WELCOMETO THE FIRST USP7 FAMILY CONFERENCE

HOUSTON, TEXAS

APRIL 7TH AND 8TH, 2017

CLINICAL ASPECTS

CHRISTIAN SCHAAF, MD, PhD

BAYLOR COLLEGE OF MEDICINE

TEXAS CHILDREN’S HOSPITAL

• November 2013

• Four patients with a neurodevelopmental disorder caused by mutations in the MAGEL2 gene

HOW IT ALL BEGAN

LEARNING ABOUT MAGEL2

Ryan Potts, PhD

OUR HYPOTHESIS

Mutations in MAGEL2 interacting proteins may lead to neurodevelopmental disorders with similar phenotypic consequences as MAGEL2 loss-of-function itself

Subject 1

Subject 2

Subject 3

Subject 4

Subject 5

Subject 6 c.429C>G (p.Y143X)

Subject 7

het deletion (18 genes)

USP7 gene

het deletion (2 genes)

het deletion (8 genes)

het deletion (8 genes)

het deletion (2 genes)

het deletion (5 genes)

X

de novo

de novo

de novo

de novo

de novo

de novo

de novo

SEVEN INDIVIDUALS WITH USP7 MUTATIONS

Phenotype 1 2 3 4 5 6 7 Sum

Developmental delay/intellectual disability + + + + + + + 7/7

Hypotonia + + - - + + - 4/7

Autism spectrum disorder + + + + + - o 5/6

Hypogonadism + + o - + o + 4/5

Aggressive behavior - + + + + - - 4/7

Epilepsy + - + + + + - 5/7

+ phenotype present - phenotype absent o unknown

CLINICAL FEATURES OF THE FIRST 7 PATIENTS

5’ 3’

USP7

USP7

Cr: 16

p13.

3

p13.

216p13.3 16p13.2

6,500,000| 7,000,000| 7,500,000| 8,000,000| 8,500,000| 9,000,000|

RBFOX1RBFOX1RBFOX1

RBFOX1RBFOX1

RBFOX1

TMEM114TMEM114

TMEM114TMEM114

ABAT

TMEM186PMM2

CARHSP1CARHSP1CARHSP1CARHSP1

USP7USP7USP7USP7USP7

Subject 2

Subject 5Subject 6

Subject 7

Subject 3Subject 4

Subject 1

* * * * * * * ***

ABATABAT

TOTAL OF 18 INDIVIDUALS WITH USP7 MUTATIONS KNOWN TO US TO DATE

HOW IS IT GENETICALLY DIAGNOSED?

“Library inventory”

~ 200,000 regions of chromosome material

“Checking for misspellings”

~ 30,000,000 letters of genetic code

Chromosome microarray Whole exome sequencing

CLINICAL FEATURES

• Developmental delay/ intellectual disability 94%

• Speech impairment 100%

• Non-verbal 25%

• Autism spectrum disorder 58%

CLINICAL FEATURES

• Neonatal hypotonia 43%

• Significant feeding problems 58%

• Contractures 27%

• Hypogonadism 58%

CLINICAL FEATURES

• Eye abnormalities (strabismus, myopia,

nystagmus, or other) 61%

• Short stature 33%

• Difficulty gaining weight 36%

GASTROINTESTINAL FEATURES

• Reflux / GERD 55%

• Chronic constipation 36%

• Chronic diarrhea 20%

NEUROLOGICAL FEATURES

• Abnormal brain MRI 90%

• Seizures 44%

• Abnormal gait 40%

• Hypotonia 63%

PWS features

MAGEL2 features

Hyperphagia

Obesity

Neonatal hypotonia

Feeding difficultiesContractures

Intellectual disability

Hypotonia

Hypogonadism Autism

Epilepsy

White matter changes

USP7 features

WE WANT TO LEARN FROM YOU