Diagnosis and Evaluation of Intellectual Disability Nothing to - PDF document

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 • Recap the explosion in • Anticipate problems intellectual disability/delay? • Order appropriate our genetic knowledge surveillance • Discuss a rational • ? Options for evaluation strategy treatment/prenatal dx • END the diagnostic • Illustrate how new odyssey! diagnoses help and • Improve support for impact patients parents and their families

First there are th e basics… . • A maternal history • Illnesses • Exposures • Delivery • Child’s developmental history pedigree • A family history • A physical exam Physical Exam • Height weight and head circumference • Patient should be undressed • Specific measurements and 764 genes for descriptions • Eyes Autism‐ • Ears overlapping • Hands phenotypes • Feet Wright‐2015

Eyes The Mouth The Hands Ears

SKIN Genetic testing • Is it just • Biochemical hypopigmented scarring? • Chromosomes • Ashleaf spots • Fragile X • Vitiligo? • Microarray • Pigmentary mosaicism • Gene Panels • Café au Lait spots • Exome sequencing • Whole Genome sequencing During my lifetime there there have been truly dramatic developments in genetic testing that Karyotypes 3‐6% have changed our ability to diagnose intellectual disability

Routine Karyotypes 1970‐1990 The Trisomies FISH FISH 6‐10% Fluorescence in‐situ hybridization

4p‐ 22q11.2 deletion Wolf Hirschhorn • Preferred term over syndrome DiGeorge or VeloCardioFacial • Greek Helmet nose • A myriad of symptoms • Seizures • 25% have psychiatric • Severe FTT issues • 95% have velopharyngeal • Severe ID insufficiency • In many, need array • Most common of the microdeletion syndrome s Fragile X • 0.5% ID FRAGILE X 0.5% • 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

Chromosome Microarray Array CGH 15‐23% • 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 oligo or BAC) • 15q11.2 deletion‐ 9% • Proximal 16p11.2 deletion ‐ 5% • Proximal 16p11.2 duplication‐ 5% • 15q13.3 deletion ‐4% • 16p13.1 duplication 4% Microarray abnormalities • NRN1 deletion 4% • 22q13 deletion 3% in my early “unknowns” Most common array abnormalities in autism

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 overlap • Variant of Unknown Significance (VUS) • Novel gene • Not predicted to be damaging • Doesn’t explain phenotype

Finding the Causes for Known Syndromes • Kabuki syndrome • KMTD2‐AD • KMD6A‐ XL • Cornelia de Lange syndrome • NIPBL~ 50% • SMC1A XL • HDAC8 XL • SMC3 • RAD21 FOXG2 Yield in 100 cases‐ Children’s Mercy Hospital Rare/Unusual SC4MOL syndromes • Severe ID • Can’t diagnose with usual testing or gestalt • No clear path to diagnosis • Exomes are the answer! CDG1A

Yield by Diagnosis Joubert • Severity important syndrome • More severe= more likely to be positive “incidental” findings • Distinct phenotype such as a • Approved by ACMG skeletal dysplasia or arthrogryposis • 59 Conditions increases yield • Actionable • Distinct clues: • Can opt out • seizures • brain malformations 3M Syndrome • global disability An important class of disorders When the yield is that will be missed on Exomes lower… • In a non‐ exonic region • Trinucleotide Expansions Curry –Jones • When array not done! • Myotonic dystrophy Syndrome • When it is not genetic • Fragile X • Spinal Cerebellar Ataxias • When it is mosaic • Huntington Disease • Need to study a different tissue ( skin, muscle etc) MCAP Syndrome Negative Exomes in Myotonic Dystrophy

Other common ID Whole genome syndromes that Seq ? 26% (pilo Exomes will miss Methylation/ Imprinting disorders !!! Prader Willi syndrome Angelman Syndrome Beckwith Syndrome 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 options but not geared to analyzing ID

Family One • Baby followed since birth in 2003 with diagnosis of “Perinatal Arterial Illustrating take home Stroke” messages about • Neonatal seizures genetic testing with • PVL and mild corpus callosum findings‐MRI several cases • Mild CP but ID, behavior problems, minimal speech, aggression and anger issues dominant • Attributed to father ‘s “genes” • 1.4 Mb Duplication 17q12 • Well described Referral of Sister microduplication syndrome • Seizures • Aggression, meltdowns, borderline IQ • MRI abn including • “what is going on here?” PVL • Family history negative for • Variable ID normal to developmental issues ( ex the two quite severe sisters) • Behavior issues • We ordered straight forward work up common • Psych issues common for delay and behavioural issues starting with the older girl • In this family inherited Abnormal results • Microarray ordered ,expecting negative from their NORMAL mother results

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 Rasmussen et al., AJMG, 2016 Kamath et al., AJMG B. 2018 • Array abnormalities can be 17q12 duplication children and families inherited from a NORMAL parent • CP can have many causes – including microarray abnormalities 2019‐ Face2Gene • Phone and Computer APP • Computer facial recognition • 1000 of syndromes Family twos • Still in development as new • Followed since birth cases added • ID in mom and child • Not clear they were the same? • Array and Fra X negative • Reevaluation. What now? Exomes?

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

Re‐referred at age 5 to rule out Williams Syndrome Family 3‐ 21 month old with DD • Negative in 2015 • Reanalysis in 2017 revealed truncating variant in PPM1D • First paper on PPM1D appeared in 2014! Exomes Jansen et al AJHG, 2014

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? Collected 8 US families • So, I took the bait ….. ( 6 unpublished) • Found out a LOT about this interesting syndrome! The Face‐ 2‐5 years Face‐ mid‐childhood

Personalities in PPM1D vs Williams The amazing PPMID moms! PPM1D WILLIAMS • Sociable • VERY sociable • Formed an informal email/phone • ”Cocktail Party” support group • ”Cocktail Party” • Have submitted an application to • Anxiety • Anxiety become a 501C3 • Hyperacusis • Hyperacusis • Have investigated possibility of • No fear of danger • No fear of danger participating in stem cell research • Tantrums • Tantrums • Can a national meeting be far • Mild‐mod ID • Mild‐ mod ID behind? • Occasional autism • Occasional ASD • Musicality To Recap….evaluation in ID Lessons from PPM1D • Don’t forget history, physical, pedigree and baseline metabolic testing • Reanalyze negative exomes! • THEN: Usually start with a microarray! • Probably almost as high a yield • Don’t forget Fragile X! as whole genome sequencing • Single gene, if appropriate • Find more families! • If negative, gene panels for ID may be • The first paper is just the appropriate beginning! ( Insurance/coverage) • Empower families • Exomes when other evaluations negative.

We have come a long way…… So where are • We can only guess at the we now? future but know it brings promise for yet more to come • There is much to do……