Javad Jamshidi Fasa University of Medical Sciences, December 2015 Chromosome and single-gene Disorders Session 3 Medical Genetics

The development of chromosome analysis in 1956 led to the discovery of several abnormality in chromosome number Down syndrome (47,XX/XY, +21), Klinefelter syndrome (47,XXY), Turner syndrome (45,X) To date, at least 20,000 chromosomal abnormalities have been registered Account for a large proportion of spontaneous pregnancy loss, childhood disability and malignancies

3 In at least 10% of all spermatozoa and 25% of mature oocytes Approximately 50% of all spontaneous miscarriages have a chromosome abnormality By birth it has declined to a level of 0.5% to 1%, although the total is higher (5%) in stillborn infants 10 % 25 %

4 Chromosome abnormalities in spontaneous abortions (percentage values related to total chromosomally abnormal abortions) AbnormalityIncidence (%) Trisomy 13 2 Trisomy Trisomy 18 3 Trisomy 21 5 Other Trisomy 25 Monosomy X 20 Triploidy 15 Tetraploidy 5 Other 10 From Emery's Elements of Medical Genetics, 14th Edition, by Peter D. Turnpenny and Sian Ellard, (2012)

5 Spontaneous pregnancy loss in commonly recognized aneuploidy syndromes Disorder Proportion undergoing spontaneous pregnancy loss(%) Trisomy 1395 Trisomy 1895 Trisomy 2180 Monosomy X98 From Emery's Elements of Medical Genetics, 14th Edition, by Peter D. Turnpenny and Sian Ellard, (2012)

6 Derives its name from Dr Langdon Down, who first described it in 1866 The chromosomal basis was established in1959 Incidence is approximately 1:1000 in UK, 1:800 in USA Strong association between the incidence of Down syndrome and advancing maternal age

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8 Congenital cardiac abnormalities in 40% to 45% Severe hypotonia in the newborn period

9 Facial characteristics of small ears, and protruding tongue, upward sloping palpebral fissures Image from Emery's Elements of Medical Genetics, 14th Edition, by Peter D. Turnpenny and Sian Ellard, (2012)

10 Single palmar creases are found in 50%

11 IQ scores ranging from 25 to 75, average of young adults is around 40 to 45 Social skills are relatively well-advanced and most children are happy and very affectionate. Adult height is usually around 150 cm Average life expectancy is 50 to 60 years, early death in 15% to 20% of cases Most affected adults develop Alzheimer disease

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13 Described in 1960, incidence for both is approximately 1:5000 Prognosis is very poor, with most infants dying during the first days or weeks of life Cardiac abnormalities occur in at least 90% of cases Both occur more frequently with advanced maternal age

14 Trisomy 13 (Patau Syndrome) Images from Emery's Elements of Medical Genetics, 14th Edition, by Peter D. Turnpenny and Sian Ellard, (2012)

15 Trisomy 18 (Edward Syndrome) Images from Emery's Elements of Medical Genetics, 14th Edition, by Peter D. Turnpenny and Sian Ellard, (2012)

16 First described clinically in 1942, Was shown in 1959 to be due to the presence of an additional X chromosome 1:1000 male live births

17 Clumsiness or mild learning difficulties, in childhood Verbal IQ is reduced by 10 to 20 points Adults tend to be slightly taller than average All are infertile (azoospermia) Treatment with testosterone from puberty onward for the development of secondary sexual characteristics

18 May look normal at birth, some show edema with puffy extremities and neck webbing.

19 Intelligence in Turner syndrome is normal The two main medical problems are: Short stature without growth hormone treatment 145 cm haploinsufficiency for the SHOX gene Ovarian failure lead infertility Estrogen replacement therapy should be initiated at adolescence

20 Approximately 0.1% of all females have a 47,XXX karyotype Usually have no physical abnormalities, but can show a mild reduction in intellectual skills Adults are usually fertile and have children with normal karyotypes. Women with more than three X chromosomes show a high incidence of learning difficulties

21 Incidence of about 1:1000 in males in newborn Physical appearance is normal and stature is usually above average, fertility is normal Intelligence is mildly impaired, with an overall IQ score of 10 to 20 points below a control sample. The additional Y chromosome must arise either as a result of non-disjunction in paternal meiosis II or as a post-zygotic event

22 Multiple congenital abnormalities Unexplained mental retardation Sexual ambiguity or abnormality in sexual development Infertility Recurrent miscarriage Malignancy and chromosome breakage syndromes

To date, more than 10,000 single-gene traits and disorders have been identified Individually are rare, affect between 1% and 2% of the general population The management of these disorders presents the major workload challenge in clinical genetics 23

24 Progressive neurological disability one of the worst hereditary disorders in man, no effective treatment or cure The prevalence is approximately 1:10,000 The onset is mostly between 30 and 50 years, but it can start at virtually any age

25 Slowly progressive movement disorder and insidious impairment of intellectual function with psychiatric disturbance The mean start age is about 40, duration is approximately 15 to 20 years Chorea is the most common

26 Image from: Netter's Neurology, Second Edition

27 Slowly progressive movement disorder and insidious impairment of intellectual function with psychiatric disturbance The mean start age is about 40, duration is approximately 15 to 20 years Chorea is the most common As disease progresses the gait becomes unsteady and speech unclear Intellectual changes in the early stages include memory impairment and poor concentration span Anxiety and panic attacks, mood changes and depression Aggressive behavior, paranoia, irrationality Gradual deterioration in intellectual function, leading eventually to total incapacitation and dementia.

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29 Autosomal dominant, variable age of onset Codes for a protein known as huntingtin, 4p16.3, contain CAG repeats at 5´end Huntingtin is expressed in many different cells throughout the central nervous system, as well as other tissues

30 Normal Alleles 26 or fewer CAG Mutable Alleles 27 to 35 CAG Reduced Penetrance Alleles 36 to 39 CAG Disease Alleles 40 or more CAG Predictive genetic test is available but…

31 The most common and most severe form of muscular dystrophy. A similar but milder condition, Becker muscular dystrophy (BMD), is caused by mutations in the same gene. The incidences of DMD is approximately 1:3500 and BMD 1:20,000 males

32 Usually present between the ages of 3 and 5 years with slowly progressive muscle weakness resulting in: An awkward gait, inability to run quickly Difficulty in rising from the floor Most affected boys have to use a wheelchair by the age of 11 years Subsequent deterioration leads to lumbar lordosis, joint contractures, and cardiorespiratory failure, resulting in death at a mean age of 18 years One-third of boys with DMD show mild-moderate intellectual impairment

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34 Both DMD and BMD show X-linked recessive inheritance, males with DMD rarely, if ever, reproduce The dystrophin gene is huge in molecular terms, consisting of 79 exons and 2.3 Mb of genomic DNA

35 There are two forms of hemophilia: A and B. Hemophilia A is the most common severe inherited coagulation disorder, with an incidence of 1:5000 males. Deficiency of factor VIII, which, plays a critical role in the pathway activation of prothrombin to thrombin. Hemophilia B affects approximately 1: 40,000 males and is caused by deficiency of factor IX. It is also known as Christmas disease

36 Protein Substitution Using plasma-derived factor VIII or factor IX Factor VIII has a half-life of 8 h Transmission of viral infection such as hepatitis B and HIV 10% of patients develop inhibitory antibodies Gene Therapy Excellent candidates for gene therapy as only a slight increase in the plasma level of the relevant factor is of major clinical benefit.

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