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 DO FAMILIES WANT TO KNOW? WHAT is it? ESSENTIAL AUTISM WHAT CAUSED it? OR SYNDROMIC WHAT does it MEAN? RISKS TO SIBLINGS WILL it happen AGAIN? AND OFFSPRING CAN it be PREVENTED?

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” Approximately 22000 A genes coding for various proteins in C the body – structural, regulatory, T developmental functions in various G cells

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

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

1q21.1 deletion: • Moderate intellectual disability • Congenital cardiac abnormality • Microcephaly • Cataracts “Segment” of chromosome – contains a number of genes – some may be CONCEPT OF DOSAGE specifically implicated in the autism phenotype, others are responsible for the other phenotypic features of the condition

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 RTT Diagnostic Criteria 2010 Consider diagnosis when postnatal deceleration of head growth observed. Required for typical or classic RTT Required for atypical or variant RTT A period of regression followed by recovery or  A period of regression followed stabilization by recovery or stabilization All main criteria and all exclusion criteria  At least 2 out of the 4 main criteria Supportive criteria are not required, although often present in typical RTT  5 out of 11 supportive criteria Main Criteria Supportive Criteria for atypical RTT Partial or complete loss of acquired purposeful hand  Breathing disturbances when awake skills.  Bruxism when awake Partial or complete loss of acquired spoken language  Impaired sleep pattern Gait abnormalities: Impaired (dyspraxic) or absence  Abnormal muscle tone of ability.  Peripheral vasomotor disturbances Stereotypic hand movements such as hand  Scoliosis/kyphosis wringing/squeezing, clapping/tapping, mouthing and  Growth retardation washing/rubbing automatisms  Small cold hands and feet Exclusion Criteria for typical RTT  Inappropriate laughing/screaming Brain injury secondary to trauma (peri- or post- spells natally), neurometabolic disease, or severe infection  Diminished response to pain that causes neurological problems  Intense eye communication - “eye Grossly abnormal psychomotor development in first 6 pointing” months of life #

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 MAJOR FEATURES MINOR FEATURES • Angiofibromas (≥3) or fibrous cephalic plaque • “Confetti“ skin lesions (numerous 1 - to 3- • Cardiac rhabdomyoma mm hypopigmented macules scattered over regions of the body such as the arms • Cortical dysplasias, including tubers and cerebral white and legs) matter migration lines • Hypomelanotic macules (≥3; ≥5 mm in diameter ) • Dental enamel pits (>3) • Lymphangioleiomyomatosis (LAM) • Intraoral fibromas (≥2 ) • Multiple retinal nodular hamartomas • Renal angiomyolipoma • Multiple renal cysts • Shagreen patch • Non-renal hamartomas • Subependymal giant cell astrocytoma (SEGA) • • Retinal achromic patch Subependymal nodules (SENs) • Ungual fibromas (≥2)

Angiofibromas Skin manifestations of TS Hypopigmented macule Forehead fibrous plaque Shagreen patch

CNS manifestations of TS CT scan showing calcified MRI scan (T2 flair) subependymal nodules. showing multiple • Most diagnostic cerebral lesion cortical tubers • Seen in ~ 80% of cases • May grow and develop in subependymal giant cell astrocytomas (SEGAs)

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 of transmitting condition to offspring

• Confirmation of ASD diagnosis based on DSMV criteria; assessment for co-occurring ID • Neurodevelopmental paediatrician / occupational ASD therapist diagnosis • 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 Type of • Genetic counselling recommended based on the polygenic risk ASD model • 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, Genetic care • Risk of recurrence in siblings; parental testing 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 of tertiary academic hospitals • NHLS offers • Array-CGH*** • Fragile X • MECP2 • TSC1, TSC2 and PTEN ****