Genetics

Trisomy 16

#2 cause of miscarriage and most common trisomy

Imprinting disorder definition

'a phenomenon whereby gene expression depends on whether the chromosome is maternal or paternal in origin. For example, both Prader-Willi syndrome and Angelman syndrome are caused by a deletion of the same part of chromosome 15. When the deletion involves the chromosome 15 that came from the father the child has Prader Willi syndrome; inheritance of the same deletion from the mother results in Angelman syndrome.' · Essentially the reflection that the parental origin of your chromosomes is important. · How do we know that the parental origin of the chromosomes is important? o 46, XX where genome is from only one parent - rare genetic event where the zygote has chromosomes from only one parent. You'd think that as they have a full set of chromosomes you'd get a normal child but you don't · Maternal - Ovarian Teratoma · Paternal - Hydatidiform Mole THIS SHOWS THAT THERE IS SOMETHING VERY IMPORTANT IN THE GENOME WHICH ISN'T THE SEQUENCE. · The genome carries an imprint of its parental origin. · It is a reversible epigenetic effect. · It's a heritable change that doesn't affect the primary sequence. DNA Methylation is the mechanism.

Trisomy 21 (Down Syndrome)

1 in 700 births. Increased with maternal age (particularly above 35)

Cystic fibrosis mechanism

1) CTFR gene on Chr 7 encodes CTFR (cystic fibrosis transmembrane conductance regulator) protein 2) Inherit 2 copies of CTFR gene 3) Absence of functional CTFR protein affects chloride ion function in epithelial cells 4) Disruption of salt/water regulation causes thick mucus and leads to symptoms

Huntington's disease mechanism

1) HTT gene on Chr 4 codes for huntingtin protein 2) Inherit one copy of a mutated form of the huntingtin gene 3) Altered gene encodes a toxic form of the protein that forms clumps 4) Cell death in basal ganglia of brain resulting in symptoms

Different types of chromosomes based on location of centromere

1) middle centromere = metacentric 2) centromere more to one side = submetacentric 3) don't have short arms, have satellites = acrocentric

genetic heterogeneity

1) same gene, different mutation, different disease - CF and CAVD from CTFR gene 2) same disease, different genes - Haemophilia A and B 3) Same disease, different genes, different inheritance patterns - different forms of epidermolysis bullosa can be autosomal recessive or dominant

List all the types of congenital abnormalities/birth defects

1)Malformation 2)Disruption 3)Deformation 4)Dysplasia 5)Association 6)Syndrome 7)Sequence

For a carrier of a Robertsonian (21:21) translocation, what are the odds of having a child with trisomy 21?

100%

Different trisomy types

13,16,18,21

Example of x-linked recessive disease

Haemophilia. Can have A or B. Symptoms of increased bruising and longer bleeding. Treatment: inject clotting factor

Mechanism of co-dominant conditions

effects of both mutated and normal genes apparent in people with both e.g. sickle cell trait

Deformation

Abnormal form, shape or position of part of body due to mechanical forces e.g. club foot, hip dislocation occurs late in pregnancy and has good prognosis because underlying structure is normal

Dysplasia

Abnormal organisation of cells into tissues e.g. thanatophoric dysplasia (bowed long bones, narrow thorax, large skull). Caused by single gene (FGFR3). High recurrence risk for siblings/offspring

Turner Syndrome treatment

Growth hormones and oestrogen for secondary sexual characteristics and prevention of osteoporosis Multidisciplinary follow up

Multiple abnormalites

Association, syndrome, sequence

Molecular bases of Huntington's disease

Caused by an unstable triplet repeat (CAG), number of repeats may expand with each generation. 10-35 repeats (unaffected), 27-35 (unaffected but may have affected child), 35-40 (may be affected), 40-120 (affected)

Haemophilia B

Caused by mutations in F9 gene on Chr X. F9 codes for coagulation factor IX. Symptoms identical to Haemophilia A. Haemophilia B is much rarer.

Example of duplication syndrome

Charcot-Marie-Tooth disease type 1A. · Diagnostic Features: o Muscle weakness o Hypotonia o Missing reflexes o Foot deformities - high arches or flat feet o Lack of sensation in hands and arms Micro-duplication of PMP22 gene on Chr 17 NOTE: PMP22 is the Peripheral Myelin Protein 22 gene which codes for an integral membrane protein that is a major component of myelin in the peripheral nervous system. Demyelinating peripheral neuropathy in adolescence. Treatment : physiotherapy, corrective surgery

Karyotype

Chromosome set of an individual or species described in terms of both number and appearance (structure) of chromosomes.

Klinefelter's syndrome symptoms

Clumsiness, verbal learning disability Taller than average, long lower limbs 30% have moderately sever gynaecomastia (enlargement of man's breasts) all infertile increased risk of leg ulcers, osteoporosis and breast carcinoma in adult life

Example of same gene, different symptoms

Congenital absence of the vas deferens (CAVD) is where vasa deferentia fail to form properly. Causes infertility (azoospermia). Affects 1 in 2500 men and most cases of CAVD are caused by mutations in the CTFR gene

Syndrome

Consistent pattern of abnormalities thought to be pathogenetically related and not representing a sequence e.g. Down Syndrome Include chromosomal abnormlaities

Autosomal recessive disease example

Cystic fibrosis.. Thick mucus in lungs causing breathing problems and repeated infections. Blockages in pancreas affect digestive enzymes.

Example of deletion syndrome

Di George Syndrome · Diagnostic Features (CATCH 22): o Cardiac abnormalities (e.g. tetralogy of Fallot) o Abnormal facies (e.g. widely-spaced eyes) o Thymic HYPOplasia o Cleft palate o Hypocalcaemia · Micro-deletion of 22q11.2 region (30-50 genes) containing the gene TBX1 NOTE: TBX1 is the T-box 1 gene that codes for a transcription factor involved in the regulation of many developmental processes.

Trisomy 18

Edwards Syndrome. Heart defects, kidney malformation, digestive tract defects, mental retardation

Haemophilia A mechanism

F8 gene on Chr X encodes the protein coagulation factor VIII. Boys with haemophilia A inherit one copy of mutated form of F8 gene. Lack of functioning factor VIII causes increased bruising and bleeding

Molecular diagnosis of Prader-Willi syndrome?

FISH - fluorescently labelling regions on chromosomes · PML (Promyelocytic Leukaemia) gene is present on Chr 15 outside PWS/AS region. · SNRPN (small nuclear ribonucleoprotein polypeptide N) is present inside the PWS/AS region. · NOTE: An alternate way of doing this is using methylation-specific PCR. As Prader-Willi and Angelman are both caused by the loss of function of the same region of Chr 15, you would expect them to be similar but they are not.

Mechanisms of dominant conditions

Gene mutation results in toxic protein that mask normal copy

Examples of monogenic disease

Huntington disease, cystic fibrosis, haemophilia

Example of autosomal dominant disease

Huntington's disease: motor, cognitive and psychiatric dysfunction (hyperkinesia), onset 35-44 years of age, survival is 15-18 years after onset

Why might genomic disorders caused by loss or gain of DNA not be visible in karyotype

If they are micro-deletion syndromes

When might a polymorphism still be called a mutation?

If they cause monogenic disease

PWS critical

In Prader-Willi Syndrome PWS Critical: · The region is large and has several genes. · Deletions: o Type 1 (T1D) - (BP1 - BP3) o Type 2 (T2D) - (BP2 - BP3) Knowledge about this molecular mechanism can be used for diagnosis.

Epistasis

Interactions between gene mutations and other modifier genes can affect phenotype. Interaction between alleles in which one allele hides the effects of another allele

Types of genetic diseases

Monogenic and complex disorders

Aneuploidy

Loss or gain of one or more chromosomes

Single abnormalities

Malformation, deformation, disruption, dysplasia

Homologous chromosomes

Matching (but not identical) pair of chromosomes. One from each parent

Angelman syndrome is from loss of function in which parental chromosome?

Maternal

Does balanced translocation usually cause abnormal phenotype?

Normally does NOT unless there's disruption of gene or gene fusion (e.g. BCR-ABL in CML)

Mosaicism

More than one cell lineage in tissue. Different cell lineages do not contains identical chromosomes. Hence, the individual has two genetically different populations of cells. It occurs due to errors in mitosis during the very early stages of embryogenesis. In the affected individual, the chromosomal defect is usually not fully expressed. How early mitotic non-disjunction happens will determine which tissues the genetic abnormality might affect e.g. once cell lineage will be Down Syndrome

Sequence

Multiple abnormalities derived from single known or presumed prior anomaly or mechanical factor e.g. Potter sequence: baby's urogenital abnormality leads to reduced urine output which leads to reduced amniotic fluid (oligohydramnios) leads to secondary abnormalities (Potter facies, plumonary hypoplasia, clubbed feet) Could have genetic component as initial factor

Silent mutation

Mutations that don't make a difference

Clinical features of Down Syndrome

Newborn period - excess nuchal skin, sleepy, hypotonia Craniofacial - eye folds, large tongue (macroglossia), small ears, brushfield spots in iris Limbs - single palmar crease, sandal gap between 1st and 2nd toe Cardiac - Atrial and ventricular septal defect Other - short stature, duodenal atresia (narrowing)

X-linked recessive characteristics

No affected parents, usually only males affected, transmitted by female carrier. Sons have 50% chance of being affected, daughters have 50% chance of being carrier

Complex disorders

No clear inheritance, environment essential, common

Association

Non-random occurrence on two or more individuals of multiple congenital abnormalities not known to be a polytopic defect, syndrome or sequence. Cause is typically unknown. e.g. VACTERL association: Vertebral, anal, cardiac, tracheoesophageal, esophageal, renal, limb

Robertsonian translocation

Nonreciprocal chromosomal transloccation that commonly involves chromosome pairs 13, 14, 15, 21, and 22. One of the most common types of translocation. Occurs when the long arms of two acrocentric chromosomes (chromosomes w/ the centromeres near the ends) fuse at the centromere and the 2 short arms are lost.

Disomy

Normal

Molecular basis of cystic fibrosis

Over 1500 mutations identified, most common mutation = delta F508, 3 bp deletion affects folding of CTFR protein and prevents it from moving to its correct place in the plasma membrane

Short and long arm also known as

P arm and Q arm

Trisomy 13

Patau Syndrome. Heart defects, holoprosencephaly (forebrain doesn't split into two hemispheres), cleft lip/palate, mental retardation

Prader-Willi syndrome is from loss of function in which parental chromosome?

Paternal

Chromosome banding

Standard human banding pattern due to staining, which is same for everyone. Centromere is starting point, start counting from 11. Written in order of: chromosome number, p/q, band number e.g. 12q11.1

What is a balanced translocation?

Straight switch of the sections of DNA - no genetic material lost

Klinefelter syndrome (47XXY)

Phenotypically male. 1 in 1000 male live births. X chromosome from either mother or father. 48 XXXY or 49 XXXXY are very rare

Polymorphism definition

Polymorphism is a mutation present in more than 1% of the population. May contribute to complex diseases

Prader-Willi syndrome

Prader-Willi Syndrome Symptoms: · Hyperphagia · Obesity/Diabetes · Mental Retardation · Muscle Hypotonia · Short Stature · Small Hands and Feet · Delayed/Incomplete Puberty · Infertility Management: · Hyperphagia managed by diet restriction · Exercise to increase muscular mass · Growth hormone treatment for short stature · Hormone replacement at puberty o Genetic Mechanism of Prader-Willi Syndrome Caused by the lack of a functional paternal copy of the PWS critical region on 15q11-q13. · 70% due to deletion of the critical region on the paternal chromosome · 25% due to inheritance of two maternal copies by uniparental isodisomy · 5% due to other mechanisms such as translocations PWS critical: · The region is large and has several genes. · Deletions: o Type 1 (T1D) - (BP1 - BP3) o Type 2 (T2D) - (BP2 - BP3) Knowledge about this molecular mechanism can be used for diagnosis. Diagnosis: FISH - fluorescently labelling regions on chromosomes · PML (Promyelocytic Leukaemia) gene is present on Chr 15 outside PWS/AS region. · SNRPN (small nuclear ribonucleoprotein polypeptide N) is present inside the PWS/AS region. · NOTE: An alternate way of doing this is using methylation-specific PCR. As Prader-Willi and Angelman are both caused by the loss of function of the same region of Chr 15, you would expect them to be similar but they are not.

Turner Syndrome Symptoms

Prenatal : oedema and swelling in neck region Newborn: webbed neck, urinary and aorta defect, low posterior hairline, short 4th metacarpals Normal intelligence In adults: short stature, ovarial failure, diabetes (renal problems), hypothyroidism

Phenocopy

Same disease but with different underlying cause

How do we usually visualise human chromosomes

Stain with Giemsa and are numbered by size

Monogenic disease

clear inheritance, no environmental influence, rare. single gene mutation that is inherited through a family e.g. cystic fibrosis

Missense mutation

codon changes to code for a different amino acid

How can be chromosomally one gender and phenotypically another?

Translocation of SRY gene from Y to X. End up with X chromosome that codes for males and Y that has lost the male determining factor. Hence when inherited, XY = female and XX = male

Monosomy X (45 X0)

Turner Syndrome. 1 in 2000 live female births. 80% due to loss of X or Y chromosome in paternal meiosis. 20% other causes (single arm deletion, ring chromosome, mosaicism). Adult sufferers are female and have ovarian failure, renal problems and short stature.

Examples of complex disorders

Type 2 diabetes, schizophrenia, crohn's disease

Nonsense mutation

codon codes for a stop codon so the polypeptide chain ends prematurely

Deceased symbol in pedigree chart

diagonal line through symbol

Variable expressivity

disease severity may vary between individuals with same disease-causing mutation

Patterns of inheritance with Huntington's disease (dominant anticipation)

age of onset decreases and severity increases

Allele

alternate forms of a gene or DNA sequence at the same locus

What are the 3 types of chromosomal abnormalities?

aneuploidy (numerical abnormalities), structural (e.g. translocations), mosaicism (different cell lines)

Mutation definition

any heritable change in the DNA sequence

Types of Mendelian inheritance patterns

autosomal dominant, autosomal recessive, x-linked dominant, x-linked recessive, mitochondrial

Affected individuals are coloured in .... in pedigree chart

black

Mechanism of recessive conditions

caused by absence of functional protein. effects only seen because normal copy is absent.

Dosage compensation

ensures equal gene expression in both sexes. Done by: 1) X chromosome inactivation (lyonization) 2) 2x expression of X chromosome genes in males e.g. D melanogaster 3) 0.5x expression of both X chromosome genes in hermaphrodites e.g. C elegans XX vs X0

Trisomy

gain of one chromosome - can be tolerated for specific chromosomes

Tetrasomy

gain of two chromosomes - can be tolerated for specific chromosomes

Frameshift mutation types

insertion and deletion (only affects that gene)

Monosomy

loss of single chromosome - almost always lethal

Malformation

morphological defect of an organ, part of an organ, or larger region of body from an intrinsically abnormal developmental process. Usually involved single organ showing multifactorial inheritance (genetic and environmental) e.g. cleft lip, atrial septal defects.

Disruption

morphological defect of an organ, part of an organ, or larger region of the body, resulting form the extrinsic breakdown of, or interference with, an originally normal developmental process e.g. amniotic band causing digital amputation Caused by infection, trauma, and ischaemia. NOT genetic, but genetic factors can predispose

Different alleles may be described as...

mutations or polymorphism

Treatment implications for dominant and co-dominant conditions

need to neutralise effects of toxic protein or switch off mutant gene to unmask the normal gene

Treatment implications of recessive conditions

need to restore activity of missing protein by replacing gene/protein product/affected tissues

Causes of Down Syndrome

o 95% caused my meiotic non-disjunction. Meiosis 1 (75%), Meiosis 2 (25%). 90% have maternal origin of extra chromosome. o 4% caused by translocation - Robertsonian translocation (1/3 due to parents are carriers of translocations) o 1-2% from mosaicism (mitotic non-disjunction)- children less severely affected as non-disjunction occurred in mitosis. Mosaicism is a condition in which an individual has two genetically different populations of cells. It occurs due to errors in mitosis during the very early stages of embryogenesis. In the affected individual, the chromosomal defect is usually not fully expressed.

Examples of mitochondrial disorders

o MELAS o LHON

Inborn errors of metabolism examples

o Phenylketonuria o MCAD Deficiency

What is uniparental isodimy?

oEnding up with a zygote that has a pair of chromosomes from one parent not both. · Caused by non-disjunction in meiosis II. · You end up with three copies of Chr 15, which would be fine if you deleted one of the copies. But if you delete the paternal copy you end up with only maternal copies and hence have Prader-Willi Syndrome. o It is caused by the failure to separate the chromosomes in meiosis II and the failure to remove the correct chromosome following the non-disjunction --> zygote has two copies of chromosome from same parent

Mendelian inheritance

process where individuals inherit and transmit one out of the two alleles present in homologous chromosomes to their offspring

Point mutation

single base pair in DNA has been changed

Symbol for male, female and sex unknown in pedigree chart

square, circle, diamond

Transcriptome

sum total of all mRNA expressed from gene in organism

Incomplete pentrance

symptoms NOT always present in individual with disease-causing mutation

What are the types of structural abnormalities?

translocation, inversion, duplication, deletion, ring

DNA methylation phenomenon

· Addition of a methyl group to the 5' position of the pyrimidine ring of a cytosine. · This only occurs in humans at CpG dinucleotides. NOTE: SAM is S-Adenosyl Methionine (source of methyl group) and DNMT is DNA Methyltransferase It is essentially a flag that can be on or off in your DNA. · Methylation in the promoter of a gene represses gene transcription · This is the underlying principle of imprinting and X-inactivation. · When the X is inactivated it is HYPERMETHYLATED. · Methylation patterns vary between tissues and vary depending on age. · Methylation patterns are affected by the environment. · DNA methylation patterns are potentially heritable.

Examples imprinting disorders

· Chr 15 Imprinting Disorders: o Prader-Willi syndrome o Angelman syndrome

What is genomic imprinting?

· Genome carries imprint of parental origin · Non-mendelian inheritance · No change in genetic sequence o Epigenetic modification . Addition of methyl group to 5' of cytosine pyrimidine occurs at CG nucleotides and underlies imprinting and X-inactivation N.b. in pic - at germline lineage arrow - this is where markers from parents are removed