By Shveta Jaishankar and Swathi Jain GCM III year

INTRODUCTION
• Heredity refers to the passing on of characteristics • DNA is deoxyribonucleic acid, our hereditary material • DNA is made up of sugar, phosphate, and 4 nitrogenous bases: Adenine, Thymine, Guanine and Cytosine • DNA has to replicate before cell division, because DNA is found in the nucleus • Chromosomes are DNA molecules curled around histone proteins • Everyone has 46 chromosomes in each of their cells • A gene is a sequence of DNA that contains instructions to make proteins

GENDER • Humans have 23 pairs of chromosomes • Chromosome pairs 1-22 work on the function or development of body • Pair 23 determines sex • Two X chromosomes means it’s a girl • A boy has X and Y chromosomes
X and Y Chromosomes of humans

• Genes accomplish important tasks, and if there is a malfunction while DNA replication, a disorder will occur in the baby developing in the womb • During cell division, the chromosome may fail to split and therefore, a daughter cell will: o Have an extra chromosome, OR o Have a missing chromosome

Down’s Syndrome
• A disorder caused by an extra chromosome 21 (trisomy 21) • Causes severe mental retardation • Prone to develop Leukemia and Alzheimer's disese • Occurs in every 1 out of 800 babies • Almost half of DS pts will have a congenital heart defect • Many babies with DS are rejected by the body and are therefore miscarried • About 92% of women who find out they are carrying a DS baby will abort

SYMPTOMS •Upward slant to eyes. •Small ears that fold over at the top. •Small, flattened nose. •Small mouth, making tongue appear large. •Short neck. •Small hands with short fingers. •Low muscle tone. •Single deep crease across center of palm. •Looseness of joints. •Small skin folds at the inner corners of the eyes. •Excessive space between first and second toe. •.

Kleinfelter’s syndrome
• Disorder occurring due to nondisjunction of the X chromosome. • The Sperm containing both X and Y combines with an egg containing the X, results in a male child. (XXY) • Males with some development of breast tissue normally seen in females. • Little body hair is present, and such person are typically tall, have small testes. • Infertility results from absent sperm. • Evidence of mental retardation may or may not be present.

Klinefelters Syndrome – Trisomy Sex chromosome (XXY)

Turners Syndrome
• Monosomy of Sex chromosome i.e only X is presnt • Turner syndrome is associated with underdeveloped ovaries, short stature, webbed, and is only in women. • Bull neck, and broad chest. Individuals are sterile, and lack expected secondary sexual characteristics. • Mental retardation typically not evident.

Turner’s Syndrome

Tay Sach’s Disease
• Monogenic, autosomal recessive • Caused by a genetic mutation on the HEXA gene on chromosome 15 • Harmful quantities of gangliosides accumulate in the nerve cells of the brain, eventually leading to the premature death of those cells • Central nervous system degrades, ultimately causing death. • Symptoms - relentless deterioration of mental and physical disabilities occurs; cognitive, motor, speech difficulties, swallowing difficulties, hypotonia and spasticity • Most common among people of Jewish (Ashkenazic Jews) – eastern Europe descent. • Occurs in about 1 for every 3600 births;

• Sex linked recessive • Cause – Mutation in DMD gene – the longest gene.(Xp21). The DMD gene codes for the protein dystrophin, an important structural component within muscle tissue. Dystrophin provides structural stability to the dystroglycan complex (DGC), located on the cell membrane • Progressive weakening of muscle control ( due to lack of protein) , psuedohypertrophy, fibrotic tissue development and loss of coordination • Occurs 1 in 3200 male births. • Females are usually carriers

Duchenne Muscular Dystrophy (DMD)

• Hemophilia is the oldest known hereditary bleeding disorder. • Caused by a recessive gene on the X chromosome. • Caused by the absence of one or more proteins necessary for normal blood clotting. Type A is caused by a mutation in the F8 gene which causes a protein called coagulant factor VIII(8)Type B is caused a mutation in the F9 gene which causes another protein called coagulant factor IX(9) • One can bleed to death with small cuts. • The severity of hemophilia is related to the amount of the clotting factor in the blood. About 70% of hemophilia patients have less than one percent of the normal amount and, thus, have severe hemophilia. • Hemophilia A occurs in about 1 in 5,000– 10,000 male births, while Hemophilia B occurs at about 1 in about 20,000–34,000

Haemophilia

X-linked Inheritance pedigree chart

Huntington’s Disease
• Autosomal Dominant Disease • An inherited, degenerative brain disorder which results in an eventual loss of both mental and physical control. • The disease is also known as Huntington's chorea. Chorea means "dance-like movements" • Symptoms - uncoordinated, jerky body movements and a decline in some mental abilities; deterioration of nervous system • Occurs 1 in 10,000 people

Phenylketonuria or PKU
• Autosomal recessive disorder • Caused by a deficiency of an enzyme which is necessary for proper metabolism of an amino acid called phenylalanine. • Phenylalanine is an essential amino acid and is found in nearly all foods which contain protein, dairy products, nuts, beans, tofu… etc. • Requires elimination of phenylalanine from diet • Brain damage can result if the diet is not followed causing mental retardation and mousy body odor (phenylacetic acid is in sweat). • Occurs one in 25000 people

Cystic Fibrosis
• An Autosomal recessive disorder • The gene responsible resides on the long arm of chromosome 7. It encodes a protein termed cystic fibrosis transmembrane conductance regulator, CFTR, which acts as a gate in the cell membrane and regulates the movement of chloride ions into and out of the cell. Patients with cystic fibrosis have a mutated, dysfunctional form of CFTR that causes the channel to stay closed, and so chloride ions build up in the cell. • Excessive mucus production causes lung infections, and affects other organs; poor nutrient absorption; chronic bronchitis; foul stools;bacterial infections • 1 out of every 2500 people of European descent; rare in other groups

Genetic testing and genetic counseling
• I Prenatal screening / testing • II Newborn screening • III Carrier and other adult testing • IV Genetic Counseling

Prenatal screening/testing
• 1. Ultrasound • 2. Maternal serum alpha-fetoprotein or multiple marker screening • 3. Amniocentesis • 4. Chorionic villus sampling (cvs) • 5. Nuchal translucency

UltraSound
• Obstetric sonography (ultrasonography) is the application of medical ultrasonography to obstetrics, in which sonography is used to visualize the embryo or foetus in its mother's uterus (womb). The procedure is often a standard part of prenatal care, as it yields a variety of information regarding the health of the mother and of the fetus, as well as regarding the progress of the pregnancy.

Obstetric sonogram of a fetus at 16 weeks. The bright white circle center-right is the head, which faces to the left. Features include the forehead at 10 o'clock, the left ear toward the center at 7 o'clock and the right hand covering the eyes at 9:00.

Maternal serum alpha-fetoprotein
• • • • MSAFP is a screening test that examines the level of alpha-fetoprotein in the mother's blood during pregnancy. MSAFP may be performed during the 16th to 18th week Alpha- fetoprotein(AFP) is found in both fetal serum and also amniotic fluid. The AFP test is measures high and low levels of alpha-fetoprotein. The results are combined with the mother’s age and ethnicity in order to assess probabilities of potential genetic disorders. High levels of AFP suggestS neural tube defect such as spina bifida or anencephaly, defects with the esophagus or a failure of your baby's abdomen to close. Low levels of AFP and abnormal levels of hCG and estriol may indicate that the developing baby has Trisomy 21( Down syndrome), Trisomy 18 (Edwards Syndrome) or another type of chromosome abnormality.

Amniocentesis
• Prenatal diagnosis of chromosomal abnormalities and fetal infections, in which a small amount of amniotic fluid, which contains fetal tissues, is extracted from the amnion or amniotic sac surrounding a developing fetus, and the fetal DNA is examined for genetic abnormalities. • Amniocentesis is performed between the 16th-20th week of pregnancy; • Possible complications include infection of the amniotic sac from the needle, and failure of the puncture to heal properly, resulting I n leakage or infection. Serious complications can result in miscarriage, preterm labor and delivery, respiratory distress, postural deformities, fetal trauma and alloimmunisation (rhesus disease). risk of amniocentesis-related miscarriage 1 in 1,600 (0.06) • One simple drawback is that administration may be painful.

Chorionic villus sampling (cvs)
• prenatal diagnosis to determine chromosomal or genetic disorders in the fetus. It entails getting a sample of the chorionic villus (placental tissue) and testing it. CVS can be carried out 10-13 weeks after the last period, earlier than amniocentesis (which is carried out as early as 14-16 weeks). CVS carries a higher risk of harming the fetus than amniocentesis (miscarriages occur in around 1 in 100 to 1 in 200 cases with CVS, versus around 1 in 1,600 with amniocentesis). a risk of miscarriage, there is a risk of infection and amniotic fluid leakage. The resulting amniotic fluid leak can develop into a condition known as oligohydramnios which is low amniotic fluid level. Additionally, there is a risk of CVS causing digit-reduction defects in the fetus if performed before 11 weeks (0.07%-0.10%

Newborn Screening
• • Purpose to find newborns who will benefit from early diagnosis and treatment historically, the criteria for inclusion in a newborn screening program:
1. 2. 3. 4. Preventable damage Frequency in population Appropriate test Needed to recognize disorder

Mandated by state law exception allowed for religious objection

Screening done for
• • • • • • • • Phenylketonuria Galactosemia Congenital hypothyroidism Biotinidase deficiency Hemoglobinopathies Congenital adrenal hyperplasia Hearing Disorders detected by tandem mass spectrometry (example: MCAD) • Cystic fibrosis • five lysosomal storage disorders: Pompe, Krabbe, Niemann-Pick, Gaucher, Fabry (to be implemented)

Newborn screening--tandem mass spectrometer tests
Organic acid disorders • 3-methylcrotonyl-CoA carboxylase deficiency (3MCC) • 3-hydroxy-3-methylglutaric-CoA lysase deficiency (HMG) • glutaric aciduria types I and II (GAI, Urea cycle disorders GAII) • citrullinemia • proprionyl CoA carboxylase deficiency • argininosuccinic aciduria (IVA) • isovaleryl CoA dehydrogenase Fatty acid oxidation disorders deficiency • carnitine palmitoyl transferase deficiency type II (CPT II) • methylmalonic acidemia (MMA) • long chain 3-hydroxy-coA dehydrogenase • mitochondrial acetoactyl-CoA thiolase deficiency (LCHAD) deficiency (b-KT) • medium chain acyl-CoA dehydrogenase • ethylmalonic adipic aciduria deficiency (MCAD)
Amino acid disorders • pku • maple syrup urine disease • tyrosinemia, types I, II and III • • • short chain acyl-CoA dehydrogenase deficiency (SCAD) trifunctional protein deficiency (TFPD) very long chain acyl-CoA dehydrogenase deficiency (VLCAD)

Carrier screening
for reproductive decisions • family history: Tay Sachs, cystic fibrosis, sickle cell disease, phenylketonuria population screening in ethnic groups • Tay Sachs • sickle cell disease • cystic fibrosis, spinal muscular atrophy for late onset disorders • Huntington disease • breast cancer • hemochromatosis

Genetic counselling
• • • • • • • possible problem detected during prenatal testing birth of an affected child family diagnosis/history of genetic disorder repeated unexplained loss of pregnancy exposure to mutagen traditionally nondirective (contrast with most health care situations) frequently can give estimates of risk:
– calculated – empiric data – test results

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