Exploding Genetic Knowledge in Developmental Disabilities How to - - PDF document

Exploding Genetic Knowledge in Developmental Disabilities

How to acquire the data and how to make use of it

Elliott H. Sherr MD PhD Professor of Neurology & Pediatrics UCSF

Disclosures

 InVitae: clinical advisory board  Personalis: consultant  Grants received from:

 NIH  NHMRC (Australia)  Simons Foundation  John and Marsha Goldman Foundation

The Genetic Principle

 Genome ≈ 3.1 billion letters of DNA  Genome ≈ 20,000 genes in it  Gene: stretch of DNA that codes for a protein  DNA>>>RNA>>>PROTEIN  Codon: three letter DNA/RNA sequence that

codes for a single amino acid

 DNA duplicates by conservative replication of

double stranded molecule

The Genetic Principle The Genetic Code Autosomal Recessive

Autosomal Dominant: One gene

A*A

X chromosome linked inheritance

Aa A Aa a AA

Mutations: what are they?

 A genetic change that is deleterious

 Nonsense  Missense  Del/Dup  Other (promoter, 3° structure, etc)

 Polymorphism

 A genetic change that may be positive or negative,

but of less clinical impact

 Each of us has ≈ 3,000,000 polymorphisms and

probably 10-20 “silent” mutations

 There is overlap between M & P

Nonsense Mutations Missense Mutations Polymorphisms

 If polymorphism is a single DNA letter; it is called a

SNP (single nucleotide polymorphism)

 Some SNPs are common

 A = 80%; C = 20%  Usually just two choices  Can screen for common changes in large numbers

throughout the genome easily

 Common differences each can contribute a small amount to

common diseases

 Some SNPs are rare

 A = 99.9%; G = 0.1%  As a collection these are important for disease  Tools for assessing these are advancing rapidly

De Novo Genetic Mutations

 Mutation occurs just in that person

 Can occur during egg or sperm formation or just

after fertilization

 Can be single base pair or chromosomal

regions

 Occur more commonly in older parents  Examples of de novo mutations

 Down syndrome (trisomy)  Prader Willi syndrome (small chrom change)  Dravet syndrome (point mutation)

Chromosomal Ideograms SNP Micro‐Arrays Detect CNVs

Whole Exome sequencing

Johnsen J M et al. Blood 2013;122:3268-3275

gDNA

Genetics of Neurodevelopment

Conditions & Identification

• Down Syndrome (1866)
• Neurofibromatosis (1882)
• Fragile X (1943 & 1969)
• Prader Willi syndrome (1956)
• Smith Lemli Opitz (1964)
• Angelman syndrome (1965)
• Costello Syndrome (1977)
• Pitt‐Hopkins syndrome (1978)

Genetic Discovery; Mechanism

• 1959

De novo

• 1990

AD, De novo

• 1995

X‐linked

• 1981

De novo

• 1998

AR

• 1987

De novo

• 2005

AD, De novo

• 2007

De novo

Expanding Number of Genetic Disorders

Expanding Diagnostic Yield in DD

Genetics of Neurodevelopment: Advancing from research to the clinic

Our patient C.O. in 2004

Our Patient in 2004

• Born Term, normal BW, Height and OFC
• Developed GTC Sz at 9 months
• At 1 yr had roseola infection and development was reported to decline after this
• 19 months: bilateral cataracts and optic atrophy noted on eye exam
• MRI at 23 months: hypoplasia of inferior cerebellar vermis cerebral hemispheres
• Follow up scan at 46 months showed worsening brain atrophy, and smaller optic

nerves and chiasm

• NCS: 23 months: sensory neuropathy with delayed conduction, amplitudes

normal, EMG normal

• Sural nerve biopsy: thinly myelinated and 30% loss of axons
• Loss of milestones, with cessation of speech.
• Phys Ex: mild dysmorphism: hypertrichosis, synophyrus, deep‐set eyes with

epicanthal folds, flat philtrum. Muscles had a doughy texture. Neuro: end gaze nystagmus with titubation, limb hypertonia, reduced reflexes, but plantar response was extensor.

Diagnostic Eval on Patient C.O.

• Metabolic Testing—negative

– VLCFA, Phytanic Acid, plasmalogens – Lactate, pyruvate – Plasma lysosomal enzymes – CK, CDG, NCL

• Genetic Testing‐‐negative

– MELAS, MERRF, NARP, SCA6,7,8; DRPLA, Friedreich ataxia – Karyotype, Subtel, Microarray

• ECHO, skeletal survey
• Pause: Focus on clinical management

– Labeled as MSS—neuropathy variant

Exome Sequencing for C.O. in 2014

• KIF1A

– R216H, c.647 G>A – Zygosity: Het; inheritance: De Novo – Kinesin: motor protein that travels on microtubule “tracks”

• NID1

– T408K, c.1223 C>A – Zygosity; Het; Inheritance: De Novo – Nidogen: binds extracellular matrix

Progressive Volume Loss In KIF1A de novo Dominant Mutation Carriers

KIF1A: Sites of Mutations Kinesin moving a vesicle on MT

Gliding assay

https://valelab.ucsf.edu/images/movies/mov‐invitmtglid.mov

Functional Consequences: Kinesin Mutations

WT V220I ‐ Polymorphism A255V – Recessive T99M – De novo E253K – De novo R216C – De novo

MT Speeds in WT and Mut KIF1A

SNP AR

Lab Questions: Autism & Neurodevelopment

START HERE

Summary

The Sherr Lab Team

Brain.ucsf.edu Elliott.sherr@ucsf.edu 415‐502‐8039