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3/22/2018

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GENETICS OF COMMUNICATION DISORDERS

Speech‐Language Impairments


Disclaimer

• I am not an SLP

• You guys are as messed up as we geneticists

• This is the framework I could sort of make sense of things

• I recognize yours may be different


Communication Disorders

• Language disorders

• Speech‐Sound disorders

• Dysfluencies

• Social Pragmatic / Autism

• Motor‐Speech‐Voice

• Secondary


1. Language Disorders


Language Disorders

• Vocabulary

• Syntax

• Grammar

• Semantics

• Morphology


FOXP2“The Speech Language Gene”

• This form of speech and language abnormality (SPCH1) is caused by heterozygous mutation in the FOXP2 gene on chromosome 7q31.

• Description– Speech‐language disorder‐1 is an autosomal dominant disorder characterized

by severe orofacial dyspraxia resulting in largely incomprehensible speech.

– Affected individuals were originally thought to have specific defects in the use of grammatical suffixation rules.

– The phenotype, however, is broader in nature, with virtually every aspect of grammar and language affected

– The disorder is characterized by abnormal development of several brain areas critical for both orofacial movements and sequential articulation, resulting in marked disruption of speech and expressive language

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FOXP1

• Cognitive Impairments

• Obesity

• SLI

‐ Oromotor difficulties‐ Open mouth‐ Lip protrusion‐ Tongue apraxia


2. Speech‐Sound Disorders(nee Phonologic Disorders)

Articulation disorders

Phonemic disorders

Mixed speech sound disorders

Residual errors


Significant difficulty learning to read and spell despiteadequate intelligence and opportunity, and without demonstrable neurological, sensory, or emotionalhandicap

Qualitative PhenotypePositive history of reading and spelling problemsP or V IQ > 90Reading Quotient < 0.80

Ratio of reading/spelling scores to expected abilitybased on age and intelligence

Quantitative PhenotypeDiscriminant score based on a function developedthrough the testing of 125 disabled readers and 125 normal readers on a battery of achievement tests

Dyslexia


Types of Dyslexia

• Surface : person can read words phonetically but has problems with whole word recognition (i.e. yacht ‐‐‐> yatchet).

• Phonological : person can read familiar words by using whole word method but has difficulty "sounding out" words that are new or letter‐to‐sound decoding problems.

• Spelling : person can read individual letters that lead to reading words if given enough time but has problems recognizing the word as a whole and phonetically (i.e. men ‐‐‐> h‐e‐n).

• Direct : person can read aloud without comprehension that is similar to speech comprehension aphasias like anomia.

Genetic map

Physical map

Candidate genes

linkage

association

mutation analysis

verify in independent population

identify new genesresearch known genes

Gene Identification: Positional Cloning Strategy

1p34-p36: Rabin et al., 1993 (lod < 3.0)6p21.3: Cardon et al., 1994; Grigorenko et al., 199615q: Smith et al., 1983, Fulker et al., 1991; Grigorenko et al., 1996

Possible Locations of Genes Influencing Reading Disability

1p

6p

15q

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What might dyslexia genes be doing?

• Affecting specific cell type

– magna (rapid transmitting) v parvo cells

• Affect myelin in some way


Dyslexia Genes

• DCDC2 gene

– Gene map locus 6p22.1

– encodes a protein containing 2 doublecortin peptide domains

– Doublecortin gene (DCX) – produces X‐linked lissencephaly


DCDC2

• A deletion in a putative regulatory sequence in DCDC2 is present in ~20% of persons with dyslexia.

• Over 20 variations (alleles) of this regulatory (enhancer) sequence have been identified

• Knockout mouse: Complete silencing of the gene

– Neuronal migration disorder ~ lissencephaly


DCDC2

• RNAi: slowing down the gene

Results in dyslexic mouse!


Articulation

• 1q21.1 duplications


3. Dysfluencies

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Dysfluency Genes

• Stuttering is a disorder of the flow of speech characterized by involuntary repetitions or prolongations of sounds or syllables, and by interruptions of speech known as blocks. Stuttering typically arises in young children, where it affects at least 15% of those in age range 4 to 6 years. Stuttering usually resolves spontaneously before adolescence, leading to a population prevalence of 1 to 2% among adults. Stuttering beyond childhood is characterized by a significant bias towards males, with males outnumbering females by a ratio of 3:1 to 5:1.


Other Dysfluency Loci(GWAS)

• 1q

• 2q

• 5q

• 7q

• 5q

• 7q

• 9p

• 13q

• 15p

• 16p

• 18p

• 21p


4. Social‐pragmatic


Genetics of Autism

• Undisputable genetic basis

• Complex inheritance

• Etiologic heterogeneity

• Genetic heterogeneity

• Likely environmental modifiers


Current Climate

• Increasing number of referrals

• New technologies

• Reported associations

• Linked loci

• Reimbursement issues

• Evidenced‐based medicine

• Cost‐benefit relationships


‘Multifactorial Inheritance’ of Autism

• Recurrence risk (sibs)– 7% if affected child is female

– 4% if affected child is male

– 33 – 50% after 2 affected

• Relative risk (recurrence)– Autism – 22.3

– Asperger – 13.4

• Sibling risk ratio (s)– 100 – 150

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Partial List of Genetic Syndromes with a Reported Association with Autism

NO WORK-UP INDICATED AUTISM EVALUATION INDICATED

Fragile X syndrome Apert syndrome

Rett syndrome Williams syndrome

Angelman syndrome De Lange syndrome

Prader-Willi syndrome, Noonan syndrome

Smith-Lemli-Opitz syndrome Down syndrome

Smith-Magenis syndrome Turner syndrome

Tuberous sclerosis Neurofibromatosis

CHARGE syndrome Myotonic dystrophy, Duchenne dystrophy

Shprintzen syndrome (22q11 deletions) Moebius anomalad

Sotos syndrome Cohen syndrome

PTEN associated disorders Oculo-auriculo-vertebral spectrum

Hypomelanosis of Ito Joubert syndrome

Lujan-Fryns syndrome


Projected Diagnostic Yield of an Extended Evaluation

• High‐resolution chromosome studies – Range (3‐5%)

• aCGH—beyond what would be detected by chromosomal analysis– Range (5‐20%)– Higher in complex autism (15–30%)

• Fragile X– Range 2 – 10%

• MECP2– (3‐13%—women only, total ~ 2‐6%)

• PTEN– (3 ‐ 6%—if head circumference >2.5 SDs)

• Other– Metabolic disorders, hearing loss, neuro‐

cutaneous syndromes, genetic syndromes, cerebral dysgenesis, teratogens

30-40%


5. Motor‐Speech‐Voice

Apraxias, dysphonias


Developmental Apraxia(Disorder of Motor‐ Speech)

• Syndromes

– 22q deletions

• Galactosemia

• Assorted CNVs

• Children with DAS often have family members who have a history of communication disorders or learning disabilities


6. Secondary

Cognition

Neurologic

Craniofacial malformations

Syndromes


* Cognitive Impairments

• Significant sub‐average intellectual behavior

IQ < 68 (Stanford – Binet)

IQ < 70 (Wechsler)

AND

• Deficits in adaptive behavior

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Polygenic Inheritance

• IQ displays all of the traits of polygenic inheritance– Distributed in a normative manner

– Close relationship to parental IQ’s

– Quantitative trait

– No sexual dimorphism

• By definition, 2.5% of the general population has an IQ in the MR range


‘Normal’ IQ = 100 + 15 (70 – 130)

Degree of CI IQ equivalent Z score (-SD)

Borderline 70 – 78 1.25

Mild 55 - 69 2

Moderate 40 – 54 3

Severe 25 – 39 4

Profound < 25 5

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Identifiable Causes of Cognitive Impairments

Chromosome abnormalities 25‐30%

Recognizable syndromes 3‐ 7%

Known single gene disorders 3‐ 9%

Structural CNS abnormalities 7‐17%

Prematurity complications 2‐10%

Environmental/teratogenic 5‐13%

“Cultural‐familial” 3‐12%

Metabolic/endocrine causes 1‐ 5%

UNKNOWN 30‐50%


Cerebral PalsyDefinitions (My favorite)

• A clinical set of static encephalopathies linked by their expression of variable disabilities of movement / posture

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Cerebral PalsyEpidemiology

• Uncommon , prevalence 2/1000 at time on entry into school

– 86/1000 in extreme prematurity

– 1.2/1000 in term infants

• Incidence stable

– Has not decreased in decades despite improvements in prenatal / perinatal care


Cerebral PalsyEtiology

• Premature infants

– Can identify etiology ~75%• 10% prenatal

• 60% perinatal / neonatal

• 30% not clear

• Term infants

– Can identify etiology ~80%• 50% prenatal

• 35% perinatal / neonatal

• 15% not clear


Cerebral PalsyPossible causes

• Hypoxic – ischemic encephalopathy

• Genetic syndromes

• Chromosome anomalies

• MCA without unifying diagnosis

• Cerebral dysgenesis

• Teratogenic

• Metabolic disorders

• Coagulopathies

• Trauma

• Slowly progressive neuro‐motor disorders


Orofacial Clefts


Cleft Lip and Palate

• Second most common structural congenital anomaly

– 1 / 1000 live births

• Can occur as isolated malformation or in the context of multiple anomalies


Etiology

Cleft Lip / Palate

Without other anomalies50 - 55%

With other anomalies45 - 50%

“isolated”“non-syndromic”

Slightly more common with CP

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Communication Issues in Orofacial Clefts

• Palatal dysfunction

• Oromotor problems

• Feeding and swallowing difficulties

• Incidence of LD 3X increased

• Otitis media / hearing


(Pierre) Robin Sequence

• Sequence of events secondary to primary anomaly (mandibular hypoplasia)

• May occur alone or in the context of a syndrome

• Neonatal emergency if airway compromise


Distraction Osteogenesis


GENETIC SYNDROMES


Genetic Syndromes

• Hundreds of described genetic syndromes

• The majority have associated neuro‐developmental problems

• Most have speech and language disorders

– Described by geneticists and thus often poorly characterized by SLP standards


Common Syndromes for the SLP

• Chromosome abnormalities

– Down syndrome (47 +21)

– Turner syndrome (45 –X)

– 22q deletion spectrum (del 22q11)

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Common Syndromes for the SLP

• Fragile X syndrome

• Fetal alcohol syndrome

• Stickler syndrome

• Williams syndrome

• Prader –Willi syndrome

• Noonan syndrome

• Neurofibromatosis


Sotos Syndrome

An Example of the Complexity of Genetic Syndromes and

Communications


• Since the description of Sotos Syndrome in 1964, literally hundreds of cases have been identified

• New cases are not considered ‘reportable’

• Affects all racial and ethnic groups

• Estimated incidence 1:5,000 to 1:15,000


Original Description of Sotos SyndromeFive cases from Sotos et al 1964 with four key features

– Overgrowth

– Advanced bone age

– Developmental delay

– Characteristic facial appearance


Hypotonia

• Almost a universal feature in Sotos Syndrome

• Low muscle tone, not weakness

• Concept of fighting gravity

• AFO’s are oftentimes helpful in early stages of walking

• Treating hypotonia is not disease specific

– i.e. your child’s therapist doesn’t have to be familiar with Sotos Syndrome to help


Developmental Delay

• Some form of learning difference is present in 97% of individuals with NSD1 mutations

• In general developmental progress is linear

• Reported IQ range 20 – 120

• Poor coordination / fine motor control

• Early developmental ‘scores’ have little predictive value

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A unique feature of Sotos syndrome lies in the “natural history” of this condition. In contrast to most other conditions with neuromotor impairments, the early developmental delays seen in patients with Sotos syndrome are poorly correlated with long term outcomes.

e.g. things often get better


Socialization and Communication

• Autism

• Autistic behaviors

• PDD nos

• None of the above


Behavioral Changes

• Attention deficit (hyperactivity) disorder

• Phobias

• Obsessions / compulsions

• Impulsivity

• Tantrums

• Frustration behaviors

• Social naivety

• More confident with younger children and adults than peers


Speech and Language

• Expressive language impairments

– Reduced variety of words

– Shorter sentences

– Simplified grammar

• Sound production impairments

– Create their own linguistic ‘rules’


Speech and Language

• Voice differences

– Hoarseness, hypernasal, pitch changes

• Social – pragmatic differences

– Monotone speech

• Stuttering

– Later onset than typical (even into adolescence)

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Auditory Processing

• Results: Except for a small percentage of participants, otoscopy, tympanometry, and pure tone screening results were unremarkable and not unlike the general population. However, adult participants had large ear canal volumes similar to those reported in older adults in the general population. DPOAE screening was attempted with greater than expected referral rates, most likely due to cooperation issues and participant noise levels. SNR loss was generally higher (poorer) than published norms, and Dichotic Digit test results revealed a slight right ear advantage and an overall depression of scores in both ears compared to normative data.

• Conclusion: Results of the audiologic screenings indicated that the majority of individuals with Sotos syndrome do not appear to have hearing sensitivity issues co‐occurring with the syndrome. However, QuickSIN and Dichotic Digit test results indicate that those with Sotos syndrome may have speech perception in noise and callosal‐specific auditory transfer issues that together negatively impact complex listening (~ 40%).

[Submitted for publication]


CLINICAL RESOURCES

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GENETICS GETS PERSONAL


1. MY HERITAGE

Why pay money to have your family tree traced? Go into politics and your

opponent will do it for you.

‐Mark Twain


Family History• “The family history is the most important tool for diagnosis and risk assessment in medical genetics, and promises to serve as a critical element in the use of predictive genetic testing in primary care. Traditional medical education about family history has been unsophisticated, and use of family history in adult primary care has been limited, compounded by multiple substantive barriers.”

J GEN INTERN MED 2004;19:273-280.archildrens.org uams.eduarpediatrics.orgarchildrens.org uams.eduarpediatrics.org

FAMILY HISTORY

• A 3 generational pedigree should be obtained and periodically updated on all families in your practice

• This includes the patient, their siblings, parents, aunts, uncles, cousins, and grandparents

• If the patient is an adult it may also include the patients children and grandchildren

• Further generations should be included if the patient knows relevant health history for those more distant relatives


Positive Family History

• First degree relatives

– Monogenic conditions

• First / second degree relatives

– Complex disorder

• Diabetes, cancer

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“Red Flags” in a Family History

• Number of relatives affected

• Degree of relationship to proband

• Age of onset

• Least affected sex

• Related disorders


Example

• New patient, 55 yo Caucasian male

• Intake form checks “Yes” for a positive family history of:

– Diabetes

– Cancer

– Heart disease

Colon

Colon Colon Colon

Colon

Uterus Uterus Eyelid

33

51

27

gene (-)

gene (+) gene (+) gene (-)

I

II

III

Trait 1: Cancer

Affected Carrier

HNPCC ‐ Pedigree


2. TAILORING MY MEDICAL CARE

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P4 Medicine

• Lee Hood coined the term to capture the growing importance of the patient’s voice in medicine

– Personalized

– Predictive

– Preventative

– Participatory


Personalized Medicine

• The application of individual specific data to:

– better target the delivery of health care

– facilitate the discovery and clinical testing of new products

– help determine a person's predisposition to a particular disease or condition

• Personalized medicine develops not only the tools to help providers deliver the care that works best “on average,” but at the same time develop a new class of tools for identifying and employing the best care for each individual patient.


What’s in a name?

• Personalized medicine

– Most recognized by general public

• Precision medicine

– President Obama SOTUA, Jan 2015

• Individualized medicine


• Following in the tradition of President Kennedy's call to action of sending a man to the moon and returning him safely to earth, in January 2015, at a State of the Union address, President Obama announced the call to action of the Precision Medicine Initiative. This Initiative has the ultimate goal of moving the United States into the era where medical treatment will be tailored to each patient.


NSIGHT(Newborn Sequencing in Genomic Medicine and Public Health)

• 4 projects funded by NICHHD

– 26 hour genomes for the management of critically ill newborns

– Genomes in healthy newborns

• Newborn exome sequencing for universal screening (2)

• Not tied to NBS (1)

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SickKids Genome Clinic

Developing and evaluating a pediatric model for individualized genomic

medicine

Bowdin et al Clin Genet. 2015 Feb 25. doi: 10.1111/cge.12579. [Epub ahead of print]


SickKids Genome clinic

• ‘Genome Clinic’ research project

• A dearth of empiric data supporting the evidence‐based introduction of clinical WES / WGS into pediatric health care

• 5 year cohort study

– 100 patients per year being investigated for putative genetic disorders

• Interdisciplinary team

– Bioinformatics

– Health care economists

– Health services and policy researchers

– Ethicists

– Geneticists

– Genetic counselors

– Other clinicians


Is the time now?

• In the realm of Pediatric Genomic Medicine, few centers have made any reasonable transition from the bench to the bedside

• ACH has the right environment to be out in front of the nation in this arena


7 questions for Personalized Medicine

• How Should Institutional Conflicts of Interest Be Managed in Personalized Medicine?

• How Will Personalized Medicine Affect the Costs of Medical Care?

• Where Is the Public Health Benefit?

• Will Gene‐Based Drug Targeting and Development Fulfill it’s promise?

• Does the Human Genome Contribute to Disease Risk Prediction?

• What Will EMRs Contribute?

• What Kinds of Studies Should Be Mounted in Personalized Medicine?

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3. HOW I RELATE TO MY ENVIRONMENT

• Genetic Susceptibility

Breast Cancer Patients

Sporadic 65% Familial 35%

Familial 26%

Hereditary 9%


Breast Cancer Gene (BRCA1) ‐ 17q21

• 5% of all breast cancer

• 50% of familial breast cancer

• 80% of familial breast / ovarian cancer

• 65% of sporadic cases show loss of heterozygosity for 17q locus

• a tumor suppressor gene (?) functions specific in sex‐steroid responsive tissues


BRCA1

• Female carriers:

– 60 to 85% risk for breast cancer

– 20 ‐ 60% risk for ovarian cancer

• Male carriers:

– may have increased risk of prostrate cancer and male breast cancer


Cancer Susceptibility GenesClinical testing available

• BRCA1/BRCA2 (breast / ovarian cancer)

• APC (familial adenomatis polyposis)

• P53 (LiFraumeni syndrome)

• MLH1, MSH2, MSH6, PMS2 (hereditary non‐polypotic colorectal cancer)

• PTEN (Cowden disease)

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Polymorphisms and Susceptibility to Common Disorders

• Lung cancer and smoking– GSTM1 (glutathione transferase, class mu, 1) null phenotype and

susceptibility to lung cancer• Complex decision making, smoking cessation

– DRD• TB infections

– NRAMP1 (natural resistance‐associated macrophage protein 1) gene and susceptibility to tuberculosis

• HIV infections– Resistance with CCR5 mutations

• Alcohol and cirrhosis– Epoxide hydrolase

• Outcome in head trauma– ApoE polymorphisms – mimics Alzheimer risks


4. WHAT I LOOK LIKE

Dysmorphology


Malformation

• By definition occurs within first 11 weeks of pregnancy (exception = CNS)

• Major malformation : never normal, functional significance

• Minor malformation : sometimes normal, no functional significance

–Most people have 1 maybe 2 minor malformations


Major malformation

Minor Malformations


Minor Malformations

• Importance

– Clinically insignificant

– As clues to more serious problems

– Recognition of malformation syndromes

• Incidence

– 14% newborns have a single minor malformation (not including dermatoglyphic changes)

– 0.8% newborns have 2 or more

• As number goes up so does major malformation rate

– 3 or more – evaluation indicated

• May be a familial trait

– Normal variant

– Familial disorder

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Normal Variation


Familial Variation

Avoid terms like:“Funny Looking Kid”

Familial Benign Ugliness


What Do We Perceive As Beautiful?

• Symmetry

• Pattern / predictability

• Reflection of health

• Reflection of success

• Population average

• Similarity to self

• Experience (familiarity)

Birth defects violate all of these rules!


Perception of BeautySymmetry


Perception of Beauty

• Similarity to self


Facial Beauty

• Major attractive features:

– IC ~ PF

– Width nose : width mouth ~ 1:2

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Perception of Beauty

• Reflection of success


SuccessRalph Waldo Emerson

To laugh often and muchTo win the respect of intelligent people and the affection of children

To earn the appreciation of honest critics and endure the betrayal of false friends

To find the best in othersTo leave the world a bit better whether by a healthy child or a garden patch or a redeemed social condition

To know even one life has breathed easier because you have lived

This is to have succeeded

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