DISORDERS ANSWERS IN OUR DNA? DR CANDICE FEBEN MEDICAL GENETICIST - - PowerPoint PPT Presentation

AUTISM SPECTRUM DISORDERS – ANSWERS IN OUR DNA?

DR CANDICE FEBEN MEDICAL GENETICIST NATIONAL HEALTH LABORATORY SERVICE AND THE UNIVERSITY OF THE WITWATERSRAND

D S M V

• A. Persistent deficits in social communication and social interaction across multiple

contexts

• B. Restricted, repetitive patterns of behaviour, interests, or activities
• C. Symptoms present in the early developmental period (but may not become fully

manifest until social demands exceed limited capacities, or may be masked by learned strategies in later life)

• D. Symptoms cause clinically significant impairment in social, occupational, or other

important areas of current function

• E. Disturbances are not better explained by intellectual disability (intellectual

developmental disorder) or global developmental delay

WHAT is it? WHAT CAUSED it? WHAT does it MEAN? WILL it happen AGAIN? CAN it be PREVENTED?

WHAT DO FAMILIES WANT TO KNOW?

ESSENTIAL AUTISM OR SYNDROMIC RISKS TO SIBLINGS AND OFFSPRING

GENETIC ARCHITECTURE

“A gene is a distinct sequence of nucleotides

forming part of a chromosome, the order of which determines the order of monomers in a polypeptide or nucleic acid molecule which a cell may synthesize”

A C T G

Approximately 22000 genes coding for various proteins in the body – structural, regulatory, developmental functions in various cells

REFERENCE SEQUENCE POLYMORPHISM ALTERED PROTEIN STRUCTURE OR FUNCTION SINGLE NUCLEOTIDE VARIATION (SNV)

COPY NUMBER VARIATION (CNV)

ESSENTIAL AUTISM (SIMPLEX)

• Accounts for 75% of ASD diagnoses
• Implies that there are no associated congenital anomalies,

microcephaly or significant dysmorphism – child needs a comprehensive examination

• Can be associated with intellectual disability (in 31% of

cases) and epilepsy (20-37%)

• 20% of cases have a positive family history of an ASD –

variable severity/ misdiagnoses

• Complex multifactorial aetiology – strong genetic component

– not often a single genetic cause – susceptibility genes

• Sibling recurrence risk 6-19%
• Baseline genetic testing IS INDICATED as results may change

the diagnosis to syndromic/complex autism and may change the recurrence risk information/ surveillance

Combination of SNV’s and CNV’s, both inherited and de novo, in an affected individual – enriched in ASD genes OLIGENIC/POLYGENIC MODEL

COMPLEX / SYNDROMIC AUTISM

• Accounts for 25% of autism diagnoses
• ASD associated with physical/functional congenital

anomaly or dysmorphic features

• Possible to identify a primary genetic aetiology for the

condition - comprehensive medical genetics assessment and genetic testing is indicated.

• Sibling and offspring recurrence risk is dependent on the

cause – if a specific genetic aetiology is not identified, risk may be as high as 20%

CHROMOSOME DISORDERS AND ASD

• Chromosome copy number variation (CNV) – chromosome

deletions or duplications

• Clinically relevant CNV’s are diagnosed in ≈14% of

patients with ASD

• CNV’ s can be inherited or can occur de novo in the

affected child

• Most are sporadic and non-recurrent
• A number of recurrent CNV’s have been identified -

particularly involving chromosomes 1, 15, 16, 17 and 22

• Testing is by array-CGH after a comprehensive clinical

evaluation; parental testing should be considered if a CNV is diagnosed in the child

“Segment” of chromosome – contains a number of genes – some may be specifically implicated in the autism phenotype, others are responsible for the other phenotypic features of the condition 1q21.1 deletion:

• Moderate intellectual

disability

• Congenital cardiac

abnormality

• Microcephaly
• Cataracts

CONCEPT OF DOSAGE

CHROMOSOME MICRO-ARRAY TESTING

Recommended first-line investigation in all patients with ASD, unless a single gene disorder is clinically suspected

MONOGENIC SYNDROMES ASSOCIATED WITH ASD

FRAGILE X SYNDROME

• Most common form of mental retardation
• 1/6000 males; also affects females
• 4-8% of males with IQ <70
• All ethnic groups
• Inheritance pattern:
• Atypical X linked – deviates from classic

XL recessive in that males and females can be affected as well as carriers

• Triplet repeat (CGG) in FMR-1 gene on X chr
• Variable developmental delay (moderate ID: 35 – 50)
• Language delay
• Poor or no speech
• Bursts of repetitive speech
• Behaviour
• Hyperactivity
• Poor eye contact
• Physical features
• Large ears, long face, normal OFC/relative macrocephaly, prominent mandible
• Post-pubertal macro-orchidism
• Can have: ligamentous laxity, mitral valve prolapse, hypotonia, epilepsy,

hypertension, GORD, strabismus, recurrent otitis media

• Diagnosed in up to 3% of children with ASD

RETT SYNDROME – DIAGNOSED IN 1% OF FEMALE ASD PATIENTS

Required for typical or classic RTT A period of regression followed by recovery or stabilization All main criteria and all exclusion criteria Supportive criteria are not required, although often present in typical RTT Main Criteria Partial or complete loss of acquired purposeful hand skills. Partial or complete loss of acquired spoken language Gait abnormalities: Impaired (dyspraxic) or absence

• f ability.

Stereotypic hand movements such as hand wringing/squeezing, clapping/tapping, mouthing and washing/rubbing automatisms Exclusion Criteria for typical RTT Brain injury secondary to trauma (peri- or post- natally), neurometabolic disease, or severe infection that causes neurological problems Grossly abnormal psychomotor development in first 6 months of life# Required for atypical or variant RTT

• A period of regression followed

by recovery or stabilization

• At least 2 out of the 4 main

criteria

• 5 out of 11 supportive criteria

Supportive Criteria for atypical RTT

• Breathing disturbances when awake
• Bruxism when awake
• Impaired sleep pattern
• Abnormal muscle tone
• Peripheral vasomotor disturbances
• Scoliosis/kyphosis
• Growth retardation
• Small cold hands and feet
• Inappropriate laughing/screaming

spells

• Diminished response to pain
• Intense eye communication - “eye

pointing” RTT Diagnostic Criteria 2010 Consider diagnosis when postnatal deceleration of head growth observed.

MAJOR FEATURES

• Angiofibromas (≥3) or fibrous cephalic plaque
• Cardiac rhabdomyoma
• Cortical dysplasias, including tubers and cerebral white

matter migration lines

• Hypomelanotic macules (≥3; ≥5 mm in diameter)
• Lymphangioleiomyomatosis (LAM)
• Multiple retinal nodular hamartomas
• Renal angiomyolipoma
• Shagreen patch
• Subependymal giant cell astrocytoma (SEGA)
• Subependymal nodules (SENs)
• Ungual fibromas (≥2)

MINOR FEATURES

• “Confetti“ skin lesions (numerous 1- to 3-

mm hypopigmented macules scattered

• ver regions of the body such as the arms

and legs)

• Dental enamel pits (>3)
• Intraoral fibromas (≥2)
• Multiple renal cysts
• Non-renal hamartomas
• Retinal achromic patch

TUBEROUS SCLEROSIS

• Multi-systemic disease, caused by mutations in the TSC1 and TSC2 genes
• Autosomal dominant inheritance
• Variable clinical phenotype
• Diagnosed in 1% of patients with ASD

Angiofibromas

Forehead fibrous plaque Shagreen patch Hypopigmented macule Skin manifestations of TS

MRI scan (T2 flair) showing multiple cortical tubers CT scan showing calcified subependymal nodules.

• Most diagnostic cerebral lesion
• Seen in ~ 80% of cases
• May grow and develop in

subependymal giant cell astrocytomas (SEGAs) CNS manifestations of TS

AUTOSOMAL DOMINANT PEDIGREE

• Affected members in each

generation, variable presentation

• Males and female affected
• Transmission from male to male/

female to female/ male to female and female to male

• Affected individual has 50% risk
• f transmitting condition to
• ffspring

ASD diagnosis

• Confirmation of ASD diagnosis based on DSMV criteria;

assessment for co-occurring ID

• Neurodevelopmental paediatrician / occupational

therapist

Type of ASD

• Referral to Medical Geneticist/ neurodevelopmental paediatrician

– clinical examination/assessment

• Baseline array-CGH in all essential/simplex cases
• Consideration of Fragile X testing and Rett testing if ID present
• Genetic counselling recommended based on the polygenic risk

model

Genetic testing

• Consideration of additional genetic testing in syndromic cases –

may include PTEN, FMR1, Rett and Rett-like testing, WES, WGS

• Genetic Counselling
• Information on the condition – prognosis, associated features,

care

• Risk of recurrence in siblings; parental testing
• Prenatal diagnosis

PRENATAL TESTING AND PRE- IMPLANTATION GENETIC DIAGNOSIS

AVAILABILITY OF GENETIC TESTING & SERVICES IN SA

STATE-FUNDED SERVICES & TESTING

• Genetic Clinics at Charlotte Maxeke Johannesburg Academic

Hospital, Chris Hani Baragwanath Hospital & Rahima Moosa Mother & Child Hospital in Johannesburg

• Genetic Clinics also run at Groote Schuur Hospital, Tygerburg

Hospital, Universitas Hospital, Albert Luthuli Hospital, Steve Biko Pretoria Academic Hospital – service very limited outside

• f tertiary academic hospitals
• NHLS offers
• Array-CGH***
• Fragile X
• MECP2
• TSC1, TSC2 and PTEN ****

Privately funded services and testing

• Private Genetic Clinics available at Wits Donald Gordon

Medical Centre and Ampath Centurion in Gauteng; private Genetic Counselling Services offered by Pathcare and GC Network

• NHLS tests are available to privately funded patients
• Ampath Genetics – offers array-CGH, single gene testing and

can aid with referral of samples to overseas laboratories

• Network of international laboratories – tests can be requested

by the treating genetic professional Research testing

• DDD-Africa

References:

• 1. Wisniowieck-Kowalnik B & Nowakowska BA. 2019. Genetics and

epigenetics of autism spectrum disorder – current evidence in the field. Journal of Applied Genetics 60: 37-47

• 2. Velinov M. 2019. Genomic Copy Number Variations in the Autism Clinic –

Work in Progress. Frontiers in Cellular Neuroscience 13:57

• 3. Bourgeron T. 2016. Current knowledge on the genetics of autism and

propositions for future research. Comptes Rendus Biologies.

• 4. Alonso-Gonzalez A et al. (2018).De novo Mutations (DNM’s) in Autism

Spectrum Disorders (ASD’s): Pathway and Network analysis. Frontiers in Genetics 9:406

• 5. Turner T, et al. 2017. Genomic patterns of de novo mutations in simplex
• autism. Cell 171(3): 710-722