Medic_Summaries (IMS) Topic 10
Clinical Genetics
Etiology of disease: for any condition, the overall balance of genetic
and environmental determinants can be represented by a point
somewhere within the triangle
Continuum of penetrance: there is a continuum of penetrance from
fully penetrant conditions, where other genes and environmental
factors have no effect, through to low-penetrance genes that simply
play a small part, along with other genetic and environmental factors,
in determining a person’s susceptibility to a disease
Multiple sclerosis is used as an example of a multifactorial
condition, where genetic factors play a major part in
determining susceptibility, but current research suggests
that each individual factor has a very low penetrance.
Genetic factors:
- MUTATIONS in single genes (often causing LOSS of function) - single gene disorders
- VARIANTS in genes (often causing ALTERATION of function) - multifactorial diseases
- Chromosomal imbalance (causing alteration of gene dosage) - chromosome disorders
Multifactorial: common
- Environmental influences + genetic predisposition = susceptibility to a disease
- Variants in genes cause alteration of function
- One organ system affected
Single gene: 1% live-born
- Dominant/recessive pedigree patterns (Mendelian inheritance)
- Mutations in single genes (often causes loss of function)
- Can affect structural proteins, enzyme, receptors, transcription factors
Chromosomal: 0.6% live-born, but much more common in spontaneous abortions
- Thousands of genes may be involved
- Chromosomal imbalance causes alteration in gene dosage
- Multiple organ systems affected at multiple stages in gestation
- Usually de novo (trisomies, deletions, duplications)
- In rare cases, can inherited (translocations)
Syndrome: a collection of feature
Down’s syndrome:
- Round face
- Protruding tongue
- Upslanting palpebral fissures
- Epicanthic folds
- Developmental delay
1 Adapted from Lectures at the University of Leeds Medical School
, Medic_Summaries (IMS) Topic 10
Ultrasound features of t-21:
- Short femurs
- Nuchal translucency
- Echogenic bowel
- Choroid plexus cyst
- Sandal gap, single palmar crease
Chromosomal patterns that can cause Down’s syndrome: three
- Trisomy 21: 95% people have three separate copies of chromosome 21
- Robertsonian translocation: causes 4% to have the extra copy of chromosome 21
- Mosaicism: 1% have this with normal trisomy 21 cell lines (and usually have much milder
features because of the presence of the normal cells); occurs post-zygotically
Other important AUTOSOMAL trisomies: two
- Edwards syndrome (trisomy 18)
- 1/3000 births
- Multiple malformations (especially heart, kidneys)
- Clenched hands with overlapping fingers
- Patau syndrome (trisomy 13)
- 1/5000 births
- Multiple malformations
- Affects midline structure, particularly: incomplete lobation of brain, cleft lip, and
congenital heart disease
- Both of these syndromes have a very poor prognosis
- Majority of babies die in the first few weeks of life
- If a baby survives (very unusual), there is severe mental retardation
Important conditions caused by anomalies of sex chromosome number: two
- Klinefeldter syndrome (47, XXY)
- 1/1000 males
- Infertility (atrophic testes do not produce sperm)
- Poorly developed secondary sexual characteristics in some (lack of testosterone)
- Tall, disproportionately long limbs, thin build
- Gynaecomastia in late puberty
- Hypogonadism (testicular dysgenesis, azoospermia, oligospermia)
- Turner syndrome (45, X)
- 1/5000 females
- 99% are lost spontaneously in pregnancy
- Short stature
- Primary amenorrhoea (ovaries involute before birth)
- Congenital heart disease (contraction of aorta) in 20%
- Low hairline
- Narrow hip development
- Hyperconvex nails
Numerical chromosome abnormalities:
- Gain/loss of complete chromosome
- Common cause is non-disjunction (usually in germ cells at meiosis)
- Occasionally in somatic cells (resulting in mosaicism)
- Serious, often lethal, consequences (particularly autosomal anomalies) - eg. multiple
congenital anomalies/mental retardation syndromes
- Autosomal monosomies are catastrophic (not compatible with life)
- Fewer serious effects from sex chromosome anomalies
2 Adapted from Lectures at the University of Leeds Medical School
Clinical Genetics
Etiology of disease: for any condition, the overall balance of genetic
and environmental determinants can be represented by a point
somewhere within the triangle
Continuum of penetrance: there is a continuum of penetrance from
fully penetrant conditions, where other genes and environmental
factors have no effect, through to low-penetrance genes that simply
play a small part, along with other genetic and environmental factors,
in determining a person’s susceptibility to a disease
Multiple sclerosis is used as an example of a multifactorial
condition, where genetic factors play a major part in
determining susceptibility, but current research suggests
that each individual factor has a very low penetrance.
Genetic factors:
- MUTATIONS in single genes (often causing LOSS of function) - single gene disorders
- VARIANTS in genes (often causing ALTERATION of function) - multifactorial diseases
- Chromosomal imbalance (causing alteration of gene dosage) - chromosome disorders
Multifactorial: common
- Environmental influences + genetic predisposition = susceptibility to a disease
- Variants in genes cause alteration of function
- One organ system affected
Single gene: 1% live-born
- Dominant/recessive pedigree patterns (Mendelian inheritance)
- Mutations in single genes (often causes loss of function)
- Can affect structural proteins, enzyme, receptors, transcription factors
Chromosomal: 0.6% live-born, but much more common in spontaneous abortions
- Thousands of genes may be involved
- Chromosomal imbalance causes alteration in gene dosage
- Multiple organ systems affected at multiple stages in gestation
- Usually de novo (trisomies, deletions, duplications)
- In rare cases, can inherited (translocations)
Syndrome: a collection of feature
Down’s syndrome:
- Round face
- Protruding tongue
- Upslanting palpebral fissures
- Epicanthic folds
- Developmental delay
1 Adapted from Lectures at the University of Leeds Medical School
, Medic_Summaries (IMS) Topic 10
Ultrasound features of t-21:
- Short femurs
- Nuchal translucency
- Echogenic bowel
- Choroid plexus cyst
- Sandal gap, single palmar crease
Chromosomal patterns that can cause Down’s syndrome: three
- Trisomy 21: 95% people have three separate copies of chromosome 21
- Robertsonian translocation: causes 4% to have the extra copy of chromosome 21
- Mosaicism: 1% have this with normal trisomy 21 cell lines (and usually have much milder
features because of the presence of the normal cells); occurs post-zygotically
Other important AUTOSOMAL trisomies: two
- Edwards syndrome (trisomy 18)
- 1/3000 births
- Multiple malformations (especially heart, kidneys)
- Clenched hands with overlapping fingers
- Patau syndrome (trisomy 13)
- 1/5000 births
- Multiple malformations
- Affects midline structure, particularly: incomplete lobation of brain, cleft lip, and
congenital heart disease
- Both of these syndromes have a very poor prognosis
- Majority of babies die in the first few weeks of life
- If a baby survives (very unusual), there is severe mental retardation
Important conditions caused by anomalies of sex chromosome number: two
- Klinefeldter syndrome (47, XXY)
- 1/1000 males
- Infertility (atrophic testes do not produce sperm)
- Poorly developed secondary sexual characteristics in some (lack of testosterone)
- Tall, disproportionately long limbs, thin build
- Gynaecomastia in late puberty
- Hypogonadism (testicular dysgenesis, azoospermia, oligospermia)
- Turner syndrome (45, X)
- 1/5000 females
- 99% are lost spontaneously in pregnancy
- Short stature
- Primary amenorrhoea (ovaries involute before birth)
- Congenital heart disease (contraction of aorta) in 20%
- Low hairline
- Narrow hip development
- Hyperconvex nails
Numerical chromosome abnormalities:
- Gain/loss of complete chromosome
- Common cause is non-disjunction (usually in germ cells at meiosis)
- Occasionally in somatic cells (resulting in mosaicism)
- Serious, often lethal, consequences (particularly autosomal anomalies) - eg. multiple
congenital anomalies/mental retardation syndromes
- Autosomal monosomies are catastrophic (not compatible with life)
- Fewer serious effects from sex chromosome anomalies
2 Adapted from Lectures at the University of Leeds Medical School
