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Home , Late talker, Silent mutation, Trisomy 9

September 2015 Genetic causes of childhood apraxia of speech: Case‐based introduction to DNA, inheritance, and clinical management

Beate Peter, Ph.D., CCC‐SLP Assistant Professor Dpt. of Speech & Hearing Science Arizona State University

Adjunct Assistant Professor AG Dpt. of Communication Sciences & Disorders ATAGCT Saint Louis University T TAGCT Affiliate Assistant Professor Dpt. of Speech & Hearing Sciences

University of Washington 1

Disclosure Statement

Dr. Peter is co‐editor of a textbook on speech development and disorders (B. Peter & A. MacLeod, Eds., 2013), for which she may receive royalty payments. If she shares information about her ongoing research study, this may result in referrals of potential research participants. She has no financial interest or related personal interest of bias in any organization whose products or services are described, reviewed, evaluated or compared in the presentation.

Agenda

Topic Concepts Why we should care about genetics.

Case 1: A sporadic case of CAS who is missing a • Cell, nucleus, chromosomes, genes gene. Introduction to the language of genetics • From genes to proteins • CAS can result when a piece of DNA is deleted or duplicated

Case 2: A multigenerational family with CAS • How the FOXP2 gene was discovered and why research in genetics of speech and language disorders is challenging • Pathways from genes to proteins to brain/muscle to speech disorder

Case 3: One family's quest for answers • Interprofessional teams, genetic counselors, medical geneticists, research institutes • Early signs of CAS, parent education, early intervention • What about genetic testing?

Q&A

“Genetic Causes of CAS: Case-Based Introduction to DNA, Inheritance and Clinical Management,” Presented by: Beate Peter, PhD, CCC-SLP, September 29, 2015, Sponsored by: CASANA 2

Why should you care about genetics?

If you are a parent of a child with childhood apraxia of speech …

When she was in preschool, He doesn’t have any friends. she would always play by They all run away from him. herself. I asked her, Why don’t He brought one if Thomas you go play with the other trains to preschool as a gift, girls? She didn’t want to, hoping that the other kids because the other girls would talk to him. wouldn’t know what she was saying. Mom of a 4‐y‐o with a diagnosis of childhood Mom of a 6‐y‐o with diagnosis apraxia of speech of childhood apraxia of speech

If I had known how hard this would be, I wouldn’t have had any more kids.

Mom of a 4‐y‐o with a diagnosis of childhood apraxia of speech and 2‐y‐old twins with speech problems

“Genetic Causes of CAS: Case-Based Introduction to DNA, Inheritance and Clinical Management,” Presented by: Beate Peter, PhD, CCC-SLP, September 29, 2015, Sponsored by: CASANA 3

“Thank you so much for doing the research to see if we can find a way to identify speech risks while the child is still young and can start speech therapy at an earlier age.”

Mother of a 14‐year old with severe CAS

• … You want to know why your child has CAS • You wonder about your own DNA • You want to know what your odds are of having another child with CAS • You want to help researchers find the link between DNA and speech disorders so that other children can receive extra early interventions • Perhaps you have many other reasons

If you are a clinical service provider …

“Genetic Causes of CAS: Case-Based Introduction to DNA, Inheritance and Clinical Management,” Presented by: Beate Peter, PhD, CCC-SLP, September 29, 2015, Sponsored by: CASANA 4

… You see disorders with a genetic etiology on a daily basis • Angelman syndrome • Autism • Cardio‐velar‐facial syndrome • Charcot‐Marie‐Tooth disease • CHARGE syndrome (Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth and/or development, Genital and/or urinary abnormalities, and Ear abnormalities and deafness) • Clefting • Dyslexia • Fragile X • Fronto‐temporal dementia • Hearing impairment • Huntington’s disease • Language impairment • Parkinson disease • Prader‐Willi syndrome • Rett syndrome • Rolandic epilepsy • Speech sound disorder • Trisomy 21 • Usher syndrome • Waardenburg syndrome • Williams syndrome • …

“In my experience, the referral for genetic counseling is often initiated by an SLP who noticed something about the patient that everyone else had missed. Maybe this is because speech and language involve such complex behaviors.”

Meg Hefner, M.S., Genetic counselor and Associate Professor, St. Louis University

Genetics for Clinicians

• Better understanding of your client’s disorder • Better idea of what the prognosis might be • Better information about whether or not to qualify for intervention and if yes, what kind • Better equipped to know when to refer to a genetics professional • Better equipped to educate parents to look for early signs of the familial disorder

“Genetic Causes of CAS: Case-Based Introduction to DNA, Inheritance and Clinical Management,” Presented by: Beate Peter, PhD, CCC-SLP, September 29, 2015, Sponsored by: CASANA 5

http://www.nchpeg.org

National Coalition for Health Professional Education in Genetics BASELINE COMPETENCIES At a minimum, each health‐care professional should be able to: a. examine one’s competence of practice on a regular basis, identifying areas of strength and areas where professional development related to genetics and genomics would be beneficial. b. understand that health‐related genetic information can have important social and psychological implications for individuals and families. c. know how and when to make a referral to a genetics professional.

“Genetic Causes of CAS: Case-Based Introduction to DNA, Inheritance and Clinical Management,” Presented by: Beate Peter, PhD, CCC-SLP, September 29, 2015, Sponsored by: CASANA 6

1. KNOWLEDGE All health professionals should understand: 1.1 basic human genetics terminology. 1.2 the basic patterns of biological inheritance and variation, both within families and within populations. 1.3 how identification of disease‐associated genetic variations facilitates development of prevention, diagnosis, and treatment options. 1.4 the importance of family history (minimum three generations) in assessing predisposition to disease.

1. 5 the interaction of genetic, environmental, and behavioral factors in predisposition to disease, onset of disease, response to treatment, and maintenance of health. 1.6 the difference between clinical diagnosis of disease and identification of genetic predisposition to disease (genetic variation is not strictly correlated with disease manifestation). 1.7 the various factors that influence the client’s ability to use genetic information and services, for example, ethnicity, culture, related health beliefs, ability to pay, and health literacy. 1.8 the potential physical and/or psychosocial benefits, limitations, and risks of genetic information for individuals, family members, and communities. 1.9 the resources available to assist clients seeking genetic information or services, including the types of genetics professionals available and their diverse responsibilities. 1.10 the ethical, legal and social issues related to genetic testing and recording of genetic information (e.g., privacy, the potential for genetic discrimination in health insurance and employment). 1.11 one’s professional role in the referral to or provision of genetics services, and in follow‐up for those services.

2. SKILLS All health professionals should be able to: 2.1 gather genetic family history information, including at minimum a three‐ generation history. 2.2 identify and refer clients who might benefit from genetic services or from consultation with other professionals for management of issues related to a genetic diagnosis. 2.3 explain effectively the reasons for and benefits of genetic services. 2.4 use information technology to obtain credible, current information about genetics. 2.5 assure that the informed‐consent process for genetic testing includes appropriate information about the potential risks, benefits, and limitations of the test in question.

3. ATTITUDES All health professionals should: 3.1 appreciate the sensitivity of genetic information and the need for privacy and confidentiality. 3.2 seek coordination and collaboration with an interdisciplinary team of health professionals.

Case 1: Sporadic Case

Age 11 No one in the extended family had CAS Late walker Late talker Muscle weakness Mild learning disability Signs/symptoms of CAS • Difficulty with DDK • Increased errors with increased word/phrase complexity What does this child’s DNA • Vowel errors have that neither of his • Groping postures parents have? • Inconsistent speech production • Still working on intelligible speech at age 11

“Genetic Causes of CAS: Case-Based Introduction to DNA, Inheritance and Clinical Management,” Presented by: Beate Peter, PhD, CCC-SLP, September 29, 2015, Sponsored by: CASANA 7

What are chromosomes?

Cell in its membrane

www.http:/[email protected] 19

Nucleus

Cell membrane made transparent

[email protected] 20

http://www.fitorfake.com/archives/823 21

“Genetic Causes of CAS: Case-Based Introduction to DNA, Inheritance and Clinical Management,” Presented by: Beate Peter, PhD, CCC-SLP, September 29, 2015, Sponsored by: CASANA 8

http://dna‐and‐the‐cells.blogspot.com/2010/12/ribosome‐makes‐proteins‐of‐ cell.html 22

http://hazell11bio.blogspot.com/2013/02/cell‐organelles‐and‐their‐function.html

Chromosomes

http://www.genome.gov 24

“Genetic Causes of CAS: Case-Based Introduction to DNA, Inheritance and Clinical Management,” Presented by: Beate Peter, PhD, CCC-SLP, September 29, 2015, Sponsored by: CASANA 9

[email protected] 25

Chromosomes are long pieces of DNA, tightly coiled.

http://www.sciencephoto.com/media/312872 26 /enlarge

Karyotype Autosome Sex chromosome X, Y Diploid (= 2 copies of each autosome) Humans have 22 sets of autosomes, plus • two X chromosomes in females • one X and one Y chromosome in males

27 http://www.genome.gov

“Genetic Causes of CAS: Case-Based Introduction to DNA, Inheritance and Clinical Management,” Presented by: Beate Peter, PhD, CCC-SLP, September 29, 2015, Sponsored by: CASANA 10

If you stretched out the chromosomes in a single cell, the total length would be 2 meters (5 to 6 feet). With 50 trillion DNA‐ containing cells in one human, the DNA would stretch to the moon and back 109,000 times

http://publications.nigms.nih.gov/genetics/science.html

“Genetic Causes of CAS: Case-Based Introduction to DNA, Inheritance and Clinical Management,” Presented by: Beate Peter, PhD, CCC-SLP, September 29, 2015, Sponsored by: CASANA 11

Anatomy of a Chromosome

parm q arm

gene

Exons (~1.5% of DNA) code for proteins. The rest are introns. nucleotides 32 amino acids

How many genes do we have?

• The haploid genome consists of about 3 X 10 9 bases – 3,000,000,000 (we are diploid, so multiply by 2) • 23 chromosomes – 22 autosomes (2 copies) – Sex chromosomes X, Y (XX for females, XY for males) • 20,000 to 30,000 genes – Two copies of each except for genes on X and Y

“Genetic Causes of CAS: Case-Based Introduction to DNA, Inheritance and Clinical Management,” Presented by: Beate Peter, PhD, CCC-SLP, September 29, 2015, Sponsored by: CASANA 12

From DNA to Proteins

34 stemcells.nih.gov/.../images/figurea6.jpg

From DNA to biomarkers to observable behaviors

Disruption (deletion, duplication, or mutation)

Hearing

Spoken words

Written words

SSD 35

When things go wrong

• Large scale – Level of chromosomes • Whole chromosomes: missing or extra copies • Pieces of chromosomes: deleted, duplicated, or translocated • Small scale – Level of DNA sequences in exons or regulatory elements (mutations) • Changes in nucleotide sequence • Short fragments repeated too many times

“Genetic Causes of CAS: Case-Based Introduction to DNA, Inheritance and Clinical Management,” Presented by: Beate Peter, PhD, CCC-SLP, September 29, 2015, Sponsored by: CASANA 13

Trisomy 21

Learn Genetics. Genetic Science Learning Center, The University of Utah

http://learn.genetics.utah.edu/content/disorders/whataregd /down/ 37

How do extra chromosomes happen?

When egg or sperm cells are formed from their precursor cells, normally pairs of chromosomes go their separate ways. When both of them go into the same egg or sperm cell, that cell will end up with three instead of two copies.

http://quizlet.com/15893327/gene‐expression‐in‐trisomy‐21‐flash‐cards/ 38

Deletion of a piece of chromosome Example: DiGeorge syndrome

http://trialx.com/curebyte/2011/08/19/deleti on‐22q11‐syndrome‐photos/ Jones, C.H., & Gawronski, M.J. (2002). The genetics of 22q11.2 deletion syndrome. Progress in Pediatric Cardiology, 15 (2), 99‐ 101 39

“Genetic Causes of CAS: Case-Based Introduction to DNA, Inheritance and Clinical Management,” Presented by: Beate Peter, PhD, CCC-SLP, September 29, 2015, Sponsored by: CASANA 14

Duplication of a piece of chromosome Example: autism)

Hogart, A., Wu, D., LaSalle, J.M., & Schanen, N.C. (2010). The comorbidity of autism with the genomic disorders of 15q11.2‐q13. Neurobiology of Disease, 18 (2), 181‐ 191. 40

How do deletions and duplications happen? When egg or sperm cells are formed from their precursor cells, each chromosome makes an exact copy of itself. When these four copies stick together, they exchange pieces and the breakpoints get “glued” back together. Sometimes they get attached incorrectly and a piece goes missing or is duplicated.

http://www.cs.cmu.edu/~genetics/units/instructions/instructions‐3FC.pdf 41

Chr (Partial) Monosomy Trisomy 1Trisomy 1 2Trisomy 2 3Trisomy 3 4Wolf‐Hirschhorn Trisomy 4 syndrome 5Cri du chat, 5q deletion Trisomy 5 syndrome 6Trisomy 6 7 Williams syndrome Trisomy 7 8Warkany syndrome 9Trisomy 9 10 Trisomy 10 11 Jacobsen syndrome Trisomy 11 12 Trisomy 12 13 Patau Missing an entire syndrome chromosome (1 through 22) is 14 Trisomy 14 15 Angelman syndrome, Trisomy 15 not compatible with life. Prader‐Willi syndrome 16 Trisomy 16 17 Miller‐Dieker Trisomy 17 syndrome, Smith‐ Magenis syndrome case where complete non‐mosaic trisomy can never survive to term 18 Edwards case where complete non‐mosaic trisomy can occasionally (barring other syndrome complications) survive to term 19 Trisomy 19 case where complete non‐mosaic trisomy can always (barring other 20 Trisomy 20 complications) survive to term 21 Down syndrome http://en.wikipedia.org/wiki/Aneuploidy 22 DiGeorge syndrome Cat eye 42 syndrome

“Genetic Causes of CAS: Case-Based Introduction to DNA, Inheritance and Clinical Management,” Presented by: Beate Peter, PhD, CCC-SLP, September 29, 2015, Sponsored by: CASANA 15

Back to Case 1

Peter, Matsushita, Oda, & Raskind (2014)

Suppresses fetal hemoglobin Regulates cell migration when production in newborns the brain’s cortical layers are built in embryos Pleiotropy One gene influencing two or more traits that seem to be unrelated to each other 45

“Genetic Causes of CAS: Case-Based Introduction to DNA, Inheritance and Clinical Management,” Presented by: Beate Peter, PhD, CCC-SLP, September 29, 2015, Sponsored by: CASANA 16

So, is this what always causes CAS?

• No. We checked 10 families with CAS and didn’t find anyone missing BCL11A • Back to the drawing board. There must be something else causing CAS in other children.

Case 2: The KE Family with syndromic CAS

• “KE “ family in the UK • Nearly unintelligible speech • Orofacial dyspraxia • Expressive, receptive language deficits • Abnormalities in brain structures • Learning disabilities What does the DNA of the people with CAS have that the other’s don’t?

Vargha‐Khadem et al, 'Praxic and nonverbal cognitive deficits in a large family with a genetically transmitted speech and language disorder', Proc Nat Acad Sci 47 USA 92, 930 – 933 (1995)

Genetics in multigenerational families

“Genetic Causes of CAS: Case-Based Introduction to DNA, Inheritance and Clinical Management,” Presented by: Beate Peter, PhD, CCC-SLP, September 29, 2015, Sponsored by: CASANA 17

Video clip “5 Things About Me” Member of the KE family talking about his family’s genetic disorder

Liegeois et al. (2011) 50

When things go wrong

“Genetic Causes of CAS: Case-Based Introduction to DNA, Inheritance and Clinical Management,” Presented by: Beate Peter, PhD, CCC-SLP, September 29, 2015, Sponsored by: CASANA 18

Codons are three‐letter groups of DNA that get translated into an amino acid. The amino acids get strung together into proteins. Example: letters form words, which form sentences. THE CAT WAS BIG. • Silent mutation – One nucleotide got swapped but the codon makes the same amino acid as the original one • THE CAT WAS BiG. (UUU ‐> UUC) • Nonsense mutation – One nucleotide got swapped. Now the codon gives the order to “stop” translating the RNA into amino acids • Duchenne muscular dystrophy • Cystic fibrosis • THE CAT. (UAU ‐> UAA) • Missense mutation – One nucleotide got swapped. The codon now makes a different amino acid • Sickle‐cell disease • THE CAT WAS BIT. (UUU ‐> UUA) 52

Frameshift Mutations

– Insertion or deletion – Changes the grouping of three nucleotides (codons) • Analogy: Each 3‐letter word represents a codon that gets translated into an amino acid – THE CAT WAS BIG (correct) – TXH ECA TWA SBI (insertion) – TEC ATW ASB (deletion) – Drastically different protein – Can cause severe diseases, e.g., Tay‐Sachs or Cystic Fibrosis

Small scale: Point mutations

http://en.wikipedia.org/wiki/File:Point_mutations‐en.png 54

“Genetic Causes of CAS: Case-Based Introduction to DNA, Inheritance and Clinical Management,” Presented by: Beate Peter, PhD, CCC-SLP, September 29, 2015, Sponsored by: CASANA 19

Small scale: Repeat expansions Example: Fragile X

Typical individuals have 29 or 30 repeats of the CGG “letters” within the FMR1 gene. Fragile X: over 200 repeats.

http://www.cbs.dtu.dk 55

THE FOXP2 STORY c’d

• Next step: Cytogenetics • Karyotype was normal.

[email protected]

THE FOXP2 STORY c’d • Linkage analysis: • What is the likelihood of getting this pattern of inheritance and and this piece of DNA in the family assuming that this piece of DNA is inherited along with the disorder, compared to assuming that this piece of DNA is not inherited along with the disorder? • Genome‐wide search: q arm of chromosome 7

Fisher, S. E., Vargha‐Khadem, F., Watkins, K. E., Monaco, A. P. & Pembrey, M. E. (1998) Localisation of a gene implicated in a severe speech and language disorder. Nat Genet 18, 168‐170. 57

“Genetic Causes of CAS: Case-Based Introduction to DNA, Inheritance and Clinical Management,” Presented by: Beate Peter, PhD, CCC-SLP, September 29, 2015, Sponsored by: CASANA 20

THE FOXP2 STORY c’d • Fine mapping (zooming in to the candidate region): SPCH1, later named FOXP2

Fisher, S. E., Vargha‐Khadem, F. , Watkins, K.E., Monaco, A.P. & Pembrey, M.E. (1998). Localisation of gene implicated in a severe speech and language disorder. Nat Genet 18, 58 168‐170.

THE FOXP2 STORY c’d

Point mutation: G‐> A, caused protein change from arginine to histidine

Lai, C. S., Fisher, S. E., Hurst, J. A., Vargha‐Khadem, F. & Monaco, A. P. (2001). A forkhead‐domain gene is mutated in a severe speech and language 59 disorder. Nature, 414(6855), 465‐466.

THE FOXP2 STORY c’d

“Genetic Causes of CAS: Case-Based Introduction to DNA, Inheritance and Clinical Management,” Presented by: Beate Peter, PhD, CCC-SLP, September 29, 2015, Sponsored by: CASANA 21

http://en.wikipedia.org/wiki/File:PBB_Protein_ FOXP2_image_2.png

The “Human Speech and Language Gene” A forkhead‐domain gene is mutated in a severe speech and language disorder p519 Cecilia S. L. Lai, Simon E. Fisher, Jane A. Hurst, Faraneh Vargha‐Khadem and Anthony P. Monaco (2001)

Molecular evolution of FOXP2, a gene involved in speech and language p869 Wolfgang Enard, Molly Przeworski, Simon E. Fisher, Cecilia S. L. Lai, Victor Wiebe, Takashi Kitano, Anthony P. Monaco and Svante Pääbo (2002)

THE FOXP2 STORY c’d

• Popular press: Found the human speech and language gene! • Turns out: – Most common forms of speech and language disorders are NOT caused by FOXP2 mutations or polymorphism. – FOXP2 is also expressed in • Neanderthals • Song birds (knockouts can’t learn the song from the tutor) • Mice (knockouts don’t squeak normally; human knockins have altered neuron structures in basal ganglia) – I have not found FOXP2 mutations in my data, either. • So, it’s back to the drawing board again …

“Genetic Causes of CAS: Case-Based Introduction to DNA, Inheritance and Clinical Management,” Presented by: Beate Peter, PhD, CCC-SLP, September 29, 2015, Sponsored by: CASANA 22

Some other forms of syndromic CAS

CAS in 7q duplication syndrome

• Duplication of the same region that is deleted in Williams syndrome • 25 genes in this region

Somerville, M., et al. (2005). Severe Expressive‐ Language Delay Related to Duplication of the Williams–Beuren Locus. New England Journal of Medicine, 20;353(16):1694‐701 65

Commonly observed: Compared to Williams syndrome: • Oral apraxia • Higher intellectual ability • Speech apraxia • Higher spatial ability • Phonological errors • Lower speech production ability

Velleman, S. L., & Mervis, C. B. (2011). Children with 7q11.23 Duplication syndrome: Speech, language, cognitive, and behavioral characteristics and their implications for intervention. Perspectives on Language Learning and Education, 18(3), 108‐116. 66

“Genetic Causes of CAS: Case-Based Introduction to DNA, Inheritance and Clinical Management,” Presented by: Beate Peter, PhD, CCC-SLP, September 29, 2015, Sponsored by: CASANA 23

CAS in 16p11.2 microdeletion syndrome • Previously described as mild cognitive impairment, autism spectrum disorder, various personality disorder types • More recently, speech and language impairments were also described • Three 2012 papers describe 1 (Newbury et al.) and 2 (Raca et al.) children with CAS and accompanying speech and language impairments who also have a 16p11.2 microdeletion

CAS in Rolandic epilepsy

• Candidate genes ELP4 and PAX6 http://upload.wikimedia.org/wikipedia/co on chr 11p13 (recessive) mmons/8/88/Central_sulcus_diagram.png • Autosomal dominant forms have also been suggested • Causal genes still unknown • Phenotype – Impaired language – Apraxic speech

– Reading deficits Addis, L., Lin, J.J., Pal, D.D., Hermann, B., & Caplan, R. (2012). Imaging and genetics of language and cognition in pediatric epilepsy. Epilepsy & Behavior, epub http://dx.doi.org/10.1016/j.yebeh.2012.09.014 68

CAS in galactosemia

• Caused by mutations in the GALT gene on chr 9p13 • Recessive = child inherits a mutation from both parents • Inability to digest galactose, one of two sugars in lactose • Even when diet is controlled from birth, many children with galactosemia have low IQ and delayed language • 18% of children with galactosemia have CAS (Shriberg et al., 2011)

“Genetic Causes of CAS: Case-Based Introduction to DNA, Inheritance and Clinical Management,” Presented by: Beate Peter, PhD, CCC-SLP, September 29, 2015, Sponsored by: CASANA 24

So many different ways to get CAS!

• Heterogeneity: a trait that has many different genetic causes in different people • Do these genes explain CAS in most cases? – No. There must be something else out there. – Back to the drawing board again!

Case 3: Multigenerational family with nonsyndromic CAS

Word Girl Age 3;5 Girl Age 3;10 (GFTA2 RS=42 GFTA2 RS=53 SS=77, %ile=13) SS=59, %ile=3) wagon [ˈwæɡən] [ˈwænə]

shovel [ˈjafʃɔ][θɛo]

cup [dʌp] [dʌp]

spoon [bus] [bu]

car [dao] [doɪ]

zipper [ˈwɛbzɪˌbæg] [ˈðɪpɔ] [bzɪˈbæɡ] fishing [ˈwɪʃin] [ˈfɛʔə]

swimming [ˈwɪpsin] [ˈwɪmɪn]

slide [laɪs] [θaɪ]

“Genetic Causes of CAS: Case-Based Introduction to DNA, Inheritance and Clinical Management,” Presented by: Beate Peter, PhD, CCC-SLP, September 29, 2015, Sponsored by: CASANA 25

pa/pata pa/pata pa/pata ratio .97 ratio .48 ratio .66

7 Intelligible 6 1;3 10 speech in K First words Never Intelligible 9 at 3 babbled speech in K No words First words 3;10 at 3 3;5 Unusual Unusual speech speech errors errors Sequencing Sequencing errors errors 73

Sound file: Girl 10 multisyllabic words

Sound file: Woman /pata/

Diadochokinetics Keyboard Tapping (Oral Motor) (Finger Motor)

papapa … Repetitive tatata … kakaka …

pata … Alternating taka … pataka …

Peter & Raskind (2011) Peter, Matsushita, & Raskind (2012) 75

“Genetic Causes of CAS: Case-Based Introduction to DNA, Inheritance and Clinical Management,” Presented by: Beate Peter, PhD, CCC-SLP, September 29, 2015, Sponsored by: CASANA 26

10 adults from Family Note: U = unaffected, A = affected. Error bars indicate ±1 SD. Peter, Button, Chapman, Stoel‐Gammon, & Raskind (2013)

“specific” “burloogajendaplo” “chinoitoub”

Sequencing errors during spelling test in affected family members

Omission Migration, insertion Metathesis

Woman, age 36, suspected history of severe CAS

Man, age 34, suspected history of severe CAS

Man, age 66, suspected history of severe CAS

Girl, age 10, history of severe CAS

“Genetic Causes of CAS: Case-Based Introduction to DNA, Inheritance and Clinical Management,” Presented by: Beate Peter, PhD, CCC-SLP, September 29, 2015, Sponsored by: CASANA 27

Summing up the phenotype in this family • Familial childhood apraxia of speech • Difficulty with processing information sequentially – Speech sounds – Alternating finger tapping – Reading nonwords (“sheel”/shlee) – Spelling

Could you just do therapy on sequential processing? • Like giving kids piano lessons or putting beads on a string? • Good question. We don’t know yet. • We need to do more research to find out whether this will help or not.

Penetrance, Expression

Nonpenetrance

Scrambles Leaves off the order of speech final sounds in consonants in words words 81

“Genetic Causes of CAS: Case-Based Introduction to DNA, Inheritance and Clinical Management,” Presented by: Beate Peter, PhD, CCC-SLP, September 29, 2015, Sponsored by: CASANA 28

Single‐gene (Mendelian) inheritance

Linkage analysis

Peter et al. (under review)

Other cases of nonsyndromic CAS

• Not much is known about causal genes • Laffin et al. (2012) examined the DNA of 24 children with CAS for deleted or duplicated regions – 1 had a FOXP2 mutation! – 12 had duplications or deletions – 16 regions in the genome – Causal genes may reside in some of these regions

“Genetic Causes of CAS: Case-Based Introduction to DNA, Inheritance and Clinical Management,” Presented by: Beate Peter, PhD, CCC-SLP, September 29, 2015, Sponsored by: CASANA 29

Why is it so hard to find causal genes in disorders of speech, language, and reading/spelling?

• Different genes may cause the disorder in different families (“heterogeneity”). • Someone may carry the genetic risk variant but not express the disorder (“reduced penetrance”) • Several or many genes may work together to produce the disorder (complex disorder), whereas most cases of hearing impairment are caused by single genes • A case in a family may be a phenocopy • Many genetic diseases can be studied in animals (animal model) but that is difficult to do in speech disorders

What about genetic testing?

• There are no mail‐order or clinical tests that you can use for speech disorders –not enough is known about genetic causes • You can contact a geneticist and request a scan looking for deletions and duplications • You can contact a researcher to see if your family can be included in a research project

What about gene therapy?

• Gene therapy can involve: – Silencing a defective gene – Fixing not the gene but just the RNA transcript – “Importing” a good copy of the gene into cells – Gene editing: inserting, removing, or replacing pieces of DNA into the chromosome • Can only do gene therapy if you know exactly which gene is not functioning correctly • Gene therapy is not yet available widely • In the future, gene editing may become widely available

“Genetic Causes of CAS: Case-Based Introduction to DNA, Inheritance and Clinical Management,” Presented by: Beate Peter, PhD, CCC-SLP, September 29, 2015, Sponsored by: CASANA 30

The interprofessional team

• The family! • Pediatrician • Developmental pediatrician • Nutritionist (infant feeding issues) • Neurologist (MRI scan) • Geneticist • Genetic counselor • Teacher, school district • Speech‐language pathologist • OT/PT • Social worker • Researcher • …

What is a genetic counselor?

• Master’s degree • “Genetic counselors use their specialized education in both medial genetics and counseling to help you understand complex genetic information. Genetic counselors can also work with your physician and you to make informed decisions.” Is there anything I Can you help me can do to protect share my genetic or improve my information with health? my relatives, or Can you help me I have a condition with my doctors? figure out what and want to learn genetic tests I whether I could should do –or pass it to my whether to be children. tested or not! 89

What parents and clinicians should know

• Once causal genes become known, infants can be tested for risk carrier status • Meanwhile, parents and clinicians can – Watch for early signs of CAS – Initiate a referral to a genetic counselor – Be savvy about personal genomics testing – Learn about insurability and employment nondiscrimination when risk genotypes become available – Know about available resources

“Genetic Causes of CAS: Case-Based Introduction to DNA, Inheritance and Clinical Management,” Presented by: Beate Peter, PhD, CCC-SLP, September 29, 2015, Sponsored by: CASANA 31

Genetic Information Nondiscrimination Act

Watch out for early signs of CAS

• Typical development and signs of CAS are contrasted in a 2007 technical by ASHA http://www.asha.org/policy/TR2007‐00278/

Some early signs of CAS. Note: Not all signs are observed in all cases! Age (m) Typical Infants Children at Risk for CAS 0 –2 Sucking and swallowing normal Difficulty feeding, may need feeding tube 2 ‐ 4 Cooing Little to no cooing 6 –8 Babble with repetitive consonants (“bababa”) Very little babbling 8 –12 Babble with a mixture of consonants Little babbling, consonants don’t vary (“agebabega”) 12 –18 Less babbling, first words at 12 m, ~50 words First words appear much later; few words at 18 at 18 m m 18 –24 Many new words; 2‐ and 3‐word Lots of consonants are omitted or replaced by combinations; words may be simplifications of the “h” sound. Speech is very difficult to the adult form, e.g., missing final consonants, understand. Unusual speech patterns such as repeating syllables (“wawa” for “water”). By omitting word‐initial consonants or speech 24 m, 50% of speech is understood by sounds in incorrect order. unfamiliar listeners. 24 –36 Vowel accuracy increases to near perfect. Vowel errors. Shorter sentences. Speech is very Simple sentences. 75% of speech is difficult to understand. understood clearly. 36 ‐ 48 More complex sentences. 100% of speech is Shorter sentences. Speech is still difficult to understood, even if some sounds are still understand. inaccurate.

“Genetic Causes of CAS: Case-Based Introduction to DNA, Inheritance and Clinical Management,” Presented by: Beate Peter, PhD, CCC-SLP, September 29, 2015, Sponsored by: CASANA 32

Future Directions for CAS

Long ways to go …

To‐do list:

• Create a list of causal genes • Observe how CAS is expressed in different families with different causal genes • Do clinical trials of different early intervention or even prevention approaches • Compare the efficacy of traditional interventions to that of early intervention and prevention approaches • If prevention is more effective than interventions after onset of symptoms: change eligibility criteria

Resources

• Learn Genetics – http://learn.genetics.utah.edu/ • GeneEd – http://geneed.nlm.nih.gov • Online Mendelian Inheritance in Man – http://www.ncbi.nlm.nih.gov/omim • GeneReviews – http://www.ncbi.nlm.nih.gov/sites/GeneTests/review • GeneTests – http://www.ncbi.nlm.nih.gov/sites/GeneTests/ • National Society of Genetic Counselors – www.nsgc.org • National Coalition for Health Professional Education in Genetics – http://www.nchpeg.org/index.php

“Genetic Causes of CAS: Case-Based Introduction to DNA, Inheritance and Clinical Management,” Presented by: Beate Peter, PhD, CCC-SLP, September 29, 2015, Sponsored by: CASANA 33

“Genetic Causes of CAS: Case-Based Introduction to DNA, Inheritance and Clinical Management,” Presented by: Beate Peter, PhD, CCC-SLP, September 29, 2015, Sponsored by: CASANA