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
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
