFs) are a family of growth factors involved inregulating a variety of processes, including angiogenesis and wound healing aswell as embryo development. FGFs function is binding to FGF receptors (FGFRs)
and activating different signaling pathways. Several mutations inFGFR genes havebeen found to be related to a number of skeletal disease syndromes. FGFR2 genehas been shown to affect several processes, disruption of which can result in a
number of disorders.
Indications for genetic testing:
1. Confirmation of clinical diagnosis
2. Genetic counseling
3. Prenatal diagnosis
FGFR2 gene mutation analysis is indicated by fetal increased nuchal translucency
in the first trimester and/or skeletal abnormalities detected during the first or secondtrimester.

FGFR3 gene mutation analysis
Fibroblast growth factors (FGFs) are a family of growth factors involved inregulating a variety of processes, including angiogenesis and wound healing aswell as embryo development. FGFs function is binding to FGF receptors (FGFRs)
and activating different signaling pathways. Several mutations in FGFR genes havebeen found to be related to a number of skeletal disease syndromes. FGFR3genehas been shown to participate in the regulation of several processes,disruption of which can result in a number of disorders.
Indications for genetic testing:
1. Confirmation of clinical diagnosis
2. Genetic counseling
3. Prenatal diagnosis
FGFR3 gene mutation analysis is indicated by fetal increased nuchal translucency
in the first trimester and/or skeletal abnormalities detected during the first or secondtrimester.

Hutterite Genetic Diseases
A number of autosomal recessive disorders have been described in the Hutterite
population. Some diseases − for example Limb-girdle muscular dystrophy,
Carnitine Palmitoyltransferase I deficiency, and Cystic fibrosis − are very common
in the Hutterite population. Genetic testing facilitates early diagnosis and improves
health care services for individuals and families with genetic disorders.
Indications for genetic testing:
1. Confirmation of clinical diagnosis
2. Carrier testing for at-risk family members
3. Estimation of reproductive risks
4. Genetic counseling

Male Factor Infertility
Infertility is a widespread medical problem, affecting the lives of 15–20% ofcouples, with male factor infertility (MFI) occurring in almost half of the cases.
The unfavourable genetic background is thought to be the cause in 15–30% ofmale factor infertility cases. Main genetic causes of male infertility are numericaland structural chromosomal aberrations of sex (Klinefelter syndrome 47XXY) andautosomal chromosomes, meiotic defects, microdeletions in the region q11.21-23 of
the Y-chromosome, mutations in the CFTR gene and genetically determined
syndromes in which infertility is a symptom. The correct determination of thegenetic basis of infertility is important for the further treatment of patients.
A clear advantage of performing the MFI-APEX (arrayed primer extension) assay
with the addition of a quick determination of Y-deletions is the simultaneous testing
for a number of known genetic causes of male infertility. This allows confirmation/
exclusion of diagnosis and provides insight into the causes of infertility that could
be valuable in planning the treatment for the patient. Furthermore, MFI testing isstrongly recommended before a couple undergoes assisted reproduction in orderto prevent the possible inheritance of the genetic lesion to the next generation.
Indications for genetic testing:
1.
2.
3.

Confirmation of suspected diagnosis
Reasons other than genetic have been ruled out (environment and lifestyle
related reasons, medical reasons that include hormone imbalance, infections,varicocele)
Patient’s phenotype is indicative of a syndrome or condition associated withgenetic male infertility (for example, small testicles and lower testosterone
levels in case of Klinefelter syndrome)

Noonan Syndrome
Noonan syndrome is an autosomal dominantly inherited disease characterized byshort stature, congenital heart defect and delayed mental development of varying
degree. Patients with Noonan syndrome also have a characteristic appearance:
short neck, cervical skin fold, low set ears, hypertelorism. Additionally lymphatic
system dysplasia may occur, which is the basis of cystic hygroma and occipital foldenlargement in the fetus.
The incidence of Noonan syndrome is about 1:1000-2500. Noonan syndrome isgenetically heterogeneous. In 50% of patients mutations occur in the PTPN11gene. 10% of cases are associated with mutations in the SOS1 gene, 3% in theRAF1 gene and 1% in the KRAS gene.
Indications for genetic testing:
1.
2.
3.
4.

Confirmation of clinical diagnosis
Parental testing in case of a causative mutation has been identified in an
affected individual
Genetic counseling
Prenatal diagnosis

Sickle Cell Disease
Sickle-cell disease (SCD), also known as sickle-cell anemia is characterized bytendency of haemoglobin molecules within red cells to polymerise and deform thered cell into a sickle shape resulting in vaso-occlusive events (VOE). VOE areassociated with tissue ischemia and variable degrees of hemolysis, both of which
contribute to multi-organ dysfunction. Acute and chronic bone pain is the mostcharacteristic feature of SCD. Chronic hemolysis leads to anemia, jaundice,cholelithiasis, and delayed growth and sexual maturation. Individuals with severe
hemolysis are predisposed to pulmonary artery hypertension, priapism, and leg
ulcers.
Sickle cell disease is inherited in an autosomal recessive manner.
Indications for genetic testing:
1.
2.
3.
4.

Confirmation of clinical diagnosis
Carrier testing
Genetic counseling
Prenatal diagnosis for known familial mutation

Skeletal Dysplasia
Skeletal malformations are caused by a number of different hereditary disorders
and syndromes resulting from mutations with many genes. The most common
syndromes associated with skeletal malformations are achondroplasia,craniosynostosis, campomelic dysplasia,hypochondroplasia.
Indications for genetic testing:
1. Confirmation of clinical diagnosis
2. Testing for at-risk family members
3. Determination of disease prognosis
3. Genetic counseling
4. Prenatal diagnosis
Testing is indicated by fetal increased nuchal translucency in the first trimester and/or skeletal abnormalities detected during the first or second trimester.

Smith-Lemli-Opitz Syndrome
Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessively inheritedmultiple malformation syndrome due to an inborn error cholesterol synthesis –insufficiency of enzyme 7-dehydroxycholesterol reductase. The syndrome ischaracterized by intrauterine and also postnatal growth retardation, moderate tosevere mental retardation, malformations in many organ systems (cardiovascular,urogenital, gastrointestinal and central nervous systems). The patients have acharacteristic appearance: ptosis, polydactyly, syndactyly of the II and III toes onboth feet.
The incidence of SLOS is 1:20,000-70,000. SLOS is associated with mutations inthe DHCR7 gene.
Indications for genetic testing:
1. Confirmation of clinical diagnosis
2. Carrier testing for at-risk family members
3. Genetic counseling
4. Prenatal diagnosis

Spinal Muscular Atrophy
Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized bymuscle weakness and atrophy resulting from progressive degeneration and loss of
the lower motor neurons in the spinal cord and the brain stem nuclei. Theweakness is almost always symmetric and progressive. Poor weight gain,
pneumonia, sleeping problems, scoliosis, and joint contractures are common
symptoms of SMA.

Spinal muscular atrophy is divided into five subtypes (SMA 0, SMA I, SMA II, SMAIII, SMA IV), distinguished by the age of onset and maximum function attained.
SMA is inherited in an autosomal recessive manner. Disease incidence rate is 4-10
per 100,000 live births.
Indications for genetic testing:
1. Differential diagnostics
2. Carrier testing for at-risk relatives
3. Prenatal testing for known familial mutations
4. Genetic counseling

Syndromes related to increased NuchalTranslucency of fetus
The ultrasound finding of increased nuchal translucency (NT) from weeks 11 to
14 of gestation is most commonly associated withchromosomal abnormalities.
However, even in the absence of chromosomal defects, increased NT has been
associated with an increased risk for adverse pregnancy outcome, including fetalabnormalities and genetic syndromes.
The test of syndromes associated with increased NT of the fetus allows
examination of the most common genetic changes that cause syndromes such asCongenital adrenal hyperplasia (21-hydroxylase insufficiency),Noonan
syndrome, Smith-Lemli-Opitz syndrome and Spinal muscular atrophy.
Indications for genetic testing:
1. Confirmation of clinical diagnosis
2. Carrier testing for at-risk family members
3. Genetic counseling
4. Prenatal diagnosis
Testing is indicated by fetal increased NT (measurement 3 mm and more) during
weeks 11-14 of gestation. Before genetic testing it is recommended to exclude fetal
aneuploidy.

Venous Thrombosis
The annual incidence of venous thrombosis ranges from approximately 1 to 3 per1000 people. Venous thrombosis events often occur when multiple risk factors,including genetic and environmental, are present simultaneously. Acquired risk
factors of venous thrombosis are age, immobilization, surgery, trauma, malignancy,
myeloproliferative disorders, obesity, pregnancy, postpartum period, hormone

replacement therapy or use of oral contraceptives. Genetic risk factors are related
to a 30- to 80-fold higher risk for developing a thrombotic episode.
Indications for genetic testing:
1.
2.
3.
4.
5.
6.

Vein thrombosis before the age of 50
Recurrent vein thrombosis in family
Identified genetic variant for higher risk of venous thrombosis in family
For women in addition to the above named:
Myocardial infarction in 50-year-old women who are smoking
Vein thrombosis in the period of taking oral contraceptives
The presence of pregnancy complications, for example multiple miscarriages,
preeclampsia and stillbirth.

Exome Sequencing
Exome sequencing includes the sequencing of the protein coding regions andtheir flankingintronic regions in ~20,000 genes of the human genome. The coding
region represents 1-2% of the human genome but contain approximately 85% ofdisease-causing mutations. Exome sequencing can be an efficient tool for clinicians
to confirm patients’ diagnosis of complicated conditions not covered byconventional testing approaches.
Indications for genetic testing:
1. Confirmation of clinical diagnosis
2. Diagnosis of patients with genetic disorders for which diagnostic panels are notavailable
3. Identification of novel genes responsible for diseases
4. Genetic counseling