C LINICAL GENETICS
INTRODUCTION
Classification of genetic disorders
Multifactorial (gene and environment)
Single gene - Mutations in single genes often causing loss of function
Chromosomal - Imbalance causes alteration in gene dosage
Mitochondrial
Somatic mutations (cancer)
Continuum of penetrance – proportion of people carrying a particular allele
Fully penetrant conditions - other genes and environmental factors have no effect
Low-penetrance genes - play a small part, with other genetic/environmental factors
If a single gene – fully penetrant (only contributing factor)
As it gets more multifactorial, penetrance is reduced e.g. MS
Multifactorial (common)
Environmental influences (e.g. drugs/infections) + genetic predisposition = susceptibility of disease
One organ system affected
Polygenic Modern investigations
Person affected if liability above a threshold Multiple genetic influences
Variants in genes - alteration of function Each of small effect
Important in population terms
Single gene (1% live-born) Describe pathways which may be of
Dominant/recessive pedigree patterns (Mendelian inheritance) therapeutic interest
Mutations in single genes (often cause loss of function)
Can affect structural proteins, enzymes, receptors, transcription factors
Chromosomal (0.6% live-born, but much more common in spontaneous abortions)
Thousands of genes may be involved (genes located on chromosome)
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 it can be inherited (translocations)
Anatomy of a chromosome Ultrasound features of Chromosome +21
Ends – telomeres, centre - Centromere Short femurs, sandal gap, single palmar crease
P section short section Nuchal translucency (back of neck), Choroid Plexus cyst
Q section longer section (in brain)
Echogenic bowel (fetal bowel bright)
Down’s Syndrome - autosomal
Round face, protruding tongue, up-slanting palpebral fissures, epicanthic folds, developmental delay
‘Syndrome’ – collection of features
Three patterns of chromosomes can cause Down’s
95% - three copies of chromosome 21 – Trisomy 21
4% - extra copy of chromosome 21 because of Robertsonian translocation
1% - mosaicism with normal and trisomy 21 cell lines (usually much milder features because presence of the normal
cells); occurs post-zygotically
Monosomy: 1 missing chromosome, Trisomy – one extra chromosome
Two other important autosomal trisomies
, Poor prognosis: majority of babies dying in first few weeks of life. If a baby survives - severe mental retardation
Edwards syndrome (trisomy 18)
o 1 in 3000 births
o Multiple malformations (especially heart, kidneys)
o Clenched hands – overlapping fingers
Patau syndrome (trisomy 13)
o 1 in 5000 births
o Multiple malformations
o Affects midline structures particularly; incomplete lobation of brain; cleft lip; congenital heart disease
Conditions caused by anomalies of sex chromosome number
Klinefelter syndrome
o 47,XXY
o Infertility (atrophic testes do not produce sperm)
o Poorly developed 2nd sexual characteristics in some (lack of testosterone)
o Features: Tall, Gynaecomastia (benign enlargement of breast tissue) and osteoporosis
Turner syndrome
o 45,X
o 99% are lost spontaneously in pregnancy
o Features: short stature, puffy feet, skin at back of neck, primary amenorrhoea (no menstrual bleeding)
o Congenital heart disease (coarctation of aorta) 20%
o Histology of gonads: ovarian cortical stromal devoid of germ cell elements
Numerical chromosome abnormalities
Gain/loss of complete chromosomes
Common cause: non-disjunction (usually in germ cells at meiosis)
Occasionally in somatic cells - mosaicism
Serious, often lethal consequences (particularly autosomal anomalies)
o Multiple congenital anomalies/mental retardation (MCA/MR) syndromes
Autosomal monosomies catastrophic
Fewer serious effects from sex chromosome anomalies
Microdeletions
Bit of chromosome missing (too small to be seen down the microscope)
Identified by use of specific molecular cytogenetic techniques
Appearance: small mouth, prominent nose, heart defects
Fluorescence In Situ Hybridisation (FISH)
Probe contents is labeled/denatured to the target - then hybridized and visualized fluorescently
Detects microdeletions
Williams-Beuren syndrome
Bright eyes, stellate irides, wide mouth, upturned nose, heart defect
Deletion of about 26 genes from the long arm of chromosome 7
Single Gene Disorders – Mendelian genetics
Dominant – heterozygotes with one copy of the altered gene are affected
Recessive – homozygous with two copies of the altered gene are affected
X-linked Recessive – males with one copy of the altered gene on the X-chromosome are affected
o High risks to relatives
o Some isolated cases due to new dominant mutations
o Structural proteins, enzymes, receptors, transcription factors
Familial hypercholesterolaemia
Cholesterol deposition in patients heterozygous, high levels of LDL
Can be homozygous – more rare and severe
Tendon xanthomata (fat deposits under skin), Corneal arcud (white/pale blue ring), high risk of CV disease
INTRODUCTION
Classification of genetic disorders
Multifactorial (gene and environment)
Single gene - Mutations in single genes often causing loss of function
Chromosomal - Imbalance causes alteration in gene dosage
Mitochondrial
Somatic mutations (cancer)
Continuum of penetrance – proportion of people carrying a particular allele
Fully penetrant conditions - other genes and environmental factors have no effect
Low-penetrance genes - play a small part, with other genetic/environmental factors
If a single gene – fully penetrant (only contributing factor)
As it gets more multifactorial, penetrance is reduced e.g. MS
Multifactorial (common)
Environmental influences (e.g. drugs/infections) + genetic predisposition = susceptibility of disease
One organ system affected
Polygenic Modern investigations
Person affected if liability above a threshold Multiple genetic influences
Variants in genes - alteration of function Each of small effect
Important in population terms
Single gene (1% live-born) Describe pathways which may be of
Dominant/recessive pedigree patterns (Mendelian inheritance) therapeutic interest
Mutations in single genes (often cause loss of function)
Can affect structural proteins, enzymes, receptors, transcription factors
Chromosomal (0.6% live-born, but much more common in spontaneous abortions)
Thousands of genes may be involved (genes located on chromosome)
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 it can be inherited (translocations)
Anatomy of a chromosome Ultrasound features of Chromosome +21
Ends – telomeres, centre - Centromere Short femurs, sandal gap, single palmar crease
P section short section Nuchal translucency (back of neck), Choroid Plexus cyst
Q section longer section (in brain)
Echogenic bowel (fetal bowel bright)
Down’s Syndrome - autosomal
Round face, protruding tongue, up-slanting palpebral fissures, epicanthic folds, developmental delay
‘Syndrome’ – collection of features
Three patterns of chromosomes can cause Down’s
95% - three copies of chromosome 21 – Trisomy 21
4% - extra copy of chromosome 21 because of Robertsonian translocation
1% - mosaicism with normal and trisomy 21 cell lines (usually much milder features because presence of the normal
cells); occurs post-zygotically
Monosomy: 1 missing chromosome, Trisomy – one extra chromosome
Two other important autosomal trisomies
, Poor prognosis: majority of babies dying in first few weeks of life. If a baby survives - severe mental retardation
Edwards syndrome (trisomy 18)
o 1 in 3000 births
o Multiple malformations (especially heart, kidneys)
o Clenched hands – overlapping fingers
Patau syndrome (trisomy 13)
o 1 in 5000 births
o Multiple malformations
o Affects midline structures particularly; incomplete lobation of brain; cleft lip; congenital heart disease
Conditions caused by anomalies of sex chromosome number
Klinefelter syndrome
o 47,XXY
o Infertility (atrophic testes do not produce sperm)
o Poorly developed 2nd sexual characteristics in some (lack of testosterone)
o Features: Tall, Gynaecomastia (benign enlargement of breast tissue) and osteoporosis
Turner syndrome
o 45,X
o 99% are lost spontaneously in pregnancy
o Features: short stature, puffy feet, skin at back of neck, primary amenorrhoea (no menstrual bleeding)
o Congenital heart disease (coarctation of aorta) 20%
o Histology of gonads: ovarian cortical stromal devoid of germ cell elements
Numerical chromosome abnormalities
Gain/loss of complete chromosomes
Common cause: non-disjunction (usually in germ cells at meiosis)
Occasionally in somatic cells - mosaicism
Serious, often lethal consequences (particularly autosomal anomalies)
o Multiple congenital anomalies/mental retardation (MCA/MR) syndromes
Autosomal monosomies catastrophic
Fewer serious effects from sex chromosome anomalies
Microdeletions
Bit of chromosome missing (too small to be seen down the microscope)
Identified by use of specific molecular cytogenetic techniques
Appearance: small mouth, prominent nose, heart defects
Fluorescence In Situ Hybridisation (FISH)
Probe contents is labeled/denatured to the target - then hybridized and visualized fluorescently
Detects microdeletions
Williams-Beuren syndrome
Bright eyes, stellate irides, wide mouth, upturned nose, heart defect
Deletion of about 26 genes from the long arm of chromosome 7
Single Gene Disorders – Mendelian genetics
Dominant – heterozygotes with one copy of the altered gene are affected
Recessive – homozygous with two copies of the altered gene are affected
X-linked Recessive – males with one copy of the altered gene on the X-chromosome are affected
o High risks to relatives
o Some isolated cases due to new dominant mutations
o Structural proteins, enzymes, receptors, transcription factors
Familial hypercholesterolaemia
Cholesterol deposition in patients heterozygous, high levels of LDL
Can be homozygous – more rare and severe
Tendon xanthomata (fat deposits under skin), Corneal arcud (white/pale blue ring), high risk of CV disease
