A Family With Autism, Williams Syndrome, & Apraxia: Genetic Findings Presented at: ASHA 2012, Atlanta

Transcription

1 A Family With Autism, Williams Syndrome, & Apraxia: Genetic Findings Presented at: ASHA 2012, Atlanta Sudha Iyengar, PhD Case Western Reserve University

2 Our team All authors have no relevant financial or non-financial relationships to disclose Iyengar Lab (Epidemiology and Biostatistics, SOM-CWRU) CJ Miller Barb Truitt Cathy Stein (Epidemiology and Biostatistics, SOM-CWRU) Christine Curtis (Center for Human Genetics, University Hospitals) H Gerry Talyor (Pediatrics, University Hospitals and CWRU) Lewis Lab (Psychological Sciences, CWRU) Lisa Freebairn Jessica Tag

3 Background Speech sound disorder has a prevalence of ~4-6% in the general population of which Childhood Apraxia of Speech (CAS) is a subtype CAS has a prevalence of 1 in 1000 CAS is typically seen as an isolated case, but some reports also suggest familial aggregation with other speech sound disorders FOR MORE INFO... ASHA 2007 Technical Report on CAS

4 Project Goals We identified a single family with three siblings who had three different communication disorders, Williams Syndrome, Autism, and CAS Our goal was to understand the genetic architecture in this family We used high-dimensional genetic data from a data chip with 2.5 million markers and exome sequencing to determine the common and uncommon genetic features of this family and examined this information with respect to the known phenotypic data

5 Family History Proband: CAS, ADHD, Depression Sib 1: Autism, Speech, Lang, RD, ADHD, Developmental delay Sib 2: Williams, Speech, Lang, RD, ADHD, Developmental delay

6 Proband with CAS History Diagnosed at 2 yrs by SLP. Developmental milestones WNL. History of ear infections before age 3. Therapy through elementary school. Diagnosed with ADD at age 16. Some history of depression. Currently works as pharmacy assistant. Completed 2 year college. Results Age 4- Khan-Lewis: 8%tile, TOLD Sentence Imitation: 8. Age 8- PIQ:120, GFTA:99%tile, CELF Rec: 91/ Exp:80, PPVT: 121, EOWPVT: 122, WRMT- Word ID: 112/ Word Attack:111. Age 17- PIQ:125, GFTA-2:101, CELF Rec:106/Exp:96, PPVT:102, EOWPVT:95, WRMT- Word ID:108/ Word Attack:108 *Age 23- PIQ: 105, GFTA-2:101, CELF Screen: Above Criterion, PPVT:103, EOWPVT:98, WRMT-Word ID:101/ Word Attack:105 Passage Comprehension:106

7 Brother with Williams Syndrome History Diagnosed at 6 months. by physician, tiny, failure to thrive, esophogitis, NG tube, torticollis, developmental milestones delayed, dentition delays, small head, short stature, underbite, narrow palatal arch, large tongue, large incisors, tiny canines & bicuspids, flat cheekbones, large low set ears, close set eyes, hypernasal, diagnosed with ADHD in school, history of special needs, current diagnosis of OCD, allergies, thick saliva, dry eyes, sees neurologist regularly, takes many meds, loves people, no fear of strangers, happy. Test Results Age 2- not testable-ot & PT services, tiny Age 5- not testable, but physician reports very social, talks in full sentences, questions, functional vocab, interactive play, OT & PT, tiny Age 14- IQ- was able to do one subtest of WISC- Picture Completion SS:1, GFTA-2: 84, (note: used CELF-P to observe what he could do using 6:6 norms. Rec:77/Exp:72) PPVT:54, EWOPVT:-55, cannot read Age 21-IQ: CNT, GFTA-2 SS:<40, would not sit for language testing, PPVT-55, EOWPVT:59, cannot read, oral motor difficulties & very sensitive

8 Brother with Autism History: Diagnosed by pediatric neurologist at 16 months, developmental milestones WNL, late talker, hosp for flu at 2yrs, solitary, therapy preschool thru high school & history of special services, speech, OT, ADD, voice robotic, harsh, hyponasal, sensitive to touch, diff with interactions, upset easily, anger, moody, many meds, lives at home. Testing: Age 3- not testable for study Age 7- not testable for study Age 16- PIQ:54, GFTA-2 SS: 41 (could do individual CELF subtests not all. Concept&Dir:3, Word Class:3, Sem Rel: 3, Recall Sent:3, PPVT:55, EOWPVT:84, WRMT- Word ID:55/ Word Attack: 56. Age 22- would not cooperate for PIQ test, GFTA-2 SS:49, CELF Screen: failure, PPVT:58, EWOPVT-77, WRMT- Word ID:57/ Word Attack:67

9 Parents of these children History Mom Mom reported no history of speech/language & her parents had no history. Sister with articulation difficulties, 1 brother with ADHD, math, reading & learning disabilities, another brother with dyslexia. Mom diagnosed with adult ADD by time of last visit. Some depression reported. Testing Results Age 34- Did not test PIQ at time 1, GFTA:99%tile, CELF-Rec:117/Exp:99, WRMT- Word ID: 95/ Word Attack:108 Visit 2 no testing Visit 3- no testing Age 46- PIQ: 94, GFTA SS:101, CELF Rec: 96 /Exp:96, PPVT-98, EOWPVT:98, WRMT- Word ID:105/ Word Attack:121 History Dad Dad had speech/articulation issues and has spelling difficulties. His parents had no history of speech/language. One brother with spelling difficulties and another brother with spelling and reading issues Testing Dad Dad did not want to participate in the testing.

10 Why are we interested in studying the genetics of this family? WBS is caused by a deletion (loss) of ~1Mb on chromosome 7q11.22 encompassing genes Prevalence: 1/7,500 to 1/20,000 Typical features include mental retardation, visual spatial impairment, overfriendliness and strength in verbal skills Most importantly: numerous reports of dosage changes (partial deletions, duplications (Dup7), inversions etc.) on 7q11.22 are associated with other behavioral disorders including autism and speech/language (mostly expressive language) delays Conclusion: Dosage of genes in this region is important FOR MORE INFO... up7: Perspect Lang Learn Educ Oct 1;18(3): ; NEJM 2005;353: utism: Neuron Jun 9;70(5):863-85;

11 Genes in the Williams deletion region show molecular functions that may be key to understanding CAS FOR MORE INFO... Front Psychol. 2012;3:168; J Med Genet May;47(5):312-20; CNS Spectr Dec;12(12):903-7.

12 Technology We used several different types of genetic technologies to examine the DNA of this family Very dense microarrays with over 2.5 million markers spread out throughout the genome (Omni 2.5M microarray) Exome sequencing: Sequencing of mostly the protein coding regions of the genome only Fluorescence In-Situ Hybridization (FISH)

13

14 Microarrays allow us to assess variation at many loci and people

15 Exome Sequencing

16 Genetic Experimental Design 0 Omni Exome # Individuals 5 4 Omni Genotyped (Omni2.5-4) Exome Sequenced (SureSelect 50Mb) Both Omni Genotyped and Exome Sequenced Hypothesis: Childhood apraxia of speech (CAS), Williams Syndrome and Autism share genetic determinants Alternative Hypothesis: Childhood apraxia of speech (CAS), Williams Syndrome and Autism have no common genetic determinants

17 Results The child diagnosed with Williams Syndrome had a predicted hemizygous deletion (Copy Number = 1) overlapping the Williams deletion region. This deletion was predicted to be 1.4 Mb based on boundary probe position (chr7: ) and covered 25 genes

18 Comparison of FISH between Williams Sib (left) and Apraxic Child (right)

19 The sibling with Williams is Haploinsufficient in the 7q11.22 region Wild-type gene provides insufficient product to fulfill normal cell function Proband with CAS has two copies Brother with Autism also has two copies (FISH data available, but not shown)

20 The sibling with Autism shows a different arrangement of chromosomes in this region The child diagnosed with autism had a run of homozygosity that partially overlapped the Williams region. The run of homozygosity was predicted to be 1.1 Mb based on boundary probe position (chr7: ) and covered 18 genes The region of chromosome 7 in the mother and the father are virtually identical (potentially because of assortative mating)

21 Family History Proband: CAS, ADHD, Depression Sib 1: Autism, Speech, Lang, RD, ADHD, Developmental delay Sib 2: Williams, Speech, Lang, RD, ADHD, Developmental delay

22 The proband with Apraxia of Speech shows no altered structural arrangements in this region We have been unable to find any gross structural changes in the chromosomes of the CAS child in this region Our exome sequencing showed that she had no structural changes/mutations in FOXP2, CNTNAP2, ROBO1, DCDC2, KIAA0319

23 Summary of genetic changes in family

24 Conclusions and Future Directions We found a clear genetic link between two sibs with Williams-Beuren Syndrome and Autism on chromosome 7q11.22, but not with Apraxia of Speech Ongoing work on the exome of this family Families of patients with Williams-Beuren Syndrome should be carefully scanned for alternative genetic variants in family members, because the 7q11.22 region is prone to rearrangement We are performing similar detailed experiments in other families with childhood apraxia of speech and other speech sound disorders

25 Acknowledgements Thanks to all the participants Funding for this research provided by NIH- NIDCD R01DC [Lewis] R01DC [Iyengar]