Genetic life time prevalence
3,4-7,3 %
Phenotype description, molecular basis known: 5625
Allel
One of several alternative forms of a gene
In the 22 pair of autosomes, you have 2 alleles; one from mom and one from dad
A/a = Heterozygous
A/A or a/a = Homozygous
Polymorphism
a genetic variant that is conserved in the population, and has an allele frequency of ≥ 1%.
Common genetic variants.
Over 340 mill known Single Nucleotide Polymorphisms (SNPs) in the human genome.
Mutasjoner:
Most chromosome abnormalities (aneuploidies, translocations, deletions, duplications) have no previous family history.
Prevalence of chromosomal abnormalities
• Newborns: 0.5%
• Stillborns: 5%
• Spontaneous abortions, 1st trimester: 50%
• Robertsonian translocation (between acrocentric chromosomes). Balanced carriers: 1/1000
Kromosomal: Numerical alterations
e.g. monosomy, trisomy, triploidy
Regional: Deletions, duplications, translocations.
Gen:
- Punktmutasjoner; Deletion and insertion of one or more nucleotides. Missense, nonsense, splice site
Missense mutation
One aa is replaces by another one
Nonsense mutation
an aa codon is replaced by a stop codon
Frameshift mutation
Deletion (or insertion) of a base resulting in a shift in all subsequent codons)
Splice site = no splicing
Leads to «exon-skipping» and deletions at the mRNA
level.
DNA analysis:
to detect changes that are not visible under an optical microscope
• PCR (Polymerase Chain Reaction)
• MLPA (Multiplex Ligation-dependent Probe Amplification) used for Deletion and Duplications.
Eks:
Duchenne muscluar dystrophy (deletion) Charcot Marie Tooth disease.
• SNP- array (single nucleotide polymorphism)
• DNA Sequencing. Can detect any point mutation
and small deletion/insertion.
Classical Mendelian inheritance
• Autosomal recessive
• Autosomal dominant
• X-linked inheritance
Non Mendelian inheritance
• Mitochondrial inheritance, from mother
Pedigree (genogram)
Is a family tree showing the pattern of inheritance for a specific phenotypic trait
Autosomal (ikke kjønnsbundet) recessive diseases
- Healthy parents may have one or more affected children.
- Men and women are affected equally often.
- The parents of an affected child are obligate carriers.
- Each of their children has a 25% risk of inheriting the disease.
- Each healthy sibling of an affected child has a 67% risk of being a carrier.
Mor og far må begge være bærere: 1 unge får sykdommer, 2 blir bærere, 1 blir frisk. Så 2/3 = 67% bærere.
• The affected gene resides on one of the 22 autosomal chromosomes.
Examples:
- Cystic fibrosis is a disease caused by “thick mucous”: mucoviscidosis; chronic lung infection !!
pancreatic insufficiency – malabsorption, increased CHLORIDE concentration in sweat !!
More than 1500 known mutations. Most frequent mutation is del F508 (Phe508). - Phenylketonuria (PKU) (Følling’s disease)
Neonatal screening Caused by mutations in the PAH gene (Phenylananine hydroxylase).
Phenylalanine accumulates in the body fluid and damages the developing CNS.
Therapy: Restricted dietary intake of phenylalanine. - Spinal muskel atrofi: 1/30-40 er bærere
SMA-1, onset før 6 måneder, death before 2 years
SMA-2, onset 6-18 måneder, 70% overlever til 25 år.
Behandling: Nusinersen: Spinraza
In total over 2000 autosomal recessive diseases, including many congenital metabolic diseases.
Autosomal (ikke kjønnsbundet) dominant disorders
- Each child of an affected person has a 50% risk of inheriting the disease
- Occurs in each generation. Often late onset.
- Men and women are affected equally often. Male-to-male transmission occurs, which is an important way of distinguishing these disorders from X-linked recessive disorders.
- Penetrance; is the proportion of individuals with the mutation who exhibit clinical symptoms.
- Expressivity; is the variations in a phenotype among individuals carrying a particular genotype.
• Autosomal dominant disorders may be caused by new mutations (relatively rare) originating from germline mosaicism in one of the parents or from early embryonic mutations in the offspring.
Examples:
- Huntington’s disease; neurodegenerative
- Marfan syndrome; connective tissue disorder
- Colon polyps; origin of colon cancer
- Myotonic dystrophy; progressing muscular dystrophy
More than 2600 known autosomal dominant diseases
X-linked recessive disorders
- Mainly affecting men!
- Diseases are transmitted by healthy* mothers
- Heterozygous women are generally unaffected. Exceptions: skewed X inactivation, monosomy X (Turner)
- All daughters of any man with the disease become carriers. Each of his daughters’ sons has a 50% risk of inheriting the disease
- Not transmitted from father to son.
- Can be transmitted unrecognized via several female carriers
Examples:
• Haemophilia type A and B
• Duchenne muscular dystrophy
1/ 3500 boys, very few girls
• Fragile X syndrome
Mitochondrial inheritance
- Caused by mutations in mtDNA
- Inherited from mother to child; maternal inheritance (sperms do not transmit mitochondria)
- Low incidence
- Affects both sexes
Examples:
– Lebers’ inheritable optic neuropathy (LHON)
– Inheritable hearing impairment
• Most proteins in mitochondria are encoded by nuclear genes. Mutations in these genes may cause mitochondrial disease.
The genetic consultation
Laboratory analyses
1) Chromosome analysis
I. Traditional chromosome analysis (G-band, living cells)
• Chromosomes only visible in dividing cells
• Living cells from different tissues cultured to divide
– Blood lymphocytes (Na-heparin sample)
– Skin fibroblasts (or achilles tendon biopsy)
– Amnion - amniocytes
– Chorionic villi biopsy - fetal cells
- Culture cells, make them divide
- Arrest cells, metaphase
- Stain with ie Giemsa = G-band preparation
- Microscope (11 cells or more)
- 2-3 weeks for result
III. QF-PCR
Quantitative Fluorescence–Polymerase Chain Reaction
DNA based, RAPID test for aneuploidies
– 1-2 days
Amplifies amount of DNA in specific regions
– Quantifies chromosomes 13, 18, 21, X, Y
Indications for chromosomal analyses
• G-band analysis
– 3 or more spontaneous abortions or infertility.
– Suspected structural chromosomal aberration.
– Suspected sex chromosome abnormality (growth, pubertal development)
• QF-PCR including sex chromosomes
– Prenatal diagnostics
– Learning difficulty
• SNP array
– Intellectual disability, severe autism
– Congenital malformations – major, or several minor
IV. Chromosomal microarrays
• Submicroscopic (< 5-7 Mb) chromosomal aberrations by DNA based methods.
• Several names/methods
– (Genomic) Copy number analysis («kopitallsanalyse»)
– Array CGH (comparative genome hybridisation)
– SNP array (Single Nucleotide Polymorphisms)
– «Matrisebasert kopitallsundersøkelse»
- Detects deletions, duplications
- NB! Normal variation
- Indications: ID, (multiple) malformations, syndromes,…
- Probably replacing most traditional G-band analyses
- Detects only unbalanced abnormalities
Aneuploid = Extra/missing single/few chromosomes
- Monosomy (e.g. 45, X)
- Trisomy (e.g. 47, +21)
- Sex chromosomes or autosomes
Euploid = Extra set(s) of chromosomes
– Polyploidy (e.g. triploidy 69, XXX)
– Not compatible with life (but occurs at conception, or mosaic)
Klinefelter syndrome (Høy)
- 47, XXY
(48, XXXY etc)
Turner syndrome, 45, XO (Lav)
Congenital anomalies:
• Major congenital anomaly: 2-3% newborns
Huntington disease
- Irregular involuntary movements (chorea)
- Cognitive and mental changes
- Dementia
- Gradual weight loss
- Appears in adulthood
- Risk of early/serious illness if inherited from father
- Autosomal dominant inheritance
• CAG repeat expansion of exon 1 in HTT gene; polyglutamine tract
– normally: < 26
– Intermediate 27-35
– w/ reduced penetrance 36-39
– Full penetrance > 40
– Juvenile > 60 (rare, usually from father)
Myotonic dystrophy –> Maternal transmission!
• Atrophy (dystrophy): face, distal in upper and lower extremities
• Myotonia: inability of the muscles to relax after contraction (EMG)
• Cataracts
• Frontal balding
• Endocrine symptoms / gastrointestinal / cardiac
• Mental retardation can occur
• Autosomal dominant inheritance
• Type 1: CGG repeats ”in ” DMPK gene: – Normal 5-34 - premutation 35-49 – Mild 50-150 - classic 100- 1000; RNA disturbance – Congenital (from mother) > 1000
• Type 2: CCTG repeat expansion in intron 1 of CNBP
– No anticipation No congenital presentation
– Extreme somatic instability, RNA disturbance
Genomic imprinting:
- Normal development requires the complementary presence of both maternal and paternal genetic material.
- An imprinted gene will be inactivated (turned off) and therefore not be expressed during gametogenesis in individuals of one sex, whereas in the opposite sex it will be expressed.
Examples of genomic imprinting:
- Prader-Willi
• neonatal hypotonia ”floppy infant”
• failure to thrive, feeding difficulties
• later on; excessive eating (insatiable appetite, aldri mett)
• slight mental retardation
• MLPA Methylation testing: > 99%
– paternal deletion 15q11-q13
- AngelMan syndromes • Normal at birth • Seizures w/ specific EEG pattern? • microcephaly – 50% by 12 months • Ataxia • Mental retardation • MLPA Methylation testing ~ 80% – maternal deletion of 15q11-q13
Duchenne MD (DMD):
• CK: >10x normal , almost complete lack of dystrophin in biopsy.
• Clinical onset at the age of 2-3 with progressive proximal muscle weakness (lower extremities).
• Historically premature death around the age of 20
– (cardiomyopathy, respiratory problems)
- Hypertrophy of calves (tykke legger)
- Gowers sign, holder seg til knærne når røyser seg opp.
BeckerMD (BMD):
- CK: >5x normal, reduced dystrophin in biopsy
- Greater clinical variation and later onset
Hereditary cancer
• 5-10 % of all cancers
- Germline (mostly inherited) mutations in:
- Tumor suppressor genes (common cause):
- Negative regulate cell cycle
- «Loss of function» mutations
- Two hit.
- BRCA1/2, TP53, RB1, APC
• Proto-oncogenes (rare cause):
- Positive regulate cell cycle
- «Gain of function » mutations
- One hit.
- RET (MEN2B).
But cancer is common – > 40% of aging population
Knudson 2 hit hypothesis:
Both copies of the gene must be knocked out in order to cause malignancy.
Sporadic cancer: 2 acquired mutations
Hereditary cancer: 1 acquired mutation, 1 inherited
Familial cancer is caused by?
- A germline mutation plus a somatic mutation in affected tissue.
Heterozygosity of mutation (inherited via germline) in a tumour- suppressor gene.
A second hit on the other allele (in somatic tissue) is required for tumour formation.
