Genetics PDF

Genetics -------- - ##### Learning objectives: - Demonstrate understanding of chromosome abnormalities - Solve problems concerning hereditary diseases in pediatrics. ##### Human chromosomes: - Chromosomes carry all the genetic features of the individual. - Each chromosome is formed o...

Genetics -------- - ##### Learning objectives: - Demonstrate understanding of chromosome abnormalities - Solve problems concerning hereditary diseases in pediatrics. ##### Human chromosomes: - Chromosomes carry all the genetic features of the individual. - Each chromosome is formed of two chromatids (DNA and proteins) connected together at a point by the centromere. - There are two types of chromosomes: autosomes and sex chromosomes (X and Y chromosomes). - Each somatic cell contains 46 chromosomes (diploid number) arranged in pairs: 22 pairs of autosomes and two sex chromosomes (XX in females and XY in males). - Each germ cell (ova or sperm) contains 23 chromosomes (haploid number), 22 autosomes and one sex chromosome (either X in the ova or Y in the sperm). - Karyotyping is a laboratory way to detect the count and structure of the individual's somatic cell (leukocytes or fibroblasts are usually used). - ##### The Gene: ##### Genetic disorders 1. ##### Numerical abnormalities: - **Autosomal abnormality:** - Trisomy: cells contain extra chromosome e.g. trisomy 21(Down syndrome), trisomy 13 and 18. - Monosomy: one chromosome is missing e.g. monosomy 22. - **Sex chromosomes abnormality**: Turner syndrome (45, X) female and Klinfelter syndrome (47, XXY male). 2. ##### Structural abnormalities: - Translocation: transfer of material from one chromosome to another. - Deletion: loss of a portion of the chromosome. - Ring chromosome: a special type of deletion in which the broken ends re-unit to form a ring. - Inversion: fragmentation of a chromosome followed by reconstruction. - Duplication: presence of an extra piece of a chromosome. - Isochromosomes: it is the division of chromosomes transversely instead of longitudinally. - Non-disjunction  ##### П- Single gene disorders: - Autosomal dominant inheritance: it appears with only one single copy of the abnormal gene. - Autosomal recessive inheritance: it appears if the two copies of the abnormal gene is present. - X-Linked inheritance: the abnormal gene is on the X chromosome (X-linked dominant or recessive). ##### Ш- Multifactorial (polygenic) inheritance - - It is exclusively transmitted by the mother \[Sperm does not contain mitochondria\] - Example: mitochondrial encephalopathy and cardiomyopathy. ##### Down Syndrome (Trisomy 21 or Mongolism) ##### Etiology: 1. Non-disjunction: In 95% of cases, with higher incidence with advanced maternal age. Karyotyping will show that the cells carry 47 chromosomes. 2. Translocation: In this type (4% of cases), karyotyping reveals that cells carry 46 chromosomes, and one of the 21 chromosome is structurally abnormal. 3. Mosaic type: Some cells of the affected individual are normal (46 chromosome) while others carry 47 chromosomes. The clinical manifestation and the mental retardation are usually mild. ##### Clinical manifestations: Characteristic features: - Head: small head circumference, flat occiput, upward slanting palpebral fissure, depressed nasal bridge, malformed ears, silky hair and protruded tongue. - Hands: broad with simian crease. - Feet: wide space between first and second toe. - Delayed physical, mental and motor development: - Short stature and underweight for age. - Delayed, abnormal speech with delay in all developmental aspects. - Body systems: - Cardiovascular system: structural defects, the commonest are endocardial cushion defect, ventricular septal defects, patent ductus arteriosus, and maybe Fallot tetralogy. - Nervous system: generalized hypotonia. - Associated anomalies: - Heart: cardiac anomalies (40 *% of* cases): endocardial cushion defect: VSD, ASD, common atrioventricular canal, PDA and Fallot tetralogy. - GIT: duodenal atresia - Joints: congenital hip dislocation. - [Possible complications:] 1\. Higher susceptibility to recurrent respiratory tract infections. 2\. Heart failure in cases with congenital heart disease. 3\. Higher incidence of leukemia: 4\. Accidents are one of the most important causes of death in Down syndrome ##### Investigations: 1. Karyotyping 2. Investigations for associated problems e.g. heart defects. 3. [Antenatal Diagnosis of Down syndrome:] [Indications]: - Old maternal age \> 35 years - Previous baby with Down syndrome - Family history of translocation [Methods:] **a-** [Triple test: done in maternal serum at 15-16 weeks of gestation] **b-** [Fetal karyotyping]: Amniocentesis: 14-16 weeks of gestation Chorionic villus sample: 9-12 weeks of gestation **c-** [Fetal US] Nuchal Translucency thickening: thickening of the nuchal fold at the back of the neck due to delayed drainage of fluid from the upper part of the body Short femur Cystic hygroma of the neck, duodenal stenosis ##### Treatment: ##### ##### ##### Trisomy 18 (Edwards Syndrome) - Genetics-older maternal age; nondisjunction - [Findings] **Trisomy 13 (Patau Syndrome)** ##### ##### ##### ##### Fragile X Syndrome #####  New insights into Fragile X syndrome and the fetal brain \| Science Codex - [Genetics] - Fragile site on long arm of X in affected males and some carrier - females Molecular diagnosis-variable number of repeat CGG (preferred diagnosis = DNA-based - X-linked dominant-males (most common cause of inherited intellectual disability); - There are generally fewer abnormalities seen in girls but they may present with decreased IQ - [Findings] - Mild to profound intellectual disability; learning problems; anxiety, depression, and autistic-like behaviors - Large ears, dysmorphic facial features, large jaw, long face - Large testes---mostly in puberty (macroorchidism)(fertile) - Natural history---normal lifespan ##### Achondroplasia/Hypochondroplasia - **Genetics:** autosomal dominant; most common short-limb dwarfism; 90% from new gene mutation; older paternal age; mutations in gene for fibroblast growth factor receptor 3 at 4p16.3 (*FGFR3*) - ##### Findings: - Short stature (increased upper-to-lower segment ratio; short-limbed dwarfism) - Proximal femur shortening - Megalocephaly, small foramen magnum (may have hydrocephalus), small cranial base, prominent forehead - Lumbar lordosis - ##### Natural history - Normal intelligence - Spinal cord compression is rare (cervicomedullary junction); usually occurs in first year of life - Tendency of late childhood obesity - Small Eustachian tube---otitis media and hearing loss - Early cervical compression, respiratory problems, obstructive and central apnea, ##### Marfan Syndrome C:\\Users\\Eman\\Pictures\\OIP (4).jpeg **Genetics:** autosomal dominant with wide variability; mutation in fibrillin gene (*FBN1*)---15q21.1 - ##### Findings - Early rapid growth of the appendicular skeleton and anterior ribs - Major findings are skeletal, cardiovascular, and ocular - Tall stature with long, slim limbs and little fat - Arm span \> height - Arachnodactyly - Decreased U: L segment ratio (as with XXY) - Joint laxity with kyphoscoliosis - Pectus excavatum or carinatum - Lens subluxation (upward; defect in suspensory ligament); secondary glaucoma, myopia, retinal detachment - Ascending aortic dilatation with or without dissecting aneurysm (uncommon in children and adolescents unless case is severe) with secondary aortic regurgitation. - Mitral valve disease (MVP and regurgitation) is the most common in children. - ##### Natural history - Prevent scoliosis - Vascular complications chief cause of death ##### Sex chromosomes abnormalities: Turner Syndrome (45, XO female): - This is a rather common disorder occurring in 1/3000 newborns (1/500 females). - The basic defect is loss of one X chromosome (monosomy). - Clinically, there is short stature, webbing of the neck, cubitus vulgus (increased carrying angle) and gonadal dysgenesis. - Associated cardiac (Co-arcitation of the aorta) and renal anomalies may occur. ##### KlinefelterSyndrome (47, XXY male) - Occurs in 1/1000 males due to the presence of an extra X chromosome. - Clinical features are gynecomastia, small atrophic testes and azospermia. - It is usually not diagnosed except after puberty. ##### Single Gene Disorders ##### Autosomal dominant inheritance: - Affected individual can be homozygous or heterozygous, and has at least one affected parent. If the individual is heterozygous, 50% of his children will be affected. The trait appears in every generation with no skipping. Usually associated with structural defects. - Unaffected individuals are normal (no carrier state). - Examples: skeletal diseases as achondroplasia, renal diseases as polycystic kidney. II. ##### Autosomal recessive inheritance: - A single mutant gene, located on an autosome, expresses itself only in homozygous individual. - Affected individual should be homozygous, and both his parents have the affected gene. - Unaffected individual may be normal or heterozygous for the affected gene (carrier). - Recurrence risk: when parents have one affected child, the risk of having another affected offspring is 1 in 4. - Strong correlation to consanguinity. ##### Sex-linked inheritance: a. ##### X-linked recessive inheritance: - The carrier female transits the abnormal gene to 50% of her daughters (carriers), and 50% of her sons (affected). - No male to male transmission - Females are affected if homozygous for the affected gene, or she has a Turner syndrome. - Examples: hemophilia A, glucose-6-phosphate deficiency. b. ##### X-linked dominant inheritance: - The affected gene expresses itself in heterozygous female c. ##### Y- linked inheritance: [Genetic Counseling] ================================ A communication process whereby an individual or family obtains information about a genetic condition, is helped to understand the implications and significance of the condition, and is given resources to help with coping and management. [Value:] - Assess the risk of having another child with a genetic disorder - Assess the possibility of other family members having a child with an inherited disease - Assess the risk of having an inherited disease that affects your health later in life, such as mitochondrial disorders, Fabry disease and Marfan syndrome  - Make recommendations for genetic testing - Explain possible scenarios and outcomes