Common genetic disorders 201........6.pptx

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1. Common genetic disorders By: Dr.Bethelhem Damtie Assistant professor of pediatrics and child health

2. Objectives At the end of this lecture, the student should be able to understand Basic principles of genetics C linical manifestations and diagnosis of common genetic disorders in children

3. Outline Introduction to genetic disorders Fundamentals of genetics Patterns of genetic transmission AD disorders AR disorders X-linked disorders Chromosomal disorders

4. Introduction Genetic disorders are diseases that are caused by abnormalities in an individual’s DNA. Abnormalities can range from a small mutation in a single gene to the addition or subtraction of an entire chromosome or set of chromosomes. The prevalence of congenital malformations is much greater in inpatient pediatric populations; 30-50% of hospitalized children have congenital anomalies or genetic disorders.

5. In children with congenital malformations, the condition's etiology may be classified into one of five different categories: 1. Single-gene mutations, occurring in 6% of children with congenital anomalies 2. Chromosomal disorders, accounting for approximately 7.5% 3. Multifactorially inherited conditions, accounting for 20% 4. Disorders that show an unusual pattern of inheritance, accounting for 2-3% 5. Conditions caused by exposure to teratogens, accounting for 6%

6. Fundamentals of genetics DNA is composed of 4 nucleotide building blocks: adenine , guanine , cytosine , and thymine . The purine nucleotides, adenine and guanine, cross link by hydrogen bonds to the pyrimidines, thymine and cytosine. Separating the two strands permits complementary nucleotides to bind to each DNA strand; this copies the DNA and replicates the sequence.

7. DNA exists as multiple fragments that, together with a protein skeleton (chromatin), form chromosomes . Human cells have 23 pairs of chromosomes, with one copy of each chromosome inherited from each parent. 22 pairs of chromosomes are autosomes ; the remaining pair consists of sex chromosomes . Females have two X chromosomes; males have one X and one Y. Spread along the chromosomes like beads on a string, DNA sequences form genes , the basic units of heredity.

8. Most of the genetic material is contained in the cell's nucleus. The mitochondria (the cell's energy-producing organelles) contain their own unique genome. The mitochondrial chromosome consists of a double-stranded circular piece of DNA. Sperm do not usually contribute mitochondria to the developing embryo, so all mitochondria are maternally derived.

9. Patterns of genetic transmission Mendelian inheritance A utosomal dominant Autosomal recessive X-linked Non traditional inheritance Multifactorial/polygenic inheritance

10. Pedigree Drawing Pedigrees are pictorial representations of patterns of inheritance in families. Males are represented by squares and females by circles. Matings are connected with a solid line. Children from a couple are represented below their parents and are the next generation. The proband is indicated with an arrow. Affected individuals are indicated by shading or some other technique, which should be explained in a key. Carriers are indicated by a dot in the center of their symbol.

11. What kind of inheritance does this pedigree shows?

12. Autosomal dominant disorders If a single copy of a gene bearing a mutation is sufficient to cause disease and that gene is not on one of the sex chromosomes, that condition is inherited in an AD fashion. In AD disorders, each child of an affected parent has a 50% chance of inheriting the mutated gene. Possessing one working gene and one nonworking gene is termed heterozygous . If both copies are the same, they are referred to as homozygous .

13. Some people who are obligate carriers of a mutation known to cause an AD disorder do not show clinical signs of the condition, while other such individuals manifest symptoms. This phenomenon is referred to as penetrance . If all individuals who carry a mutation for an AD disorder show signs of that disorder, the gene is said to have complete penetrance . Often, AD disorders show variability in symptoms expressed in different individuals carrying the same mutated gene. This phenomenon is referred to as variable expressivity . AD disorders sometimes appear in a child of unaffected parents because of a spontaneous mutation .

14. Autosomal Recessive Disorders Disorders that are inherited in an AR manner manifest only when both copies of a gene pair located on a non-sex chromosome have a mutation. Children affected with AR disorders are usually born to unaffected parents, each of whom carries one copy of the mutation. If both members of a couple are carriers (or heterozygotes) for this mutation, each of their offspring has a 25% chance of being affected.

15. X-Linked Disorders Approximately 2,000 genes have been identified on the X chromosome, whereas only 200 are believed to be present on the Y chromosome. Females, whose cells have two copies of an X chromosome, possess two copies of each of these genes, whereas males, who have one X chromosome and one Y chromosome, have only one copy. Early in female development, one X chromosome is randomly inactivated in each cell.

16. All daughters of affected males with X-linked dominant trait will be affected. Affected mothers will transmit to 50 percent of offspring, regardless of sex, resulting in 50 percent of their children being affected. 100% of daughters of affected males with an X-linked recessive condition will be obligate carriers. Maternal carriers will pass the mutation to 50 percent of offspring. Therefore, 50 percent of sons will be affected and 50 percent of daughters will be carriers.

17. Examples of X-linked disorders Red-green color blindness Duchenne muscular dystrophy Hemophilia There are some X-linked disorders, called X-linked dominant, in which female carriers typically manifest abnormal findings. Example; Vitamin D resistant Rickets

18. Chromosomal disorders occur in approximately 1% of live births. Chromosome anomalies include abnormalities of number and structure and are the result of errors during cell division . Two common errors of cell division may occur during meiosis or mitosis, and either can result in an abnormal number of chromosomes.

19. The 1st error is nondisjunction , in which 2 chromosomes fail to separate during meiosis and thus migrate together into one of the new cells, producing 1 cell with 2 copies of the chromosome and another with no copy. The 2nd error is anaphase lag , in which a chromatid or chromosome is lost during mitosis because it fails to move quickly enough during anaphase to become incorporated into 1 of the new daughter cells.

20. Abnormalities of chromosomal number Aneuploidy and Polyploidy Human cells contain a multiple of 23 chromosomes (n = 23). A haploid cell ( n) has 23 chromosomes (typically in the ovum or sperm ). If a cell's chromosomes are an exact multiple of 23 (46, 69, 92 in humans), those cells are referred to as euploid . Polyploid cells are euploid cells with more than the normal diploid number of 46 (2n) chromosomes: 3n, 4n. Polyploid conceptions are usually not viable , but the presence of mosaicism with a karyotypically normal cell line can allow survival.

21. Mosaicism is an abnormality defined as the presence of 2 or more cell lines in a single individual. Polyploidy is a common abnormality seen in 1st-trimester pregnancy losses. Triploid cells are those with 3 haploid sets of chromosomes (3n) and are only viable in a mosaic form.

22. Aneuploidy is the most common and clinically significant type of human chromosome abnormality, occurring in at least 3–4% of all clinically recognized pregnancies. The most common cause of aneuploidy is nondisjunction, the failure of chromosomes to disjoin normally during meiosis. Monosomies occur when only 1, instead of the normal 2, of a given chromosome is present in an otherwise diploid cell.

23. In humans, most autosomal monosomies appear to be lethal early in development, and survival is possible in mosaic forms or by means of chromosome rescue. An exception to this rule is monosomy for the X chromosome (45,X), seen in Turner syndrome; the majority of 45,X conceptuses are believed to be lost early in pregnancy.

24. The most common cause of aneuploidy is nondisjunction , the failure of chromosomes to disjoin normally during meiosis. Nondisjunction can occur during meiosis I or II or during mitosis, although maternal meiosis I is the most common nondisjunction in aneuploidies. Trisomy is characterized by the presence of 3 chromosomes, instead of the normal 2, of any particular chromosome .

25. The most common numerical abnormalities in live born children include: - Trisomy 21 - Trisomy 18 - Trisomy 13 Sex chromosomal aneuploidies: - Turner syndrome - Klinefelter syndrome

26. Down syndrome(Trisomy 21) Down syndrome (DS) is the most common chromosome abnormality among live born infants. The incidence of Down syndrome in live births is approximately 1 in 733 live births. It is the most frequent form of intellectual disability (mental retardation) caused by a microscopically demonstrable chromosomal aberration . The occurrence increases with advanced maternal age (≥35 year). Cytogenetics Non-disjunction(47xx/ xy )-(95%) Translocation- (4%) Mosaic Down syndrome (1%)

27. Clinical features Characteristic dysmorphic features of DS affecting the head and neck include: Upslanting palpebral fissures Epicanthic folds Flat facial profile/flat nasal bridge Folded or dysplastic ears and low-set small ears Brachycephaly Brushfield spots Open mouth and protruding tongue Short neck Excessive skin at nape of the neck Narrow palate Abnormal teeth

28. Characteristic dysmorphic features of DS affecting the extremities include: Short broad hands Incurved fifth finger with hypoplastic mid phalanx Transverse palmar crease Space between the first and second toes (sandal gap) Hyperflexibility of joints

29. Affected individuals are more prone to CHD (50%) such as AVSD, VSD, isolated secundum ASD, PDA, and TOF. Pulmonary complications include recurrent respiratory infections, sleep-disordered breathing, laryngo- and tracheobronchochomalacia, tracheal bronchus, pulmonary hypertension, and asthma. Affected Children are at increased risk for GI anomalies , including duodenal atresia or stenosis, imperforate anus, and EA with TEF. They are also at increased risk for celiac disease and HSD.

30. Ophthalmologic disorders are common in patients with DS and increase in frequency with age. These disorders include refractive errors, strabismus, nystagmus, cataracts, and keratoconus. Hearing loss is also common, and otitis media is a frequent problem. Endocrine abnormalities in DS include thyroid dysfunction and type 1 diabetes.

31. Hematologic abnormalities are common in DS and include polycythemia, macrocytosis, leukopenia, thrombocytosis, and leukemia (transient, acute megakaryoblastic, and acute lymphoblastic). Alzheimer disease like dementia is a known complication that occurs as early as the 4th decade and has an incidence 2-3 times higher than sporadic Alzheimer disease. Most males with Down syndrome are sterile, but some females have been able to reproduce, with a 50% chance of having trisomy 21 pregnancies.

32. Developmental delay is universal. Cognitive impairment does not uniformly affect all areas of development. Social development is often relatively spared, but autism spectrum disorder can occur . Up to 15% of children with Down syndrome have misalignment of the 1 st cervical vertebra (C1), which places them at risk for spinal cord injury with neck hyperextension or extreme flexion . The life expectancy for children with Down syndrome is reduced and is approximately 50-55 yr.

33. All women should be offered screening for Down syndrome in their 2nd trimester by means of 4 maternal serum tests ( free β- hCG , unconjugated estriol , inhibin , and α-fetoprotein). This is known as the quad screen ; it can detect up to 80% of Down syndrome pregnancies. During the 1st trimester, fetal nuchal translucency (NT) thickness can be done alone or in conjunction with maternal serum β- hCG and pregnancy-associated plasma protein-A (PAPP-A ).

34. If both 1st- and 2nd-trimester screens are combined using NT and biochemical profiles ( integrated screen ), the detection rate increases to 95 %. Detection of cell-free fetal DNA in maternal plasma is also diagnostic and replacing conventional 1st- and 2nd-trimester screens . Chromosome analysis is indicated in every person suspected of having Down syndrome.

35. In approximately 95% of the cases of Down syndrome, there are 3 copies of chr 21. The origin of the supernumerary chr 21 is maternal in 97% of the cases as a result of errors in meiosis. If a translocation is identified, parental chromosome studies must be performed to determine whether one of the parents is a translocation carrier. Translocation (21;21) carriers have a 100% recurrence risk for a chromosomally abnormal child, and other robertsonian translocations, such as t(14;21), have a 5–7% recurrence risk when transmitted by females.

36. Edward syndrome(Trisomy 18) The second most common autosomal trisomy observed in live births. The incidence is 1 in 5500 live births. There is a 3:1 female to male ratio among affected infants . 50 percent of affected infants die within the first two weeks of life, and only 5 to 10 percent survive the first year. Related to advanced maternal age. Cytogenetics; 90% percent of cases of trisomy 18 are the result of meiotic nondisjunction. The remaining; translocation and mosaicism.

37. Clinical features Low birth weight Short sternum M icrocephaly Prominent occiput M icrognathia, Cardiac and renal malformations Closed fists with index finger overlapping the 3rd digit and the 5th digit overlapping the 4th Narrow hips with limited abduction Rocker-bottom feet Mental retardation

38. Congenital heart disease occurs in greater than 50 percent of affected individuals with common valvular involvement. VSD and PDA are the most common defects. The GI system is involved in approximately 75 percent of cases. Meckel's diverticulum and malrotation are the predominant abnormalities. Omphalocele is relatively common prenatally. IUGR associated with polyhydramnios, especially in a fetus with abnormal hand positioning ("clenched hands"), is suggestive of this disorder.

39. Patau syndome (Trisomy 13) Trisomy 13 is the least common but most severe of the viable autosomal trisomies. The incidence is 1.9 per 10,000 total births. The sex ratio at birth is slightly skewed toward females, presumably because of decreased survival among males. Median survival age is 2.5 days, with only 5% of children survive longer than 6 months. There is significant association between patau syndrome and increased maternal age.

40. Clinical features Cleft lip, cleft palate Polydactlyly (postaxial) Bulbous nose Low-set malformed ears S mall abnormal skull and Scalp defects(cutis aplasia) Cerebral malformation, especially holoprosencephaly Microphthalmia Hypotelorism Cardiac defect(80% of cases; PDA, VSD,ASD, Dextrocardia) Omphalocele Hernia NTDs

41. Abnormalities of Chromosome Structure Translocations Translocations, which involve the transfer of material from one chromosome to another , occur with a frequency of 1 in 500 live born human infants. They may be inherited from a carrier parent or appear de novo, with no other affected family member . Translocations are usually reciprocal or robertsonian, involving 2 chromosomes.

42. Reciprocal translocations are the result of breaks in nonhomologous chromosomes , with reciprocal exchange of the broken segments. Carriers are usually phenotypically normal but are at an increased risk for miscarriage. Robertsonian translocations involve 2 acrocentric chromosomes (chromosomes 13, 14, 15, 21, and 22) that fuse near the centromeric region with a subsequent loss of the short arms . The resulting karyotype has only 45 chromosomes. Carriers are usually phenotypically normal but at increased risk for miscarriage and unbalanced translocations in phenotypically abnormal offspring.

43. Inversions An inversion requires that a single chromosome break at 2 points; the broken piece is then inverted and joined into the same chromosome. Inversions occur in 1 in 100 live births. There are 2 types of inversions: pericentric and paracentric . Carriers are usually phenotypically normal , but they are at increased risk for miscarriages, typically in paracentric inversions , and chromosomally abnormal offspring in pericentric inversions.

44. Deletions and Duplications Deletions involve loss of chromosome material and, depending on their location, can be classified as terminal (at the end of chromosomes) or interstitial ( within the arms of a chromosome). They may be isolated or may occur along with a duplication of another chromosome segment . Deletions are usually associated with intellectual disability and malformations .

45. Sex Chromosome Aneuploidy Sex chromosome abnormalities are the most common chromosome abnormalities seen in live born infants, children, and adults . About 1 in 400 males and 1 in 650 females have some form of sex chromosome abnormality. Sex chromosome abnormalities can be either structural or numerical and can be present in all cells or in a mosaic form.

46. Turner syndrome Turner syndrome is a condition characterized by complete or partial monosomy of the X chromosome and defined by a combination of phenotypic features. It occurs in approximately 1 in 5,000 female live births . Half the patients with Turner syndrome have a 45,X chromosome complement . The other half exhibit mosaicism and varied structural abnormalities of the X or Y chromosome.

47. Maternal age is not a predisposing factor for children with 45,X . In 75% of patients, the lost sex chromosome is of paternal origin (whether an X or a Y ). It has been estimated that 95–99% of 45,X conceptions are miscarried.

48. Clinical findings in the newborns can include small size for gestational age, webbing of the neck, protruding ears, and lymphedema of the hands and feet, although many newborns are phenotypically normal. Older children and adults have short stature and exhibit variable dysmorphic features. Congenital heart defects (40%) and structural renal anomalies (60%) are common . The most common heart defects are bicuspid aortic valves, coarctation of the aorta, aortic stenosis, and mitral valve prolapse.

49. The gonads are generally streaks of fibrous tissue (gonadal dysgenesis ). There is primary amenorrhea and lack of secondary sex characteristics. Most patients tend to be of normal intelligence , but intellectual disability is seen in up to 6% of affected children. They are also at increased risk for behavioral problems and deficiencies in spatial and motor perception.

50. Turner syndrome may be diagnosed incidentally during prenatal testing. More commonly, it is suspected based upon characteristic clinical features, which may include webbed neck and congenital lymphedema in a neonate, short stature and reduced growth velocity in a child, and/or failure to develop breasts. The diagnosis is confirmed by karyotype analysis. Prompt diagnosis is important to permit effective treatment of short stature and management of comorbidities.

51. Klinefelter Syndrome Klinefelter Syndrome is the most common cause of hypogonadism and infertility in males and the most common sex chromosome aneuploidy in humans. T he prevalence of 47,XXY is approximately 1 in 580 live born males. Errors in paternal nondisjunction in meiosis I account for half the cases.

52. Eighty percent of children with Klinefelter syndrome have a male karyotype with an extra chromosome X-47,XXY. The remaining 20% have multiple sex chromosome aneuploidies (48,XXXY; 48,XXYY; 49,XXXXY), mosaicism (46,XY/47,XXY ), or structurally abnormal X chromosomes. T he greater the aneuploidy , the more severe the mental impairment and dysmorphism.

53. Puberty commences at the normal age, but the testes remain small. Patients develop secondary sex characters late, and 50% ultimately develop gynecomastia . They have taller stature. M any patients with Klinefelter syndrome are phenotypically normal until puberty, and it is often undiagnosed until they reach adulthood, when their infertility leads to identification .

54. Patients with 46,XY/47,XXY have a better prognosis for testicular function . Their intelligence shows variability and ranges from above to below average . They can show behavioral problems, learning disabilities, and deficits in language. Problems with self-esteem often occur in adolescents and adults. Substance abuse, depression, and anxiety have been reported. Those who have higher X chromosome counts show impaired cognition.

55. Diagnosis of Klinefelter syndrome usually can be made by determining the karyotype of the peripheral leukocytes. Testosterone deficiency and the resulting hypogonadism, if present, can be treated with testosterone. Hormone replacement is unlikely to improve the other abnormalities. Fertility has been achieved with assisted reproductive technologies.

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