2008. principles each human cell has 46 chromosomes = 23 pairs each pair consists of 1 paternal...

Principles

Each Human cell has 46 chromosomes = 23 pairs Each pair consists of 1 paternal and 1

maternal chromosome 2 genes at equivalent loci each coding

for an individual polypeptide

Principles

Gametes (ova/sperm) has only 50% of parents genetic constitution

The particle randomly selected is one of the 2 genes at each loci

Heterozygote = 2 different allele (genes) at the same locus

Homozygote -= 2 identical alleles at the same locus

Classification of diseases Diseases can be classified

from defects in Whole chromosomes – either number or form

Individual genes Lots of genes and/or the environment

Autosomal disorders

44 autosomes = 22 homologous pairs 1 pair sex chromosomes Genes have strict order on each

autosome Each gene occupies a distinct locus in

unison with its counterpart of maternal/paternal origin

Alleles are alternative genes that have arisen by mutation

Autosomal disorders

If both members of a gene pair are identical then the individual is homozygous

If both members are different then the individual is heterozygous

Gene specified characteristics are called traits

Autosomal disorders

3 types of autosomal disorder Autosomal dominant – trait is seen in

heterozygote Aa and homozygote AA Autosomal recessive – trait is only seen

in homozygote aa Autosomal co-dominant – effect of both

alleles seen in heterozygote AB

Types of autosomal inheritance Autosomal dominant inheritance

Disorder manifest in both homo and heterozygote

Both sexes can be affected but their can be different degrees of severity = variable expression between individuals

Rarely an individual with a mutant gene may have a normal phenotype = non penetrance the gene and trait may still be transmitted to the offspring

Autosomal dominant disorders• 2,200 dominant disorders known– Dominant otosclerosis 3/1000– Familial hypercholesterolemia 2/1000– Adult polycystic kidney disease 1/1000– Multiple exostoses 0.5/1000– Huntingdon’s disease 0.5/1000– Neurofibromatosis 0.4/1000– Myotonic dystrophy 0.2/1000– Polyposis coli 0.1/1000

Autosomal recessive disorders• Only appears in homozygote • Both parents usually heterozygote

carriers• They are not affected by the disease• Incidence should be 1 in 4 of offspring• Affects each sex equally• Very little variability of expression• Parental consanguinity • A few are inborn errors of metabolism

with defective enzymes

Autosomal recessive disorders Some are associated with

ethnic groups beta thalassaemia Cypriots,

Greeks, Italians Sickle cell disease Africans,

Blacks, West Indians Cystic fibrosis

Caucasians

Autosomal recessive disorders 14,000 autosomal recessive traits

known Cystic fibrosis 0.5/1000 Recessive mental retardation 0.5/1000 Congenital deafness 0.2/1000 Phenylketonuria 0.1/1000 Spinal muscular atrophy 0.1/1000

Autosomal co-dominant inheritance Can detect either or both of two

alleles in an individual The fragments can be followed

through the family tree Human blood groups ABO, duffy, kell,

rhesus exhibit this form of inheritance

Autosomal co-dominant inheritance ABO blood groups If parents both AB then

Get offspring who are A, AB, B But the ratio is 1(A) : 2(AB): 1(B)

phenotype If one allele is dominant and the other

recessive would get 3:1 ratio

Chromosomal disorders

If mutations large enough to be seen under light microscope they are called chromosomal disorders

Divided into structural and numeric disorders

The smallest alteration to a chromosome that is visible is 4x106 6 base pairs


Affect 7.5% of all conceptions but due to miscarriage only affect 0.6% of live births

60% of spontaneous miscarriages have chromosomal abnormalities

Commonest type of abnormalities are trisomies (Down’s, Edward’s), 45 (Turner’s), x or triploidy


Disorders result from germ cell mutations in parents that have been passed onto the sex chromosomes or autosomes in the affected individual

Arise out of somatic mutations in the generation affected


Autosomal chromosome disruptions are more serious than sex chromosomes disruptions

Deletions are more serious than duplications


Numeric disorders 92 xxyy tetraploidy 69 xyy triploidy 47 xx (21) trisomy 21 47 xy (18) trisomy 18 47 xx (16) trisomy 16 47 xx (13) trisomy 13 47 xxy or xxxxy Klinefelters 47 xxx trisomy x 45 x Turner’s syndrome


Aneuploidy Exists when the chromosome number is not

46 but not a direct multiple of the haploid number 23

Caused by delayed movement of chromatid in the anaphase or non disjunction of chromosomes in metaphase

Occurs with increasing frequency with Maternal age Maternal hypothyroidism During recent radiation or viral illness


Polyploidy Occurs with a complete extra set or sets

of chromosomes Triploidy arises from

Fertilisation with 2 sperm or failure of one of the maturation divisions of the egg or sperm so producing a diploid gamete 69 xxy is the commonest

Tetraploidy is due to failure of first zygotic division


Trilpoidy 69 xxy or more rarely xxx 2% of all conceptions usually leads to

miscarriage If carries on to term

Low birth weight Disproportionally small head to trunk Syndactyly Multiple congenital abnormalities Large placenta with hydatidiform like

changes


Tetraploidy Describes a situation where the genotype is 96 xxyy or some other combination of sex chromosomes

Is rapidly fatal rarely survives to term


Trisomy Is having 3 copies of a chromosome Caused by failure of disjunction during

meiosis with unequal separation of the chromosome between the gametes

Most are rapidly fatal only trisomy 21 survives beyond 1yr

Trisomy 13 – Patau’s syndrome severe mental retardation

Trisomy 18 – Edward’s syndrome


Sex chromosome abnormalities Turner’s xo short stature webbed neck Triple x xxx developmental delay

tall Double y xyy tall fertile psychiatric illness Klinefelter’s xxy tall infertile early germ

cell atrophy poor secondary sexual characteristics

Fragile x dominant x linked gene with 50% penetrance in females developmental delay


Structural disorders Arise from chromosomal breakage, once

broken attempted repair may rejoin 2 unrelated parts of the chromosome

Breakage facilitated by Ionising radiation Mutagenic chemicals Some rare inherited conditions


Recognised structural abnormalities Translocation the transference of

material between chromosomes. Carriers with balanced translocations are not affected but offspring are

Deletion this occurs at both ends of a chromosome can lead to ring chromosomes

Duplication of a section of a small section of chromosome often with little harmful consequence


Recognised structural abnormalities Inversion – breakage at 2 ends of a

chromosome with rotation and rejoining of the part in between so that it lies the wrong way round

Isochrome – deletion of one arm of a chromosome with duplication of the other arm

Centric fragments – small remaining material after translocation


Chromosomal deletion disorders Angleman syndrome Prader-willi Cri du chat


Other disorders

Multifactorial disorders

Phenotype is determined by the actions of multiple genetic loci and the environment

Risk in these families is higher than normal population it decreases with distance from affected individual

Twin concordance and family correlational studies are required if multifactorial inheritance is suspected


Examples Spina bifida

Geographical differences indicate celtic descent

Seasonal variation and greater incidence in lower social class indicate an environmental influence also happening

Cleft palate and lip CDH Diabetes epilepsy


Examples Hyperthyroidism Multiple sclerosis Psoriasis Pyloric stenosis Schizophrenia Alzheimer’s

Sex linked disorders

Women have two x chromosomes one from each parent one of which is inactivated at random

Males have only one x chromosome X linked disorders can be dominant

or recessive. In dominant disorders they are present in women as well as men


Recessive x linked disorders Only males affected No variation of expression disease

always follows predictable course Heterozygous females are not affected

but carry the gene Rarely occurs in female only if faulty

inactivation of the x chromosome


290 recessive x linked diseases are known Red green colour blind Fragile x Duchenne muscular dystrophy Becker muscular dystrophy Haemophilia A factor 8 Haemophilia B factor 9 X linked agammglobulinaemia


X linked dominant disorders Expressed in both sexes but more

common in females due to greater number of x chromosomes

Females may be homozygous or heterozygous

Males can only be heterozygous Positive father will give trait to all his

daughters but none of his sons Positive mother will give trait to half her

sons and half her daughters


X linked dominant disorders The trait is uniform seriousness in males In females it has variable seriousness

Examples – very few known disorders Xg blood group Vitamin D resistant rickets Rett’s syndrome

Digenic disorders

In these disorders two genes interact to produce the phenotype

Mode of inheritance is often simple mendelian but with another gene interfering to modulate the severity of the disease

Examples Cystic fibrosis Limb girdle dystrophy

Familial cancers

Examples Breast Ovarian Colorectal

5-10% of new cases are caused by dominantly inherited single gene mutations

Combinations of lower penetrance genes also contribute to a significant portion of family histories

Familial cancers

Features suggestive of inherited cancer High incidence in family in closely related

individuals Early age of onset Multiple primaries in an individual (rockenbach) Certain cancer combinations

Breast and ovary Breast and sarcoma Colorectal, uterine, ovarian and stomach

Ethnicity – Ashkenazi Jews high incidence of 3 common breast and ovarian cancer founder mutations

Familial cancers

Who to refer with FH breast and ovarian cancer Mother or sister breast ca < 40yrs Mother or sister bilateral breast ca any age Father or brother with breast ca any age Mother or sister with breast and ovarian ca

any age One close relative with breast ca < 50 and

relative with ovarian caany age same side of family

Familial cancers

FH breast and ovarian ca who to refer Two close relative breast ca any age Two close relative ovarian ca any

age Three or more close relative with

breast ca, ovarian ca or both on the same side of the family at any age

Familial cancers

Who to refer colorectal cancer 1 first degree relative CRC < 45yrs 1 first degree relative who has 2

separate or multiple CRC or two associated ca – CRC, endometrial, ovarian, small bowel, ureter or renal pelvis.

1 first degree relative with more than 1 bowel polyp < 40 which is tubulovillous, dysplastic, or an adenoma > 10cm

Familial cancers

Who to refer CRC cancers 1 first degree relative with FAP of FH of FAP 1 parent with multiple colorectal polyps

>100 2 close relatives who are first degree

relatives to each other can include both parents with average age < 70 of CRC

2 close relatives who are first degree relatives to each other on same side of family with associated cancers age < 50

Familial cancers

Who to refer CRC 3 close relatives on same side of family

with an associated tumour

Familial cancers

High risk pedigrees 4 close relatives with breast,

ovarian, or both any age 3 close relatives with breast ca

average age < 60 2 close relatives with breast ca

average < 50 2 close relatives ovarian ca any age Known families of carriers of BRCA1,

BRCA2

Familial cancers

High risk pedigrees 3 close relatives CRC or 2 with CRC and

one associated cancer in at least 2 generations. 1 must be under 50 at diagnosis and one should be first degree relative of the other 2

Known gene carriers of hereditary non polyposis colon ca FAP or relatives of known affected family

All others are moderate risk

Familial cancers

Moderate risk pedigrees are normally managed in secondary care Breast ca

Annual mammograms from age 40-50 then will enter national 3 yrly scheme

CRC Offered colonoscopy frequency varies

Familial cancers

High risk pedigrees Normally seen and counselled by

regional genetic centre Breast

Annual mammograms If BRAC1 or 2 then combination of annual

MRI and mammogram between ages 30-49yrs. Age 50-69 mammograms every 18 months then 3x/year after 69

Familial cancers

High risk pedigrees Ovarian ca

Only offered if FH includes either ovarian ca or the person is a known BRAC carrier as part of UKFOCSS trial which offers transvaginal ultrasound and regular ca 125 monitoring every 4 months

CRC cancer People at high risk of hereditary non polyposis crc

and crc are offered 2 colonoscopies a year from ages 25-27 if they have been assessed as a positive pedigree

Familial cancers

Summary Family histories of cancer in primary

care allows GP’s to assess risk and make appropriate referrals.

This allows families to benefit from relevant targeted screening and gene testing as per national guidelines.

Prenatal diagnosis

Investigations include Chorionic villous sampling Amniocentesis Foetoscopy ultrasound

Prenatal diagnosis

Tests offered Amniocentesis

Karyotyping for chromosomal abnormalities Down’s syndrome

X linked disorders Duchenne muscular dystrophy

Gene probes to detect individual genes Cystic fibrosis

Enzyme assay of cultured amniotic cells Inborn errors of metabolism

Prenatal diagnosis

Risks of amniocentesis Singleton preg 0.5-1% foetal loss Multiple preg 3% risk foetal loss Foetal damage very rare

Loss of one eye damage to brachial plexus Pneumothorax

Lung hypoplasia

Prenatal diagnosis

Tests offered Chorionic villus sampling

Same tests as performed on amniocentesis

Advantages Performed earlier in preg it top needed

done at much earlier stage before preg shows

Results available quicker

Prenatal diagnosis

Chorionic villus sampling Disadvantages

Greater risk of foetal loss 3% Risk of foetal damage – limb agenesis due

to disruption of foetal blood vessels Chromosome analysis less accurate Result sometimes can’t be interpreted

requiring further tests Genetic mosiaicism between chorionic

cells and the foetus resulting in false positives and false negatives i.e. Down’ syndrome

Prenatal diagnosis

Foetoscopy Enables visualisation of foetus

Foetal inspection – facial and limb abnormalities

Foetal blood sampling – haemophilia, thalassaemia, sickle cell, fragile X, alpha 1 antitrypsin deficiency

Foetal skin biopsy – lethal epidermolysis bullosa

Foetal liver biopsy – ornithine transcarbamylase deficiency – loss = 5%

Diagnosis in genetic counselling

If a major chromosomal abnormality exists then a recognised syndrome of 2 or more dysmorphic features will usually be present chromosomal analysis should be carried out if Unexplained mental retardation Known history of structural chromosomal

problem Unexplained stillbirth Female with unexplained short stature Recurrent miscarriages Ambiguous sexual development

Ethical and legal considerations Under congenital disabilities act 1976 an

action can be taken against anyone whose negligent action resulted in a child being born disabled, abnormal or unhealthy.

It is the legal duty of all doctors to provide the most recent valid information about genetic disorders. If omitting to do so and on future pregnancy a foetal abnormality occurred the doctor would be liable to litigation

Genetics in Practice

Neurofibrmatosis Sickle cell disease Beta thalssaemia trait Friedreichs ataxia Facial scapulo humeral dystrophy Beckers muscular dystrophy

Genetics in Practice

Familial breast cancer – 3 families Fragile x

2008. principles each human cell has 46 chromosomes = 23 pairs each pair consists of 1 paternal...

Documents

autosomal disorders

autosomal dominant disorders

autosomal recessive

locus slide

autosomal recessive

heterozygote ab slide

environment slide

mutation slide