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 A Aa 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 gDNA Johnsen J M et al. Blood 2013;122:3268-3275 Genetics of Neurodevelopment Conditions & Identification Genetic Discovery; Mechanism • Down Syndrome (1866) • 1959 De novo • Neurofibromatosis (1882) • 1990 AD, De novo • Fragile X (1943 & 1969) • 1995 X ‐ linked • Prader Willi syndrome (1956) • 1981 De novo • Smith Lemli Opitz (1964) • 1998 AR • Angelman syndrome (1965) • 1987 De novo • Costello Syndrome (1977) • 2005 AD, De novo • Pitt ‐ Hopkins syndrome (1978) • 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