Role of Molecular Genetic Assessment for Autism in Clinical Setting

Transcription

1 Role of Molecular Genetic Assessment for Autism in Clinical Setting Young Shin Kim, MD, MS, MPH, PhD Director STAR Center for ASD and NDDs Psychiatric Genetic Epidemiology Associate Professor Dept. of Psychiatry, UCSF

2 Disclosures Research Grant (Spouse): Janssen Consultant on a non-pharmaceutical project (Spouse): Janssen Research Support (Spouse): NIH

3 Purpose of Molecular Genetic Diagnoses Gain access to additional resources through their insurance company or school district Family support groups and online communities Decrease parental feelings of guilt Better anticipatory guidance Better genetic counseling Take account of specific management guidelines, if available, Access specific treatment considerations, if available.

4 If the genetics of breast cancer were simple, the counseling might look like this

5 However, other genetic and environmental risk factors also play a role

6 Known genetic risk factors only account for a small proportion of total risk

7 High risk genes combine with the other risk factors to give a total risk

8 Without additional insight (e.g. family history) it is very hard to interpret findings Current genetic methods cannot reliably determine where a person lies on this curve

9 Case Study 1 JP is a 16mth-old girl presenting with speech and walking delay Born at 39/40 by LCSC 2 o failure to progress; APGARs 8,10,10 Parents describe normal development in first year. No pediatrician concerns. Sat up at 6mths; cruising at 9mths; first step at 13mths, but then lost interest First word at 11mths, but did not progress A couple of months after her first birthday it felt like the lights went out

10 Case Study 1 Sequencing of MECP2 reveals missense mutation. Not observed in either parent. Diagnosed as Rett Syndrome. Important characteristics: Female Regression Progression MECP2 gene test has to be ordered specifically.

11 Mendelian causes of ASD In Mendelian disorders variants are: Necessary (mutation required for diagnosis) Sufficient (no other risk factors required) Known Mendelian causes account for <1% of ASD Rett s should be considered in a girls presenting with ASD

12 Case Study 2 DS is a 3yr-old boy presenting with mild speech delay and challenging behavior Born at 41/40 by NVD; Normal APGARs Several milestones slightly delayed: sat at 8mths; first word at 15mths; first step at 16mths Still not speaking in complete sentences Difficult to get him to concentrate on one activity Easily upset around other children and can be slightly rough Normal growth

13 Case Study 2 PCR of FMR1 reveals excess of triplet repeats Diagnosed as Fragile X Syndrome. Important characteristics: Male Reduced IQ/ASD (Anticipation) FMR1 gene test has to be ordered specifically.

14 Syndromic causes of ASD Variants are necessary and specific for the syndrome ASD is not always a feature Variants can be CNVs or SNVs Often de novo Usually associated with dysmorphology or characteristic symptoms CNVs found by microarray; single gene testing for SNVs (often requires genetics referral)

15 Syndromic forms of autism Trisomy 21 (Down) X0 or XXY (Turner, Klinefelter) 7q11.23 (Williams) 22q11.2 (digeorge/vcfs) 22q13 (Phelan-McDermid) 17p11.2 (Smith-Magenis/ Potocki- Lupski) FMR1 (Fragile X) TSC1/2 (Tuberous Sclerosis) PTEN (Cowden Disease) CACNA1C (Timothy) DHCR7 (Smith-Lemli-Opitz) PAH (Phenylketonuria) SOS1, RAF1, BRAF, KRAS, MAP2K1 (Noonan) CHD7(CHARGE) UBE3A (Angelman) MECP2 (Rett) SLC6A8 (Creatine transporter) HPRT1 (Lesch-Nyhan) MBD5 (2q31 microdeletion) NSD1 (Sotos) CNTNAP2 (Cortical dysplasia-focal epilepsy) TCF4 (Ptt-Hopkins) MED12 (Lujan-Fryns) ARX (ARX-related disorders)

16 Some Mendelian/syndromic disorders are potentially treatable PKU dietary avoidance of phenylalanine Mutation in BCKDK inactivates amino acid breakdown treatment by high amino acid diet Usher syndrome hearing and vision Cohen syndrome vision and infection MECP2, AFF2 current trials

17 Case Study 3 NP is a 6yr-old girl with a long-standing diagnosis of ASD Unremarkable birth history Presented at 2yrs of age with speech delay and mild motor delay In mainstream school with support Head on 85 th centile despite weight and height on 40 th ; no overt dysmorphic features Microarray analysis was recently ordered

18 Case Study 3 Microarray reveals 500kb deletion in 16p11.2 region Diagnosed as 16p11.2 microdeletion syndrome Important characteristics: Typical ASD presentation Microarray analysis picks up all large deletions and duplications Misses inversions, translocations, and small CNVs ~5% diagnostic yield

19 CNVs Associated with Autism

20 Who should have a microarray? Everyone with developmental delay without a clear genetic diagnosis Low IQ and dysmorphic features are not clinically predicitive

21 Case Study 4 JT is a 7yr-old boy with a being followed up after a recent diagnosis of ASD Born spontaneously at 36/40; no NICU required Presented at 5yrs due to concerns about social interaction raised by kindergarten Coping well at school, above average performance in some subjects Father is an engineer who has few social interests and collects bottle caps Mother has good social interaction Microarray shows 200kb duplication at 19q13.41

22 Case Study 4 19q13.41 duplication contains two genes: MYADM - myeloid-associated differentiation marker NLRP12 - NLR family, pyrin domain containing 12 Mutations cause familial cold autoinflammatory syndrome type 2 Rare (no other reported cases) Inherited from the mother Variant of unknown significance (VOUS) Hard to act on clinically But, always check the latest research

23 Complex Genetics No clear segregation patterns in families Genetic heterogeneity Allelic heterogeneity GxG, GxE Low penetrance, variable expressivity Common polymorphism and rare variant

24 Whole exome/genome sequencing Use of next-gen sequencing genome-wide 3-4 x 10-6 per genome Exome approaches target only coding 10,000 per exome Challenge = analysis! [and $$$$] Other findings (~2% actionable) 100 LoF, 20 ko, 75 pathogenic, 50 unique Current estimated yield Autism ~10% Recessive, X-linked, de novo

25 Data from two studies leads to 50 genes (FDR <10%) CTTNBP2 BCL11A TRIO MLL3 APH1A ASXL3 MIB1 VIL1 RELN CDC42BPB MYT1L CUL3 NR3C2 ASH1L ETFB SYNGAP1 CACNA2D3 GABRB3 SETD5 SUV420H1 NAA15 PTEN MYO9B POGZ ADNP CHD8 TBR1 KATNAL2 GRIN2B ANK2 SCN2A ARID1B DYRK1A (10) CHD2 WDFY3 TNRC6B KDM6B DSCAM PHF2 RIMS1 NCKAP1 ANKRD11 FOXP1 GIGYF1 KMT2E MED13L DIP2A WAC TCF7L2 KDM5B (23) (17) De Rubeis et al, Nature, 2014 Iossifov et al, Nature, 2014

26 Case Study 5 NP is an 8yr-old boy diagnosed with ASD, intellectual disability and attention problems Unremarkable birth history Head circumference on 90 th centile; height on 75 th ; weight on 50 th Subtle dysmorphic features Severe sleep disruption often goes 72hrs without sleep One afebrile seizure, but not on medication Recurrent constipation

27 Case Study 5 Exome sequencing reveals de novo CHD8 nonsense mutation Important characteristics: Typical ASD presentation Sleep/GI problems (but not reliably) Large head (but not reliably) Exome sequencing picks up many single gene disorders ~10% diagnostic yield Not routine practice yet...

28 Your Next Case in Psychiatry

29 Take Home Message Autism is predominantly a genetic disorder Accurate diagnoses of ASD, family history, physical examination are essential Every child with autism should have: MECP2/FMR1/PKU testing Microarray Referral to clinical geneticist if syndromic features Genetic diagnosis should be revisited every 2-3 years Exome sequencing likely to be routine soon

30 Molecular Genetic Examination of Autism

31 Role of Molecular Genetic Assessment for Autism in Clinical Setting Young Shin Kim, MD, MS, MPH, PhD Director STAR Center for ASD and NDDs Psychiatric Genetic Epidemiology Associate Professor Dept. of Psychiatry, UCSF