Give 4 examples of autosomal dominant conditions
- Inherited breast or colon cancer
- Adult polycystic kidney disease (APKD)
- Neurofibromatosis type 1 (NF1)
- Huntington disease (HD)
Explain autosomal dominant pattern of inheritance, including its characteristics
- Only one copy of the faulty gene is needed to be affected by the condition (homozygotes + heterozygotes)
- Multiple generations affected (vertical pattern of inheritance)
Characterised by
- Variable expression: range of symptoms in people with same condition
- Incomplete penetrance: some individuals who carry the pathogenic variant express the associated trait while others do not
- Modifier gene variants
- Offspring of affected individuals usually have a 50:50 risk
List features of neurofibromatosis type 1
- Cafe au lait macules
- Neurofibromas
- Short stature
- Macrocephaly
- Learning difficulties in 30%
- Variable expressivity
- Lisch nodules in the eyes
Describe autosomal recessive pattern of inheritance including its characteristics
- 2 copies of the faulty gene needed to express phenotype
- Single generation affected - horizontal pattern of inheritance
Characteristics include
- Likely consanguinity in the family
- Disease expressed in homozygotes or compound heterozygotes
- Offspring of affected individuals have a low risk
- Expressivity more constant within family
List examples of autosomal recessive conditions
Cystic fibrosis (CF)
Phenylketonuria (PKU)
Spinal muscular atrophy (SMA)
Congenital adrenal hyperplasia
Wilson disease
Tay-Sachs disease
Describe the pathophysiology of cystic fibrosis
Mutation in CFTR gene in chromosome 7
> Leads to a defective chloride ion channel and increased thickness of secretions
> Mutation is usually p.F508del, in-frame deletion of 3bp (one codon)
> Deletion of phenylalanine prevents normal folding of protein & insertion into plasma membrane
Presents with
> Salty sweat
> Thick mucus blocking airway (High rates of sinus infection)
> Blockage of pancreatic duct
> Male infertility (congenital bilateral absence of vas deferens)
> Liver disease
> Meconium ileus
How is cystic fibrosis diagnosed?
Screening of newborns by immunoreactive trypsin (IRT) level
Confirmation by DNA testing for CF mutation (ARMS kit) or sweat testing for increased chloride concentration
Described X-linked recessive inheritance and its characteristics
X chromosome carries the faulty gene so
- No male to male transmission
- Mostly or only males affected
- Occasional manifesting carriers due to skewed X inactivation
- Knight’s move: two males who are related through an unaffected female are affected
> Likely to be X-linked recessive as female has an additional unaffected X chromosome which protects her
Describe the pathophysiology of Duchenne Muscular Dystrophy (DMD)
Frameshift mutation (mostly out of frame deletions) results in shorter dystrophin protein, which damages the myocyte cell membrane
> allows creatine kinase exit and calcium entry, destroying myocytes
Muscle damage leads to progressive degenerative weakness
> onset 3y, wheelchair by 12y
> Mean life span of <30 years as heart and diaphragm are affected by muscle weakness
Describe the tests used to diagnose Duchenne Muscular Dystrophy
- MLPA (multiplex ligation-dependent probe amplification) test to detect deletions
- SCK test : measures serum creatine kinase released by damaged muscle
> confirmed by muscle biopsy then tested for absence of presence of dystrophin gene and expression in muscle fibres via immunohistochemistry (IHC)
Describe the pathophysiology of Becker Muscular Dystrophy (BMD)
- Mutations in dystrophin gene, but in-frame deletions, so there is reduced quantity of fully functional dystrophin OR full quantity of partially functional dsytrophin
- Mild phenotype of DMD
- onset age 11
- may never need a wheelchair
Explain X-linked dominant inheritance and its characteristics
- Pattern is like AD but no male-to-male transmission
- Vertical pattern of inheritance
- Male-female transmission: all daughters affected
- Female-female transmission: 50% daughters affected
- appears to be more females affected - due to male lethality
Give examples of X-linked dominant conditions
Vitamin D resistant rickets
- caused by pathogenic variants of PHEX gene
Incontinentia pigmenti
- Skin condition that causes rashes and patches of pigmentation
- Caused by partial deletions of IKBKG gene
Rett syndrome
- Causes child development to stop at 6-18 months with subsequent regression
- Due to pathogenic variants of MECP2
- Male lethality
Explains pseudo-autosomal and pseudo-dominant inheritance
- Pseudo-autosomal: seems autosomal but is actually on the sex chromosomes
- Pseudo-dominant (actually AR): if there’s a high carrier frequency or cosanguinity
> e.g. Gilbert syndrome (TA insertion within promoter region of UGT1A1 gene) - causes intermittent jaundice due to episodes of mild unconjugated hyperbilirubinaemia
Describe mitochondrial inheritance giving an example
- Smaller genome (37 genes, 17 kbp, no introns, circular)
- Inherited only from mother
> all children affected to variable extents - Syndromes often affect muscle, brain and eyes
E.g. Leigh’s disease
> In mitochondrial DNA, MT-ATP6 gene coding for ATP synthase
Heteroplasmy is when there is more than one type of mtDNA in an individual
Describe the causes of Down’s syndrome and its phenotypic features
Causes: trisomy 21 due to maternal nondisjunction or Robertsonian translocation (inheritance risk)
- Phenotypic features
> Upward slanting palpebral fissures and epicanthic folds
> Sandal gap
> Single transverse palmar crease
> Small nose
> Low set ears
>macroglossia
> High incidence of heart malformations, hypothyroidism, childhood leukaemias, early onset Alzheimer’s
Describe the cause of Edwards’ syndrome and list its clinical features
Caused by trisomy 18
Features
> Often stillborn or miscarried, survival usually <4 months due to infections/heart failure; profound intellectual disability if they survive
> Rockerbottom feet
Syndactyly
Malformations of ears, heart, kidneys…
Micrognathia: small lower jaw
Exomphalos: umbilical hernia at birth
Describe the cause of Patau syndrome and its clinical features
- Caused by trisomy 13
Features
> Not compatible with life past a few week safter birth; many miscarriages
> Hypotelorism: eyes close together; cyclopia; microphthalmia
> Abnormal ears
> Clenched fists
> Cleft lip & palate
> Scalp defects, microcephaly
> Post-axial polydactyly
> Organ problems e.g. heart difficulties
Describe the cause and inheritance of myotonic dystrophy type 1 (DM1)
DM1 is caused by a CTG repeat expansion in the 3’ UTR of the DMPK gene (serine-threonine kinase)
> Inheritance is autosomal dominant with genetic anticipation
Repeat number of alleles increases with each generation; severity of disease is directly related to the number of repeats present
Describe the pathogenesis and clinical presentation of DM1
DM1 is characterised by abnormal DMPK mRNA which has an indirect toxic effect upon the splicing of other genes, e.g. chloride ion channel CLCN1 gene, causing myotonia
> Insulin receptor also affected, causing diaberes in some
Presents as adult-onset muscular dystrophy; myotonia (muscle relaxation is impaired) and cataracts
Describe the cause and inheritance of Huntington’s Disease (HD)
Caused by a CAG repeat sequence near the 5’ coding end of the huntingtin gene (HTT) on chromosome 4, which encodes a polyglutamine tract
> Expansion of the tract causes insoluble protein aggregates & neurotoxicity
Inheritance is autosomal dominant with genetic anticipation
Describe the pathogenesis and clinical features of HD, including diagnosis
Protein is cytoplasmic and ubiquitously expressed; may be involved in transport and trafficking within the brain as well as transcription and anti-apoptotic processes
> Selective neurodegeneration: neostriatum and cerebral cortex
Features include Huntington’s chorea (progressive) and dementia
Diagnosis via triplet primed PCR (TP-PCR)
Describe the cause and clinical features of Fragile X
Caused by an expansion of the CGG repeat in the 5’ UTR of the FMR1 gene
Inheritance is X-linked recessive; most common inherited cause of learning difficulties
Can cause premature ovarian failure in female carriers and Fragile X-associated tremor ataxia in males
Define 1) genetic heterogeneity 2) pleiotropy
- Genetic heterogeneity is a term used to describe a disorder having several different genetic causes
- Pleiotropy describes when one gene causes more than one condition e.g. RET gene causes MEN2 (AD) and Hirschprung’s disease
