Angus Clarke,Institute of Medical Genetics,

Cardiff

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Outline‘Problems’ with GeneticsPotential benefits of DIAGNOSISDigression into Rett syndromeDifficult questions that remain

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‘Problems’ with GeneticsFocus on labels and biomedical processes can

lead to stigmatisation, disrespect and the neglect of patient and family experiences ...

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‘Problems’ with GeneticsFocus on labels and biomedical processes can

lead to stigmatisation, disrespect and the neglect of patient and family experiences ...

... but these problems do not arise from genetics

social attitudes to disability and difference are deep-rooted

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‘Problems’ with GeneticsEugenics, Nazism and ‘race hygiene’ have

given genetics a bad name ...

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‘Problems’ with GeneticsEugenics, Nazism and ‘race hygiene’ have

given genetics a bad name ...

... political abuse of genetic concepts in 20th century (heritability; inbreeding depression vs hybrid vigour; ‘race’)

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‘Problems’ with GeneticsGenetic determinism ...

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‘Problems’ with GeneticsGenetic determinism ... is bad science

and genetics can outlive these misinterpretations

Note some other types of inappropriately strong determinism: Marx, Freud, Skinner ...

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What is a diagnosis?

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What is a diagnosis?Does ‘neural tube defect’ count as a

diagnosis?Or cleft lip and palate?

Or are these physical signs?

What about ‘autism’? or ADHD?

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Genetics and DiagnosisGenetics aims at an explanatory diagnosis

that accounts for causation as well as phenotype

This aims to inform prognosis

And to open up possibilities for therapeutic intervention

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Diagnosis and GeneticsGenetics allows greater sophistication in

making diagnoses, leading to:

Avoidance of erroneous explanations - did I do anything in the pregnancy? - it must be his fault, it’s not in our side of the

family

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Diagnosis and GeneticsGenetics allows greater sophistication in

making diagnoses, leading to:

More precise natural history and prognosis

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Digression into Rett Syndrome

• Recognition of “cerebral atrophy with hyperammonaemia” by Andreas Rett 1966

Rett Syndrome

• Recognition of “cerebral atrophy with hyperammonaemia” by Andreas Rett 1966

• Changes to the diagnostic landscape

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Rett syndrome

• X-linked condition• Almost always affects girls (1 in 12,000)• ‘Normal’ early development• Stagnation then regression

– social contact, hand skills, speech, ...– hand stereotypies

• Stabilisation, regain social contact• Profound cognitive impairment with motor

and autonomic dysfunctions, and relative microcephaly

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Other associated features

• Truncal ataxia• Muscle tone, including spasticity in legs• Ventilatory rhythm• Vasomotor disturbances including cool,

atrophic feet• Seizures• Scoliosis• Impaired growth

– including 4th metatarsal

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Gene - Yes; Explanation - No

• Usual cause: de novo MECP2 mutation• ‘Cure’ of Adrian Bird-Jackie Guy mouse

cre-lox model

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Brain Pathology

• Normal number of cells• Reduced size of neurons• Reduced number and complexity of

dendritic trees and synapses• ‘Reversal’ of MECP2 mutation leads to

reversal of the Rett pathology (Stuart Cobb, Glasgow)

• Introduction of mutation in adult life => features of typical Rett disorder

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Rett syndrome is primarily a CLINICAL diagnosis

with a highly characteristic time course

and evolution,

although some ‘mild’ and some ‘severe’ cases - ‘incomplete’, ‘preserved speech’, ‘congenital’ and ‘early seizure’ variants

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Is regression necessary to the diagnosis?

• Essential to delineation of the syndrome• Regression may be absent in otherwise

classic cases with MECP2 mutation– ‘mild’ cases (Zappella, preserved-speech)– severe and early-onset cases (congenital

Rett; Hanefeld early seizures variant)

• 2010 criteria assert that regression is necessary even for variant RTT

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Rett syndrome is (usually) caused by mutations in MECP2, already

being studied by Adrian Bird

•Methyl-CpG-binding protein 2•Global transcription repressor•Locus at Xq28

Methyl Binding Domain

AT hooks

Transcription Repression Domain

Amir et al 1999

Large deletions in MECP2

Exon 4.2 - 4.3 (n=1)

Exon 1 & 2 (n=3)

Exon 3 & 4.1 (n=3)

Exon 3 – 4.3 (n=5)

Exon 4.1 - 4.3 (n=1)

Exon 4.3 – IRAK1 (n=1)

Exon 3 & 4 (n=3)

Exon 4.2 (n=1)

Exon 4.2 - 4.4 (n=1)

Exon 4.3 (n=1)

Exon 4 (n=1)

MECP2

Exon 1 Exon 2 Exon 3 Exon 4

~2Mb ~5kb ~60kb <1kb 1.6kb ~124kb

IRAK1 L1CAMSYBL1

Mild Rett syndrome

• Walk• Swim• Ride a bike• Talk• Use hands – self-feed, write• Better growth• Greater survival• But significant learning

disability

How do the mutations cause the disease ?

– contentious– probably involves loss of fine tuning of gene

expression– but ‘explanation’ of RTT phenotype (how

genetic change causes RTT) is still unclear

Explanation

• Descriptive explanationsPattern recognition => natural history

• Mechanistic / Linear explanations A => B => C => D; upstream and target loci

=> science

• ‘Complex System’ explanation– Complex web of molecular and pathway

interactions => despair ?

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Lessons for other diseases

• Charting the pathogenic mutations is just the beginning ...

• The ‘explanation’ for the phenotype may lie at a ‘higher‘ level of biological function, e.g. development and function of the CNS

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Diagnostic Applications of MECP2 testing

• Classical Rett Syndrome=~95% mutations

• ‘Atypical’ Rett syndrome 50% mutations

• Early seizure variant<10% mutations, nil (so far) with infantile spasms

• Is the mutation pathogenic ?– de novo ? synonymous ? conserved ?– present in healthy male ?

Diagnostic Test => 2 x 2 Table

Mutation TestClinical assessment

Test Positive: mutation found

Test Negative: mutation NOT found

Clinical diagnosis: typical or ‘atypical’ case of RTT

expected ! New and anomalous

Clinical diagnosis: NOT typical of RTT

! New and anomalous expected

Family Consequences of Mutation Testing for RTT

• Confirmation of diagnosis– Reproductive confidence in face of mosaicism– But still an emotional kick

• “Disconfirmation” of diagnosis– An anomalous category– A different emotional kick

• “Disconfirmation of normality” when MECP2 mutation found in absence of RTT

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New categories emerge

• congenital Rett syndrome (FOXG1)• early onset of seizures group (CDKL5)• Zappella variant (‘preserved speech’)

(some of the girls with R133C mutation in MECP2)

• group with some features of Rett and specific physical features (eg Pitt-Hopkins syndrome = TCF4, Angelman UBE3A, ...)

• others ....32

Facial similarities noted in congenital Rett syndrome

associated with mutations in FOXG1

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Diagnosis and GeneticsGenetics allows greater sophistication in

making diagnoses, leading to:

More precise natural history and prognosis

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Diagnosis and GeneticsGenetics allows greater sophistication in

making diagnoses, leading to:

Answer family questions (why?, when?, how to manage?, how to prevent recurrence?, who carries it?)

Practical decisions - and issues of guilt and blame - are played out on the basis of facts instead of guesses

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Diagnosis and GeneticsGenetics allows greater sophistication in

making diagnoses, leading to:

Discussion of ‘responsibility’, which has both moral and biological components

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Diagnosis and GeneticsGenetics allows greater sophistication in

making diagnoses, leading to:

Access to support:disease association/family support grouphealth care servicessocial services and benefitseducational support

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Diagnosis and GeneticsGenetics allows greater sophistication in

making diagnoses, leading to:

Surveillance for complications

(i) specific features of the diagnosis

(ii) incidental findings that emerge from genetic investigation

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Diagnosis and GeneticsGenetics allows greater sophistication in

making diagnoses, leading to:

Searches for rational treatment

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Disease Mechanisms

For Duchenne muscular dystrophy, cystic fibrosis, ectodermal dysplasia:

finding the gene => finding the protein => new insights => treatment (?)

Tuberous sclerosis

Rett syndrome: ‘Gene today, gone tomorrow’

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Disease MechanismsAdrian Bird/Jackie Guy mouse ‘cure’ => hope!

Focused treatments for the autonomic problems found in Rett syndrome become possible

Work on underlying disease processes becomes possible ....

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Disease MechanismsBut Beware!

Possible ‘Awakenings’ scenarios from rational treatment in Rett syndrome

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Disease Mechanisms

Causes of autism include CNVs and de novo point mutationsmany different ‘causes’ with variety of

‘triggers’

Metabolic or neural pathways of related diseases (Ras pathway; pathways revealed by pattern of CNVs in autism/schizophrenia)

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Difficult Questions

Difficult questions remain ...

BUT we all accept population screening for PKU and congenital hypothyroidism

Will newborn screening for fragile X syndrome become equally acceptable?

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Difficult Questions

Decisions about reproduction, population screening and the unconditional acceptance of ‘Being A good Parent’ or ‘Parental Virtue’

Rational Treatments and recruitment to therapeutic trials

What would it be like to be ‘cured’ of Rett syndrome?

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