Modes of Inheritance

What is the prevalence of type 2 diabetes?

7-8% of under 16-year-olds and 23% for under 75-year-olds 

Why is T2D so common?

• Relatively high heritability 30-70% 

• Many environmental factors that increases the incidence rate  

What are the features of neurofibromatosis type 1?

• 1/2000 individuals so sort of common 

• Autosomal dominant condition  

• Can be serve or mild condition so can have a high reproductive fitness  

• Is mainly a mild condition  

Why is neurofibromatosis type 1 common?

• NF1 gene is large and repetitive so prone to mutation  

• High de novo mutation rate around ½  

Why is cystic fibrosis so common?

• Genetic variants that are thought to be selected for as they give individuals an advantage  

• Have a protective effect against certain infections(cholera/tuberculous) so has a selection pressure  

• Makes the autosomal recessive more common   

What are the features of the founder effect?

• Have some that are more common in certain populations than anticipated  

• Due to founder effect  

• Small population breeding so many in the population has the variant so the recessive condition is more common in that population  

What makes DiGeorge Syndrome common?

• Has a mutable region that has low copy number repeats  

• Prone to new variants  

• Misaligns at recombination  

• Recurrent duplications and deletion

Why is Zellweger syndrome rare?

• No selective pressure  

• Heterozygous has no advantage over anyone else  

• Many genes associated but are very small genes  

• Not repetitive so not prone to new mutations 

How are multifactorial conditions presented?

• Monogenic or polygenic and then environmental  

• To express the condition need to meet the threshold of the disease  

• Factors can have a high risk but there are other factors that are required for the expression  Wh

What is multifactorial?

• Everything is multifactorial  

• Can be the penetrance or the expressivity in the condition  

What are the features of Schizophrenia?

• Impacts around 1 in 100 people  

• Variable responses to the treatment  

• Extremely variable: psychosis, blunting of affect/social impairment  

What are the causes of Schizophrenia?

• Looking at twins has a 80% heritability coefficient  

• Doesn't mean 80% is genetic factors as has environmental influences in it  

• Have other genomic conditions that can increase rate such as DiGeorge  

• Pregnancy complications, antenatal infections, childhood trauma, social isolation, substance misuse, second trimester influenza exposure

What are the features of polygenic risk scores?

• Take the GWAS studies and produce a weighted risk haplotype score  

• Score based on association based on importance  

• Add other risk factors  

• Stratify to produce individual intervention – health economics  H

How do economics impact PRS?

Threshold for treatment depends on the economics of the treatment  

What are haplotypes?

• Haplotype – half of the genotype (maternal or paternal) 

• Region of the genome that tends to be inherited together 

• This is because the chunk tends to be in linkage disequilibrium, but recombination can happen  

How do haplotypes work?

• Group of variants that move together  

• Have marker variants to infer the wider haplotype and what is in the surrounding region  

How are haplotypes used to determine risk?

• Uses genome sequencing more for GWAS rather than microarray so move away from haplotypes  

• Sometime know which SNP in the haplotype that is causing the disease  

• For some markers you might not have the risk SNP even though there is the risk haplotype  

What causes coeliac disease?

• Immune system has an antigen presenting ability on the T cells and detect gluten  

• Certain variants of the receptor allow the detection of gluten  

• High proportion that have the risk haplotype but only 4% will develop the disease  

• This means that it can be determined as a risk whereas others immune system isn't primed so there is no response  

What are the potential modes of inheritance?

• Only males are affected could be dominant with reduced penetrance  

• Autosomal recessive with pseudo dominant  

• Mitochondrial as it goes through the maternal line  

What are the features of HUS?

• Could be monogenic or multifactorial

• Condition with a trigger that causes haemolysis (breaking open blood cells), plates in abnormal places causing blockages  

• Blocks capillaries in the kidneys and leads to renal failure  

What is the treatment of HUS?

• Treated by plasma exchange  

• Remove blood to remove the abnormal immune system and return the working plasma  

• Now use monoclonal antibody treatment  

What is typical HUS?

• Typical HUS can happen through infections such as E.coli  

• Reaction to the infection might have genetic risk  

What are the features of aHUS?

• aHUS impacts 1 in 500000 

• 10 genes – includes CFH causing susceptibility  

• Triggers include infection, pregnancy and hormone exposure  

What are the features of HUS heterozygotes?

• Rare and common genetic variants that causes the condition  

• Does heterozygous then increase chances of invent or not  

What are features of monogenic conditions?

• Variable penetrance  

• Variable expressivity 

• Mosaicism  

• Anticipation   

What is penetrance?

Penetrance is the proportion of heterozygotes who show evidence of the pathogenic variant  

What is expressivity?

Variable expression is the variable manifestation or degree of severity  

How can X conditions be transmitted?

• Can have male and female children affected with no affected parents  

• Can have a father and affected daughter  

• Can have an affected mother and daughter  

• There can be sporadic female conditions  

What does X-inactivation do?

• Mechanism to balance the gene dosage – 8,900  

• Similar dosage to males  

• About 15% of the genes don’t undergo inactivation  

• Pseudo autosomal genes (end of X) remain active  

When does X-inactivation happen?

• Happens at the blastocyst stage (day 5-6) where the imprinting happens  

• Stable during mitosis, daughter cells have the same X (maternal or paternal) inactivated  

• This makes the cells mosaic for which chromosomes are inactivated  

How does X-inactivation happen?

• Controlled by long noncoding RNAs XIST and TSIX  

• XIST is antisense long non-coding RNA gene which coats the X chromosome to be inactive by spreading transcriptional silencing  

• Looks like a Barr body 

What are the features of skewing?

• Balanced between the paternal and maternal X being active isn’t the same for each woman  

• Some that are skewed for the paternal or maternal  

• Factors that cause this but don’t know  

Why might the X chromosome be skewed?

• Might not want one active if there something wrong  

• Artificial skewing with age as don’t need two X and some cells will lose an X  

• Random loss so causes skewing  

How do you investigate X-chromosome inactivation?

• Androgen receptor on X has polymorphic loci so maternal and paternal with have a different length polymorphism 

• Bisulphite treatment converts methylated cytosine to uracil and restriction enzymes will only bind to the active X 

• PCR and see different lengths and proportion of active  

• Doesn't tell the direction of the skewing – requires linkage for this 

Why is X-inactivation done?

• Might be do it for why a female is manifesting a condition you wouldn’t expect them to  

• Has a variant of uncertain significance / pathogenic might support the classification  

What are common X-linked conditions?

• Around 500 disorders  

• Red-green colour-blindness  

• 7-10% men and 1 in 250 females  

• Haemophilia A  

• 1 in 4000 males and 1 in 40000 females  

• DMD has 1 in 3500 males  

• Fragile X is 1 in 2500/4000 males  

• 1 in 7000/8000 females  

How many X-linked developmental disorders are there?

• Intellectual disability 2-3:1  

• Autism spectrum 4:1  

• Biased statistic and might not be due to the X chromosome but the diagnostics  

• Estimated 2-300 genes on the X-chromosome are associated with developmental disorders  

What are the features of X-linked developmental disorders?

• Non-syndromic X-linked intellectual disability  

• Not clinically distinguishable  

• Reverse phenotype grouped together and see if they are distinct and define the condition  

What is ATRX?

• X-linked recessive condition  

• Strange if female is affected such as Turner syndrome  

• Heterozygous would have skewed X chromosome  

What are the features of ATRX?

• Severe intellectual disability  

• Mild alpha-thalassaemia  

• Hypotonia, seizures  

• Microencephaly  

• Genital abnormalities  

What is Alport syndrome?

• Variants in COL4A5  

• Originally X-linked recessive  

• Now X-linked dominant condition 

• Don’t know which one  

• Males late teen renal failure  

• Hearing loss and eye features  

• Some variants where they have features their whole life but don’t go into renal failure  

How does Alport syndrome impact females?

• Blood and protein in urine  

• Renal failure – less common than males  

• Often have a milder form of the condition but have some  

• Mild number that have no symptoms  

What are the features of Rett Syndrome?

• X-linked dominant  

• 1 in 10,000 females  

• Some males are hypomortphic, Klienfelters or mosaic  

• Normally de novo but some women are completely skewed  

• Neurological condition  

• Normal – static development – regression – seizures and deteriorate further  

• Secondary microencephaly  

• Stereotypic hand movements  

What are the features of incontinentia Pigmenti?

• X-linked dominant  

• Lethal in males but inherited in females 

• Mosaicism present in woman 

• Affect brain, eyes and skin  

• Woman not diagnosed might have skin infection / eczema when born  

• Missing teeth due to inflammation  

• Back of eyes scaring  

• Can see based on the appearance of the skin which cells have the X chromosome mutation  

What are the features of craniofrontonasal dysplasia?

• X-linked dominant  

• Females are more severe than males  

• Receptor and female have some cells expressing and some that aren’t  

• Conflicting cells is worse than having the receptor missing from all cells  

• Inherited and de novo  

• Cellular inference model – abnormal tissue boundaries