genetic dse

• Genetics


  The study of a single or a few genes and their phenotypic effects
• Genomics


  The study of all genes in the genome and their interactions
• Proteomics


  Measurement of all proteins expressed in a cell or tissue
• Hereditary


  Derived from one's parent and transmitted through germ line or in the gametes
• Familial


  Runs in the family
• Congenital


  Present at birth
• Not all genetic disorders manifest in infancy and childhood, and conversely; Many pediatric diseases are not of genetic origin

  
• Categories of human genetic disorders

  • Single Gene Mutation Disorders with large effects
  • Chromosomal Disorders
  • Complex Multigenic Disorders
• Single Gene Mutation Disorders with large effects

  • Highly penetrant
  • Mendelian pattern of inheritance

  
• Chromosomal Disorders


  • Uncommon but highly penetrant
  • Arise from structural or numerical alteration in the autosomes and sex chromosomes
  • Visible with Karyotyping

  
• Complex Multigenic Disorders


  • Most common
  • Caused by interactions between multiple variant forms of genes and environmental factors
  • POLYMORPHISM: Variations in genes
  • Several polymorphisms lead to the development of a disease, hence known as MULTIGENIC or POLYGENIC
  • Examples: Atherosclerosis, Diabetes mellitus, Hypertension, Autoimmune diseases
• Mutation


  Permanent changes in the DNA
• Types of mutations


  • Mutations in GERM CELLS: are transmitted to the progeny and may give rise to inherited diseases
  • Mutations in SOMATIC CELLS: are not transmitted to the progeny but are important in the causation of cancers and some congenital malformations
• Types of point mutations

  • Conservative Missense Mutation: occurs when substituted amino acid is biochemically similar to the original
  • Nonconservative Missense Mutation: a normal amino acid replaces a biochemically different one
  • Nonsense Mutation: amino acid codon is changed to a chain terminator or stop codon
• Frameshift mutations


  Occur when the insertion or deletion of one or two base pairs alters the reading frame of the DNA strand
• Trinucleotide repeat mutations


  Characterized by amplification of a sequence of three nucleotides
• Mendelian patterns of inheritance

  • Autosomal Dominant Inheritance
  • Autosomal Recessive Inheritance
  • X-Linked Disorders

  
• Autosomal Dominant Inheritance


  • Manifested in the heterozygous state, so at least one parent in an index case usually is affected
  • Both males and females are affected, and both can transmit the condition
  • When an affected person marries an unaffected one, every child has one chance in two of having the disease
  • In many conditions, the age at onset is delayed, and symptoms and signs do not appear until adulthood

  
• Autosomal Recessive Inheritance


  • Make up the largest group of mendelian disorders
  • They occur when both of the alleles at a given gene locus are mutants
  • The trait does not usually affect the parents, but siblings may show the disease
  • Siblings have one chance in four of being affected
  • Onset is frequently early in life

  
• 1. Linked Disorders


  • All sex-linked disorders are X-linked, and most X-linked disorders are X-linked recessive
  • They are transmitted by heterozygous female carriers only to sons
  • Sons of heterozygous women have one chance in two of receiving the mutant gene
  • An affected male does not transmit the disorder to sons, but all daughters are carriers

  
• Mendelian disorders


  • Marfan Syndrome
  • Ehler's Danlos Syndromes
  • Familial Hypercholesterolemia
  • Cystic Fibrosis
  • Phenylketonuria
  • Galactosemia
  • Lysosomal Storage Diseases
• Marfan Syndrome


  • A connective tissue disorder of autosomal dominant inheritance
  • Caused by a mutation in the FBN1 gene encoding fibrillin
  • Major tissues affected: skeleton, eyes, and cardiovascular system
  • Clinical features: tall stature, long fingers, bilateral subluxation of lens, mitral valve prolapse, aortic aneurysm, aortic dissection
• Ehler's Danlos Syndromes


  • There are six variants, all characterized by defects in collagen synthesis or assembly
  • Each variant is caused by a distinct mutation
  • Clinical features: fragile, hyperextensible skin vulnerable to trauma, hypermobile joints, ruptures involving colon, cornea, or large arteries, poor wound healing
• Familial Hypercholesterolemia


  • One of the most common mendelian disorders (1 in 500 in the general population)
  • Autosomal dominant disorder caused by LDLR gene mutation
  • In heterozygotes: elevated serum cholesterol greatly increases the risk of atherosclerosis and resultant coronary artery disease
  • In homozygotes: even greater increase in serum cholesterol and a higher frequency of ischemic heart disease, cholesterol also deposits along tendon sheaths to produce xanthomas

  
• Cystic Fibrosis


  • Autosomal recessive disease caused by mutations in the CFTR gene
  • The principal defect is of chloride ion transport, resulting in high salt concentrations in sweat and in viscous luminal secretions in respiratory and gastrointestinal tracts
  • CFTR mutations can be severe (resulting in multisystem disease) or mild (with limited disease extent and severity)
  • Clinical features: cardiopulmonary complications, pulmonary infections, pancreatic insufficiency, infertility, liver disease
• Phenylketonuria


  • Autosomal recessive inheritance caused by a lack of the enzyme phenylalanine hydroxylase
  • Clinical features: severe mental retardation, seizures, decreased pigmentation of skin
  • Female patients with PKU who discontinue dietary treatment can give birth to children with malformations and neurologic impairment resulting from transplacental passage of phenylalanine metabolites
• Galactosemia


  • Autosomal recessive disorder caused by an inherited lack of the GALT enzyme
  • Clinical features: jaundice, liver damage, cataracts, neural damage, vomiting and diarrhea, E. coli sepsis
• Lysosomal Storage Diseases


  • Tay-Sachs Disease: caused by an inability to metabolize GM2 gangliosides due to lack of the β subunit of lysosomal hexosaminidase
  • Niemann-pick Disease Types A and B: caused by a deficiency of sphingomyelinase
  • Niemann-pick Disease Type C: caused by a defect in cholesterol transport and resultant accumulation of cholesterol and gangliosides in the nervous system
  • Gaucher Disease: results from lack of the lysosomal enzyme glucocerebrosidase and accumulation of glucocerebroside in mononuclear phagocytic cells
  • Mucopolysaccharidoses: result from accumulation of mucopolysaccharides in many tissues including liver, spleen, heart, blood vessels, brain, cornea, and joints

  
• Down Syndrome


  • Associated with an extra copy of genes on chromosome 21, most commonly due to trisomy 21 and less frequently from translocation of extra chromosomal material from chromosome 21 to other chromosomes or from mosaicism
  • Patients have severe mental retardation, flat facial profile, epicanthic folds, cardiac malformations, higher risk of leukemia and infections, and premature development of Alzheimer disease

  
• Klinefelter Syndrome


  • In Klinefelter syndrome, there are two or more X chromosomes with one Y chromosome as a result of nondisjunction of sex chromosomes
  • Patients have testicular atrophy, sterility, reduced body hair, gynecomastia, and eunuchoid body habitus. It is the most common cause of male sterility

  
• Turner Syndrome


  • In Turner syndrome, there is partial or complete monosomy of genes on the short arm of the X chromosome, most commonly due to absence of one X chromosome (45,X) and less commonly from mosaicism, or from deletions involving the short arm of the X chromosome
  • Short stature, webbing of the neck, cubitus valgus, cardiovascular malformations, amenorrhea, lack of secondary sex characteristics, and fibrotic ovaries are typical clinical features

  
• Fragile X Syndrome


  • Pathologic amplification of trinucleotide repeats
  • Such mutations produce neurodegenerative disorders
  • Fragile X syndrome results from loss of FMR1 gene function and is characterized by mental retardation, macroorchidism, and abnormal facial features

  
• Prader-Willi Syndrome


  Results from deletion of paternal chromosomal region 15q12 and is characterized by mental retardation, short stature, hypotonia, obesity, and hypogonadism
• Angelman Syndrome


  Results from deletion of maternal chromosomal region 15q12 and is characterized by retardation, ataxia, seizures, and inappropriate laughter