Diagnosis and Evaluation of Intellectual Disability Nothing to - - PDF document

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Diagnosis and Evaluation of Intellectual Disability Nothing to - - PDF document

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Diagnosis and Evaluation of Intellectual Disability Nothing to Disclose Cynthia J Curry, MD Professor of Pediatrics, Emerita, UCSF Goals for Today.. Understand the cause Establish the Why study and diagnose recurrence risk

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SLIDE 1

Diagnosis and Evaluation of Intellectual Disability

Cynthia J Curry, MD

Professor of Pediatrics, Emerita, UCSF

Nothing to Disclose

Why study and diagnose intellectual disability/delay?

  • Understand the cause
  • Establish the

recurrence risk

  • Anticipate problems
  • Order appropriate

surveillance

  • ? Options for

treatment/prenatal dx

  • END the diagnostic
  • dyssey!
  • Improve support for

parents

Goals for Today…..

  • Recap the explosion in
  • ur genetic knowledge
  • Discuss a rational

evaluation strategy

  • Illustrate how new

diagnoses help and impact patients and their families

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SLIDE 2

First there are the basics….

  • A maternal history
  • Illnesses
  • Exposures
  • Delivery
  • Child’s developmental

history

  • A family history
  • A physical exam

pedigree

764 genes for Autism‐

  • verlapping

phenotypes Wright‐2015

Physical Exam

  • Height weight and head

circumference

  • Patient should be undressed
  • Specific measurements and

descriptions

  • Eyes
  • Ears
  • Hands
  • Feet
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SLIDE 3

Eyes

The Mouth

Ears

The Hands

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SLIDE 4

SKIN

  • Is it just

hypopigmented scarring?

  • Ashleaf spots
  • Vitiligo?
  • Pigmentary

mosaicism

  • Café au Lait spots

Genetic testing

  • Biochemical
  • Chromosomes
  • Fragile X
  • Microarray
  • Gene Panels
  • Exome sequencing
  • Whole Genome

sequencing

During my lifetime there there have been truly dramatic developments in genetic testing that have changed our ability to diagnose intellectual disability

Karyotypes 3‐6%

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SLIDE 5

Routine Karyotypes 1970‐1990

The Trisomies

FISH 6‐10%

FISH

Fluorescence in‐situ hybridization

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SLIDE 6

22q11.2 deletion

  • Preferred term over

DiGeorge or VeloCardioFacial

  • A myriad of symptoms
  • 25% have psychiatric

issues

  • 95% have velopharyngeal

insufficiency

  • Most common of the

microdeletion syndromes

4p‐ Wolf Hirschhorn syndrome

  • Greek Helmet nose
  • Seizures
  • Severe FTT
  • Severe ID
  • In many, need array

FRAGILE X 0.5%

Fragile X

  • 0.5% ID
  • Most common XL ID
  • Trinucleotide repeat disorder
  • >250 repeats‐full expansion
  • Girls may be as affected as boys

( due to random X inactivation)

  • A routine test for all unexplained

ID

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SLIDE 7

Array CGH 15‐23%

Chromosome Microarray

  • Detects small gains or

losses of DNA

  • Can detect deletions or

duplications beyond resolution of chromosome analysis

  • A FIRST TIER test!!
  • In most cases replaces a

karyotype

  • Currently SNP array ( not
  • ligo or BAC)

Microarray abnormalities in my early “unknowns”

Most common array abnormalities in autism

  • 15q11.2 deletion‐ 9%
  • Proximal 16p11.2 deletion ‐

5%

  • Proximal 16p11.2

duplication‐ 5%

  • 15q13.3 deletion ‐4%
  • 16p13.1 duplication 4%
  • NRN1 deletion 4%
  • 22q13 deletion 3%
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SLIDE 8

Exome Sequencing 24‐33%

Exome sequencing

  • 22,000 genes
  • Exons code for protein
  • Massively parallel sequencing
  • Bioinformatics is critical

Principles in Exome Sequencing

  • Do a Trio if possible‐
  • Give the lab clear clinical

information

  • Results:
  • Normal……but NOTHING

FOUND is not always NOTHING!

  • Pathogenic‐ Seen before
  • Likely Pathogenic‐ Some
  • verlap
  • Variant of Unknown

Significance (VUS)

  • Novel gene
  • Not predicted to be

damaging

  • Doesn’t explain phenotype
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SLIDE 9

Finding the Causes for Known Syndromes

  • Kabuki syndrome
  • KMTD2‐AD
  • KMD6A‐ XL
  • Cornelia de Lange

syndrome

  • NIPBL~ 50%
  • SMC1A XL
  • HDAC8 XL
  • SMC3
  • RAD21

Rare/Unusual syndromes

  • Can’t diagnose with

usual testing or gestalt

  • No clear path to

diagnosis

  • Exomes are the answer!

FOXG2 SC4MOL

CDG1A

Yield in 100 cases‐ Children’s Mercy Hospital

  • Severe ID
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SLIDE 10

Yield by Diagnosis

  • Severity important
  • More severe= more likely to be

positive

  • Distinct phenotype such as a

skeletal dysplasia or arthrogryposis increases yield

  • Distinct clues:
  • seizures
  • brain malformations
  • global disability

Joubert syndrome 3M Syndrome

“incidental” findings

  • Approved by ACMG
  • 59 Conditions
  • Actionable
  • Can opt out

When the yield is lower…

  • In a non‐ exonic region
  • When array not done!
  • When it is not genetic
  • When it is mosaic
  • Need to study a

different tissue ( skin, muscle etc)

MCAP Syndrome Curry –Jones Syndrome

An important class of disorders that will be missed on Exomes

  • Trinucleotide Expansions
  • Myotonic dystrophy
  • Fragile X
  • Spinal Cerebellar Ataxias
  • Huntington Disease

Negative Exomes in Myotonic Dystrophy

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SLIDE 11

Other common ID syndromes that Exomes will miss

Methylation/ Imprinting disorders !!! Prader Willi syndrome Angelman Syndrome Beckwith Syndrome

Whole genome Seq ? 26% (pilo

Clinical Utility

  • Clinically Available for ~$5,000
  • Utility over Exome and exome reanalysis

unclear

  • Used at the Undiagnosed Disease

Network (UDN)

  • Project ”Baby Bear”
  • Not currently in widespread use
  • Several direct to consumer testing
  • ptions but not geared to analyzing ID
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SLIDE 12

Illustrating take home messages about genetic testing with several cases

Family One

  • Baby followed since birth in 2003

with diagnosis of “Perinatal Arterial Stroke”

  • Neonatal seizures
  • PVL and mild corpus callosum

findings‐MRI

  • Mild CP but ID, behavior problems,

minimal speech, aggression and anger issues dominant

  • Attributed to father ‘s “genes”

Referral of Sister

  • Aggression, meltdowns, borderline IQ
  • “what is going on here?”
  • Family history negative for

developmental issues ( ex the two sisters)

  • We ordered straight forward work up

for delay and behavioural issues starting with the older girl

  • Microarray ordered ,expecting negative

results

Abnormal results

  • 1.4 Mb Duplication 17q12
  • Well described

microduplication syndrome

  • Seizures
  • MRI abn including

PVL

  • Variable ID normal to

quite severe

  • Behavior issues

common

  • Psych issues common
  • In this family inherited

from their NORMAL mother

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SLIDE 13

17q12 duplication children and families

Rasmussen et al., AJMG, 2016 Kamath et al., AJMG B. 2018

Lessons from this family……

  • Examine a previous diagnosis in

light of new information

  • A patient evaluated in 2003 will not

have had up to date testing

  • Array abnormalities can be

inherited from a NORMAL parent

  • CP can have many causes –

including microarray abnormalities

Family twos

  • Followed since birth
  • ID in mom and child
  • Not clear they were the same?
  • Array and Fra X negative
  • Reevaluation. What now? Exomes?

2019‐ Face2Gene

  • Phone and Computer APP
  • Computer facial recognition
  • 1000 of syndromes
  • Still in development as new

cases added

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SLIDE 14

Differential from Face2Gene

Lessons from this family

  • Reevaluate your ”unknowns”
  • Face2Gene is always worth a

shot! Critical thinking required!

  • With 4000 syndromes no

dysmorphologist can hold all gestalts in head

  • Absence of the defining

syndrome does not exclude

the diagnosis

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SLIDE 15

Family 3‐ 21 month old with DD

Re‐referred at age 5 to rule

  • ut Williams

Syndrome

Exomes

  • Negative in 2015
  • Reanalysis in

2017 revealed truncating variant in PPM1D

  • First paper on

PPM1D appeared in 2014!

Jansen et al AJHG, 2014

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SLIDE 16

So the mom asked….

  • What about the Williams like

personality?

  • And….Aren’t there any USA

mothers that would like to chat about our kids?

  • So, I took the bait …..
  • Found out a LOT about this

interesting syndrome!

Collected 8 US families ( 6 unpublished)

The Face‐ 2‐5 years Face‐ mid‐childhood

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SLIDE 17

PPM1D

  • Sociable
  • ”Cocktail Party”
  • Anxiety
  • Hyperacusis
  • No fear of danger
  • Tantrums
  • Mild‐mod ID
  • Occasional autism
  • VERY sociable
  • ”Cocktail Party”
  • Anxiety
  • Hyperacusis
  • No fear of danger
  • Tantrums
  • Mild‐ mod ID
  • Occasional ASD
  • Musicality

WILLIAMS

Personalities in PPM1D vs Williams

The amazing PPMID moms!

  • Formed an informal email/phone

support group

  • Have submitted an application to

become a 501C3

  • Have investigated possibility of

participating in stem cell research

  • Can a national meeting be far

behind?

Lessons from PPM1D

  • Reanalyze negative exomes!
  • Probably almost as high a yield

as whole genome sequencing

  • Find more families!
  • The first paper is just the

beginning!

  • Empower families

To Recap….evaluation in ID

  • Don’t forget history, physical, pedigree and

baseline metabolic testing

  • THEN: Usually start with a microarray!
  • Don’t forget Fragile X!
  • Single gene, if appropriate
  • If negative, gene panels for ID may be

appropriate ( Insurance/coverage)

  • Exomes when other evaluations negative.
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SLIDE 18

So where are we now?

We have come a long way……

  • We can only

guess at the future but know it brings promise for yet more to come

  • There is much to

do……