Genetics Flashcards
Mitochondrial DNA features
37 genes No introns 93% maternally inherited
Definition of dynamic mutations
A mutation which changed upon transmission Trinuceltotide repeats is the best example For most dynamic mutations the larger the repeat, the earlier the onset
Trinucleotide repeat fast facts
Normal Disease causes when expanded beyond a certain threshold Below that threshold they are stable both in mitosis + meiosis (making a germ cell)
Common trinucleotide repeats + conditions
Fragile X CGG repeat Frieriech ataxia- GAA repeat Myotnic
Intergenerational instability definition
Repeat changes in size from parent to offspring Sex of transmitting parent important
Anticipation definition
More severe phenotype with succeeding generations e.g. myotonic dystrophy (frog like posture, mouth open position)
Myotonic dystrophy
CTG repeat <37 no problem > 50 disease Congenital form often > 1000 usually inherited by mother
Premutation definition
Premutation is defined based on the ability of the repeat to expand to a full mutation in one generation. e.g. Fragile X syndrome (not truly a premutation because female premutation carriers have a higher rate of premature ovarian failure + shy personality) CGG repeat < 55 normal 55-200 premutation (normal intellect but risk to offspring if female) >200 males have ID but females is variable
Friedreich Ataxia
AR Most common hereditary ataxia Carrier frequency 1:85 GAA triplet repeat in intron 1 of FXN gene FXN produces frataxin (nuclear encoded, mitochondrial localisation) Clinical features - Progressive ataxia of limbs - Absent lower limb reflexes - Reduction in vibration and proprioreception - Extensor plantar responses - Scoliosis - Foot deformity - Cardiomyopathy - Diabetes mellitis 10%
Predictive testing definition
Testing people at increased risk for a disease prior to clinical features 1) discuss genetics 2) neuro exam 3) counsel RE + and - result 4) result given 5) post result counselling Guidelines recommend against testing for adult onset disease in adolescence
NF1 diagnostic criteria
1 in 3000 Require 2 or more of - > 6 cafe au lait - > 2 neurofibromas OR 1 plexiform (~30%, can undergo malignant transformation, surgery of limited value due to regrowth, medical treatment MEK inhibitors) - Axillary and /or inguinal freckling - Optic glioma - Lisch nodules (seen with slit lamp) - Osseos lesion (sphenoid wing dysplasia, pseudoarthrosis) - 1st degree relative with NF1
NF1 complications
Learning difficulties CNS tumours (optic nerve gliomas 2 %, subclinical 15%. F:M 2:1, treatment with carboplatin) CNS tumours 5 x more common in NF1 increases to 100 x if > 10 yrs (tend to be less indolent) Peripheral nerve malignancy (lifetime risk = 10%, present with pain + rapid growth, PET scan useful for diagnosis) Scoliosis Seizures Aqueduct stenosis (if headache, low threshold for MRI) Hypertension Disturbance of puberty Reduced life expectancy
NF1 timeline of complications
0-2yrs cage au lait, plexiform neurofibromas 1-6yrs optic nerve glioma, skinfold freckling Preschool + onwards: - Learning difficulties - HTN - Neurofibromas - Scoliosis
NF1 genetics
AD 30-50% new mutations Due to NF1 gene defect Mainly a clinical diagnosis but increasingly using genetic testing
Legius syndrome
Multiple cafe au lait patches Flexural freckling Macrocephaly Mutations in SPRED1 Learning problems common
Tuberous sclerosis
= Bourneville disease 1:5000 <5yrs AD 2/3 sporadic 1/3 inherited Tumour suppressor gene mutation (TSC1 or TSC2) mTOR inhibitors can be used (sirolimus)
Prenatal genetic testing options
Chorionic villus sampling - From 11 weeks - 1 in 500 risk miscarriage - Sample of placenta Amniocentesis - From 15 weeks - 1:1000 miscarriage - Sample of fluid Preimplantation genetics - Used in IVF - Testing embryo biopsy - 1 or 2 cells aspirated from the embryo - 98% diagnostic - $10 000 cost
Definition of inversion
Inversion of a segment around the centromere (pericentric) or adjacent to it (paracentric)
Reciprocal translocation definition
Can involve any 2 chromosomes Reciprocal exchange of 2 chromosome segments If balanced- usually unaffected, common (1 in 1000), may be familial. Risk for infertility, recurrent miscarriage or fetal anomaly if unbalanced segregants in offspring
Definition of Robertsonian translocation
Occurs between 2 acrocentric (a chromosome in which the centromere is located near one end of the chromosome + not in the middle) Humans have 5 acrocentric chromosomes: 13, 14, 15, 21, 22 14;21 most common Loss of p arm (short arm) of acrocentric chromosome not importance Risk of UPD in BALANCED carrier on prenatal testing if imprinted chromosome
What is MLPA?
Multiplex ligation dependent probe amplification (PCR amplification of ligated probes to area of interest) Detection of small cryptic subtelomeric rearrangements and common chromosomal deletion / duplications Role in excluding small deletions or duplications (indels) within genes
Karyotype: - What is it? - What does it identify - What does it NOT identify - At what phase are cells arrested?
Directly analyse whole chromosomes, takes 10-12 days Identifies - Aneuploidy - Large chromosome imbalances - Balanced + unbalanced translocations Does NOT identify - Microdeletions / duplications - Single gene mutations - Triplet repeat expansion - Imprinting disorders Cells arrested in metaphase
FISH - What is it? - What does it identify - What does it NOT identify - At what phase are cells arrested?
Use of fluorescent tagged DNA probes to visualise particular areas - What does it identify Presence/ absence of specific DNA sequences - What does it NOT identify Things you are not specifically looking for (need a specific target) Can be performed in metaphase or interphase
Microarray - What is it? - What are the 2 different types? - Advantages over a karyotype? - Limitations
Identifies the differences in the amount of genetic material - gains or losses Comparative genomic hybridisation + single nucleotide polymorphisms 125-1000 fold increase in resolution over conventional karyotyping Does not detect - Balanced karyotypes (translocations, inversions) - Point mutations (e.g. Fragile X, Marfans) - Triplet repeat expansion disorders - Methylation changes (BWS, RSS, PWS/ AS) - Small deletions
What is CGH array?
Comparative genomic hybridisation Comares DNA (genome) from 2 sources; test sample (green) + patient (red) Hybridised to normal chormosome in metaphase More green = loss of genetic material More red = gain of genetic material Equal representation = yellow
What is SNP array?
Single nucelotide polymorphisms Identifies variation in a single nucleotide at a specific locus
What is the Hardy Weinberg equation?
p(2) + 2pq + q(2) = 1 p(2) = unaffected individuals (assume 1 for ease) 2pq = number of carriers q(2)= incidence of disorder *Assuming the disorder is rare in any population*
What is anticipation?
Phenotype worsens in succeeding generations (earlier onset or more severe) Often neurodegenerative disorders ( myotonic dystrophy, Huntington disease, spinocerebellar ataxia, fragine X)
Definitions: Genome Exome Nucleotides Codon
Genome- total complement of DNA Exome- 1% of genome directly codes for proteins Nucleotides: A, T, G, C Codon: 3 nucleotides that encode an amino acid
Introns are SPLICED to produce…..
mRNA
Genes are ….. into mRNA then …. to proteins
Genes are transcribed into mRNA then translated to proteins
DNA vs. RNA
DNA - Double stranded - Comprises ACGT - Deoxyribose brackbone - DNA is mainly nuclea - High stable RNA - Single stranded - Comprises ACGU - Ribose backbone - RNA is cytoplasmic - Very unstable
Locus heterogeneity vs allelic heterogeneity
Locus heterogeneity - Mutations in different genes cause the SAME clinical phenotypes (e.g. mutations in TSC 1 or TSC 2 cause tuberous sclerosis) Allelic heterogeneity - Different mutations in the same gene cause different conditions (e.g. Apert / Crouzon / Pfeiffer all FGFR2 gene mutations)
Germline vs somatic mutations
Germline mutations - Present PRIOR to conception - Present in every cells - Can be passed on to offspring Somatic mutations - Occur POST fertilisation and usually NOT passed on - May not cause disease but require acquisition of somatic 2nd mutation (Knudsen’s 2 hit hypothesis for cancer) e.g. VHL or BRCA genes + other tumour suppressors
% affected in triple repeat expansion disorders 8-50 trinucleotide repeats 51-60 trinucleotide repeats 61-75 trinucleotide repeats 100 GGC repeats
8-50 trinucleotide repeats Stable 51-60 trinucleotide repeats <1% expand into affected range 61-75 trinucleotide repeats 10-20% probability of expansion 100 GGC repeats
Effect of - Methylation - Demethylation
Methylation (addition of a chemical; methyl group, usually to cysteine in DNA= genes turned off Demethylation = genes turned on Occurs during gametogenesis - Stably transmitted during somatic mitosis Reversible
Are all chromosomes/ regions imprintable?
NO Known human imprinted chromosomes 7, 11, 13, 14, 15, 17, 22
What is uniparental disomy?
TWO copies from ONE parent e.g. PWS from maternal e.g. AS from paternal
Who am I?
2yr old boy presents with ataxia, hypotonia, developmental delay
MRI brain is performed which reveals…..
JOUBERT SYNDROME
- Autosomal recessive
- Clinical manifestations
- Key TRIAD
- Cerebellar + brain stem malformation = molar tooth sign (vermal aplasia) —> ATAXIA
- Hypotonia
- Developmental delay
- Other features
- Eye: coloboma, retinitis pigmentosa, nystagmus
- Irregular breathing
- Renal abnormalities = cystic disease
- Polydactyl
- Hormone abnormalities
- Key TRIAD
Who am I?
Bardet-Biedl Syndrome
Autosomal recessive
Ciliopathy
You are asked to review this little boy in the gen paeds clinic for severe GORD + growth retardation + microcephaly. What syndrome do they have? What is the inheritence + what is the most commonly mutated gene?
Cornelia De Lange
Genetics
- Single gene mutation
- NIPBL 60%
- SMC1A 5%
- Most commonly AD
Clinical manifestations
- Severe intellectual disability + microcephaly
- Growth retardation
- Dysmorphism
- Short nose, long philtrum
- Unibrow
- Arched eye brows
- Hirsutism
- Low set ears
- Cleft palate
- Musculoskeletal
- Ulnar ray defects
- Short stature
- Incurved 5th fingers
- Partial joining of the 2nd + 3rd toes
- Other
- Severe GOR
- Autistic + self destructive
- Infertility
- Hearing + visual impairment
- CVD = PS, VSD, ASD, coarctation
Investigations
- Single gene sequencing (cannot do microarray)
- Whole exome
Suprise it is day 1 of your relief registrar week and you are the cardiology reg in outpatient clinic and you are asked to review a boy with Aortic root dilatation (>4 SD above normal). On examination you find he has arachnodactyly, increased arm span/height, normal intelligence and the following;
What syndrome does he have and what is the inheritance?
Loeys- Dietz Syndrome
Genetics
- Heterogenous mutations – SMAD3, TGFB2, etc etc
- AD
- 75% de novo mutation
Clinical manifestations
- Vascular = cerebral, thoracic and abdominal aortic aneurysm and/or dissection
- Skeletal: Pectus excavatum or pectus carinatum, scoliosis, joint laxity, arachnodactyly, talipes equinovaru, cervical spine malformation
- Craniofacial: Widely spaced eyes, strabismus, bifid uvula, craniosynostosis
- Cutaneous = velvety and translucent skin, easy bruising
You are asked to review a 3 year old boy sent in by the GP with severe hypocalcaemia for investigation and management. History reveals a previous repair for truncus arteriosus at 3 months of life and a history of developmental, speech and language delay. A picture of him is attached:
- What syndrome does he have
- What gene is affected
- What are other associated abnormalities
Outline the key features, clinical presentation, genetics/ testing, natural history + complications of velocardial facial syndrome
You are in the outpatient cardiology clinic and asked to see a funny and bubbly 11yr for her annual review on the background of a previous supravavular aortic stenosis repair. On review you note she has a history of being very irritabile as an infant, is on thyroxine, has short stature and developmental delay and becomes very upset when you accidently hit yourself on the door walking into the outpatient room. A picture of her is attached.
- What syndrome does she have?
- What gene is affected?
- What are other associated abnormalities?
- Why was she very irritable as an infant?
You are the ED resident and asked to see a 5yr old girl who presents with lethargy, fevers and a cough with a history of likely an aspiration event. A chest x-ray reveals a RIGHT upper lobe pneumonia. Her history is significant for growth restriction, ID, microcephaly and distinctive facial features as shown:
- What syndrome does she have
- What gene is affected
- What are other associated abnormalities
Wolf Hirshom Syndrome
Genetics + pathogenesis
- Partial deletion of chromosome 4 – at 4p16.3
- Occurs de novo in 80% of cases – majority involve paternal chromosome
- Remainder due to balanced translocation
- Critical region – WHSCR1 and WHSCR2 gene
Clinical manifestations
- Pre and postnatal growth restriction
- Microcephaly
- Congenital heart disease: ASD, VSD, PS
- Distinctive facial features
- ‘Greek warrior helmet’ appearance due to appearance of th nose and high forehead
- Prominence of glabella
- Hyperterolism
- High and arched eyebrows
- Downturned mouth
- Severe ID
- Recurrent aspiration
- Autosomal dominant
- Mutation in the FGFR2 gene
- Early fusion of certain skull bones (craniosynostosis).
- Wide-set, bulging eyes
- Strabismus
- Small, “beak-shaped” nose
- Underdeveloped upper jaw
- Other features may include dental problems, hearing loss, and/or cleft lip and palate.
- Intelligence is usually normal, but intellectual disability may be present.
Crouzon syndrome
