Autosomal Dominant Inheritance

• ‘Autosomal’ – refers to the fact that the affected gene is present on an autosome (chromosomes 1-22) rather than on a sex chromosome.
• The most common type of mendelian inheritance
• Humans carry two copies of a gene – one from the mother, and one from the father. This is known as heterozygousity.
• In autosomal dominant inheritance, the affected individual will have one ‘good’ copy of the gene, and one ‘bad’ copy. They are heterozygous for the affected gene.
  • This is contrary to autosomal recessive conditions, where to be affected, an individual has to be homozygous for a particular gene (they have to have two ‘bad copies’).
• Only one ‘bad’ copy is required for phenotypic features
• There is no carrier state – if you carry an affected gene, then you will have an affected phenotype
• Punnett’s square is an easy way to determine the risk of an affected individual passing on the risk to their child.
  • The affected gene is noted by a capital letter (in this case ‘A’). The unaffected gene is noted by the same lower case character (a).
• An affected parent typically has a 50% chance of passing on the defect to any of their offspring.
• Typically, the genes involved affect the production of structural proteins.

Concepts in Autosomal Dominant Inheritance

• Pleiotropy – this is the ability of an affected gene to cause two or more seemingly unrelated clinical effects.
  • in some cases, an autosomal dominant gene may only have one obvious clinical effect (e.g. congenital cataracts)
  • More commonly, a single gene defect has severl clinical effects. This is pleiotropy.
• Variable Expressability – even within the same family, an inherited genetic defect can cause massively different degrees of clinical effect. From mild to severe symptoms.
• Reduced penetrance – this is the phenomenon whereby an individual in the family may carry the autosomal dominant gene but may not show any clinical features. The clinical features have ‘skipped a generation’.
  • Somebody who is heterozygous for a defective gene but has no clinical features is said to be reperesent non-penetrance.
  • Most conditions are around 80% penetrant. Very few are 100%. One particular example of 100% penetrance is Huntington’s disease.
• Knowing the above phenomenon is important when looking at pedigree’s. For example, don’t let an instance of non-penetrance confuse you into thinking it is not autosomal dominant!
• New mutations can occur where there is no family history. in some cases, these may e autosomal dominant mutations that can subsequently be passed onto offspring.
  • New dominant mutations have been associated to advancing paternal age.
• Homozygousity in autosomal dominant traits
  • Although rare this is possible. It usually results when the affected individual had parents who were both heterozygous.
  • Symptoms are typically worse than the heterozygous state
• Codominance – this is where two dominant states are expressed simultaneously in the same individual. A simple example is an individual of AB blood type, who expressed both group A and group B proteins.
• Gonadal mosaicism –only a small proportional of gonadal cells are affected. Thus the parent has no clinical signs, but may pass on the defect to children.

Example diseases

• Familail hypercholesterolaemia – 1 in 500
• Polycystic kidney disease – 1 in 1250
• Hereditary Spherocytosis – 1 in 5000
• Marfan Syndrome – 1 in 4000
• Huntington Disease – 1 in 15 000

Autosomal Recessive Inheritance

• Affected cases occur when both parents are carriers of a particular mutation.
• To be affected, you must have two copies of the affected gene.
• The risk of having an affected child when both parents are carriers is 25%, and the chance of having a child who is a carrier is 50%.
  • If one parent is homozygous, and one is only a carrier, then they have a 50% chance of having an effected child. In this situation, this phenomenon is sometimes called pseudodominance.
• It is thought that almost everyone in the population will carry a recessive gene for one condition or more – but usually we have children with partners who carry a different recessive gene. 
• Consanguinity  (parents are related; Generally the risk is higher the more closely the parents are related) increases the risk of having an affected child – as it increases the risk that both parents carry an affected gene.
  • The risk for the general population is roughly 2%
  • The risk for a consanguineous couple is roughly 4%
•  Typically the genes involved affect metabolic pathways

• Locus heterogeneity – this refers to the phenomenon whereby there may be more than one recessive gene that accounts for a particular condition. For example, sensorineural hearing loss. In such cases, often two deaf individuals will have children together, you would expect that this would mean they had a 100% chance of having an affected child, but many children are born with normal hearing. This is because the affected parents have different mutations at different loci – and thus the mutations can be treated as separate, and thus it is as if only one parent is affected.
  • A disorder where the same phenotype can result from different mutations is known as a genocopy.
• Mutational heterogeneity – this is the phenomenon whereby there are different mutations, but at the same loci. In reality, the vast majority of autosomal recessive cases will be due to mutational heterogeneity, and perhaps a small proportion will be truly homogeneic, particularly in consanguineous couples.

Example diseases

• Sickle cell disease – 1 in 625 (Black Africans)
• Cystic fibrosis – 1 in 2500 (Caucasians)
• Tay-Sacs disease – 1 in 3000 (Jews)

Sex Linked Inheritance

• Accounts for the vast majority of sex linked cases
• Only males are usually affected
  • Females are usually only carriers (but sometimes females may show mild clinical signs – manifesting carrier)
• Sons of female carriers have a 50% risk of being affected
  • And likewise, each daughter of a female carrier has a 50% chance of being a carrier
• Daughters of affected males will all be carriers
  • SONS OF AFFECTED MALES ARE NOT AFFECTED! – because men pass on the Y chromosome to their sons
• X-linked disorders are often clinically severe
  • Often the family history is weak (there is often gonadal mosaicism, and few affected relatives). Drawing out a good pedigree may be necessary to identify those at risk
  • Despite a weak family history, genetic testing and counselling can be necessary, as all carrier females have a 50% risk of having an affected son, whoever their partner is.
  • Sometimes called ‘Knight’s move’ inheritance – as it apparently skips generations, and presents with unusual pedigree patterns.
• An affected male is said to be ‘hemizygous’ for the mutation

Examples

• Red-Green colour-blindness
• Duchenne’s and Becker’s Muscular Dystrophies
• Fragile X syndrome
• Glucose-6-phosphate dehydrogenase defriciency
• Haemophilia A and B
• Hunter’s Syndrome

X-linked Dominant

• Both men and women will show equal phenotypes.
• Often presents like an autosomal dominant trait – but there is an important difference: For affected females:
  • 50% chance of passing on the gene
  • Sons and daughters at equal risk
• Unlike autosomal dominant – for affected males
  • All daughters will be affected
  • No sons will be affected
• An example of a condition is vitamin D resistant Rickets.

Y-linked inheritance

Mitochondrial / Cytoplasmic Inheritance

• Mitochondrial DNA is only passed on through the mother – only the oocyte contain mitochondrial DNA and not the sperm. Thus fathers with mitochondrial DNA disorders will not pass the defect onto their children.

Imprinting

• Clinical features – learning difficulties, hypotonia, obesity. A particular problem is that the affected children eat anything and everything! One patient was known to eat their whole carpet.
• In this condition, there is a defective gene copy received from the father. The copy received from the mother is not used, even if it is ‘normal’ copy.
• Thus the child must inherit the active gene from the father inorder to be free of the disease. If for any reason, no paternal copy is received, then the syndrome will result. Failure to receive the gene can be due to a de novo deletion, or it can be the result of Uniparental disomy – where two copies of one gene are received from the same parent.

Polygenic / Mul​tifactorial Inheritance

• You have a close relative with the disorder
• Several members of the family have the disorder
• The disease is known to be sex specific, and you are of that particular gender
• A relative has had a particularly severe form of the disease

Congenital Disorders:

• Neural Tube Defects
  • + environmental factors (folate)
• Congenital Heart Disease
• Cleft lip and palate
• Pyloric Stenosis
• Congenital dislocation of the hip
• Talipes
• Hypospadias

Other Conditions:

• Atherosclerosis and CHD
  • + environmental factors (obesity, smoking, sedentary lifestyle)
• Diabetes mellitus
• Asthma
• Epilepsy
• Hypertension

In many of the disorders the possible environmental factors are not fully understood

References

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In this condition there is only one X chromosome in the female.

Epidemiology

• 95% of cases result in spontaneous miscarriage
• Present in 1 in 5000

Clinical features

Fetus

• Generalised oedema (hydrops)
• Nuchal thickening / fat pad

Neonates

• Many appear completely normal
• Peripheral oedema
• Webbed neck
• Low posterior hairline
• Shortening of the 4^th metacarpal
• Nipples widely spaced
• Coarctation of the aorta

Neurological signs

• Intelligence is normal
• Social skills and some other high functional skills may be altered
• The bell curve for IQ is thought to be slightly to the left

Late signs

• Short stature – usually seen in childhood from age 5 onwards. Growth hormone therapy can help reduce the deficit. Without therapy, the average height is 145cm.
  • this is thought to be related to a lack of the SHOX gene
• Ovarian defects – often resulting in infertility. Pregnancy is still possible with IVF and donated ova.
• Hypothyroidism
• Pigmented moles
• Wide carrying angle of the arm
• Recurrent otitis media
• Delayed puberty

Treatment

• Growth hormones to avoid short stature
  • Offered from the age of 3 onwards
  • No good if epiphyseal plates have already fused
• Oestrogen at pubertal age to ensure development of secondary sexual characteristics. Infertillity still usually persists. 

Cytogenet​ics

• 50% of cases are (45,X)
• In 80% of these cases the defect is due to the loss of either an X or Y during paternal meiosis.
• In most other cases, there is deletion of part of or all of one of the arms of chromosome X.
• in some cases, there is considerable mosaicism, and thus there is a normal cell line in many of the patient’s cells (46, XX). These patients have a good chance of being fertile

References

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• intelligence is typically reduced by 10-20 IQ points. Special educational requirements are rare
• they may show aggressive / unsociable behaviour

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Klinefelter’s Syndrome is named after Dr Harry Klinefelter at Massachusetts General Hospital in the 1940s who described a series of patients with a specific set of clinical features:

• Tall height
• Small testes
• Unable to produce sperm
• Gynaecomastia
• Little facial or body hair
• There may also be learning disability in more severe cases

Epidemiology

• 1 in 660 male live births
• The most common sex chromosome disorder
• Often is goes undiagnosed, or is not diagnosed until adulthood – for example when conducting fertility testing for a couple who are struggling to conceive

Clinical features

• Clumsyness
• Learning difficulties (usually mild)
• Typically intellectual ability is reduced y 10-20 IQ points, but still within the normal range. More susceptible to behavioural and psychological problems.
• Self obsessed behaviour

Adults

• Taller than average
  • Long legs
  • Narrow shoulders
  • Wide hips
• Long limbs
• Gynaecomastia + Infertility + small soft testes (Hypogonadism) (30% of cases)
  • Testes are typically small and firm
  • Limited libido
  • Erectile dysfunction
• ↑ Risk of
  • Leg ulcers
  • Osteoporosis
  • Breast cancer
• Most patients are infertile – there is a lack of sperm in the semen (azoospermia)

Investigations

• Can be diagnosed antenatally with amniocentesis or chorionic villus sampling
• Reproductive hormonal panel may be abnormal
  • Testosterone or ↑
  • FSH ↑
  • LH ↑
• Diagnosis is confirmed by chromosomal analysis (karyotyping)

Complications and associations

Klinefelter’s syndrome is associated with increased risk for several other disorders, including:

• Endocrine abnormalities – diabetes, hypothyroidism, hypoparathyroidism, early (precious) puberty
• Autoimmune disease – SLE, rheumatoid arthritis
• Osteoporosis
• Cardiovascular disease – increased risk
• Male Breast cancer
• Increased risk of testicular cancer
• Increased risk of PE / DVT
• Increased risk of leukaemia
• Increased risk of psychiatric disorders
• Increased risk of autism
• Developmental delay

The average lifespan is slightly less than the general population – by around 2 years – usually due to the increased incidence of the above associated diseases.

Treatment

Testosterone – is often given from puberty onwards, and helps the development of secondary sexual characteristics. It also reduces the long-term risk of many of the long term complications and associations.

However, puberty is often normal in most cases.

• Also helps to increase muscle mass and increase growth of facial hair and body hair

• Injection of sperm into the egg has reportedly been successful

Plastic surgery

• May be performed for gynaecomastia

Cytoge​netics

• Extra X chromosome
• Equal chance of inheritance from mother or father
  • Maternal cases often associated with advancing maternal age
• Small proportion of cases are due to mosaicism
• >2 X chromosomes are sometimes present. These cases are associated with more severe learning difficulties, and more pronounced features of Klinefelter’s.

References

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• The normal rate of miscarriage in the general population is 15%. Miscarriage does not become statistically significant unless one particular woman has >3 instances.
• Another common cause of miscarriage is a balanced translocation in one parent

Chromosome facts

• 15-20% of all pregnancies end in miscarriage – 50% of these cases are a result of chromosomal abnormality.
  • 10% of sperm have a chromosome abnormality
  • 25% of oocytes have a chromosomal abnormality
• Only around 1% of live births has a chromosomal abnormality
  • This is about 5% in still births

Definitions

• Aneuploidy – an inappropriate number of chromosomes/copies of one particular chromosome (can be greater or fewer than normal)
• Trisomy – the existence of 3 copies of a particular chromosome

Types of chromosome

Submetacentric – these are chromosomes with a long arm and a short arm

Acrocentric – these are chromosomes with only long arm. On the other side of the centromere are ‘satellites’ that contain little genetic information, usually related to the production of ribosomes. This genetic info is generally repeated elsewhere in the genome and is not fundamental.

Reciprocal Translocations

Balanced Reciprocal Translocations

• 1 in 500 people has a balanced reciprocal translocation.
• Typically, cases are unique to a particular family, but a balanced translocation with chromosomes 11 and 22 is also a common occurrence.

• Reciprocal translocations can often only be identified with FISH, particularly if the broken segments are of equal length.

Unbalanced reciprocal translocations

At meiosis, a balanced reciprocal translocation may not be able to pair up correctly. Instead of paring in ‘two’s’ with the other same number chromosome, the balanced translocation ends up pairing in fours; known as a pachytene quadrivalent. In such a situation, all the genetic material matches up with its opposing genetic material, but because each chromosome has information from 2 chromosomes, they group in a four:

 

• Developmental delay
• Learning difficulties
• Congenital defects

Robertsonian Translocations

• Robertsonian translocations can occur in any of the acrocentric chromosomes. These are the chromosomes that have a long arm and no short arm, and include numbers 13, 14, 15, 21 and 22.
• In a Robertsonian Translocation, the satellites are lost, and the long arm of one chromosome fuses with the long arm of another acrocentric chromosome. This reduces the total number of chromosomes to 45.
• The satellites code for ribosomal RNA, but so do the satellites on all acrocentric chromosomes, so in a Robertsonian translocation, there is little genetic significance – unless the translocation affects meiosis. 
• Robertsonian translocations occur in 1 in 1000 individuals in the general population, and usually the long arms of 13 and 14 fuse, to create 13q14q.
• Down’s syndrome is the major clinical effect of robertsonian translocations. Other effects that occur as a result of meiosis in the presence of a robertsonian translocation will either result in a balanced translocation with no clinical effects, or monosomy / trisomy of any of the acrocentric chromosomes, which will result in miscarriage.

Deletions

• DiGeorge’s Syndrome – widely varying clinical effects even with familial cases. Results in congenital defects, typically cleft lip and palate, congenital heart problems and sometimes also learning difficulties. There may also be a weakened immune response.
  • Due to a deletion at 22q11.
• William’s Syndrome – again may result in learning difficulties, although individuals are often cheerful, and very friendly, especially to strangers. May have abnormal facial appearance.
  • Due to a deletion at 7q11
• Cri du chat syndrome – so called due to the meow like cry that babies with this condition are affected with. Children may also have difficulty feeding and talking (due to small pharynx and larynx) as well as developmental problems.
  • Due to a deletion on chromosome 5p

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