Cerebral Malformation gene panel Dr John Livingston Consultant Paediatric Neurologist Leeds Teaching Hospitals NHS Trust on behalf of Yorkshire Regional Genetics Service Leeds UK
Cerebral Malformation gene panel PAFAH1B1, DCX, ARX, GPR56, TUBA1A, TUBB2B, TUBA8, NDE1
Cerebral Malformation gene panel Benefits of testing Background to cerebral malformations Which genes Who to test How results will be reported Challenges The future
Rare diseases EU definition of Rare Disease: a disease that affects less than 5/10,000 population Very Rare Disease < 1/100,00 5,000-8,000 rare diseases identified 6-8 % of population will experience a rare disease in their lifetime See: ENRAH, EURORDIS, neuroped, Rare disease UK, etc
Importance of making a diagnosis 1. Prognosis and relevant counselling 2. Enable appropriate life-planning 3. Adjustment to diagnosis 4. Early involvement of relevant support services 5. Avoidance of unnecessary investigations 6. Considerable cost savings 7. Appropriate genetic counselling Antenatal diagnosis Reproductive choice Counselling of wider family 8. Participation in relevant research studies 9. Able to benefit rapidly if new treatments become available
Classification of Cortical Malformations Abnormal neuronal or glial proliferation or apoptosis Abnormal neuronal migration Abnormal cortical organization NEUROLOGY 2005;65:1873 1887 Malformations not otherwise classified
Abnormal neuronal or glial proliferation or apoptosis Abnormal neuronal migration Abnormal postmigrational development including postmigrational microcephaly
Cerebral Malformation gene panel PAFAH1B1, DCX, ARX, GPR56, TUBA1A, TUBB2B, TUBA8, NDE1
LIS1 or PAFAH1B1 platelet activating factor actyl hydrolase isoform 1B1 Gene location - 17p 13.3 Miller-Dieker (MDS) (1963) Dysmorphic syndrome associated with lissencephaly due to large deletions in this region Lis 1 gene identified in 1993 (Renier et al )
Lis - 1
DCX
Barkovich AJ, Jackson DE Jr, Boyer RS. Band heterotopias: a newly recognised neuronal migration anomaly. Radiology 1989;17:455-8
DCX doublecortin DCX is on X chromosome Mutations in DCX can cause X-linked lissencephaly in males Mild lissencephaly or SBH in females X-linked mental retardation in females NB. Lis 1 mutations can cause Posterior SBH
ARX Aristaless related homeobox gene X - Linked lissencephaly X- linked lissencephaly with ambiguous genitalia (XLAG) X - linked Ohtahara syndrome X - linked infantile spasms X- linked mental retardation others
GPR56 G protein-coupled receptor 56 Hypotonia and motor delay Normal CK Walking but ataxic Pyramidal signs Mostly normal head size Severe cognitive delay Eye movement abnormalities Epilepsy
Tubulins Extensive gene family encoding components of microtubules Microtubules play an important role in neuronal migration TUBA1A TUB2B TUBA8A?TUBB3
TUBA1A Delayed development Static microcephaly Epilepsy Squint Spastic cerebral palsy of varying severity Moderate to severe cognitive problems TUB2B Motor impairment Moderate to severe cognitive delay Epilepsy
TUBA8A Severe phenotype Profound motor and cognitive delay Epilepsy Optic hypoplasia
NDE1 Extreme prenatal microcephaly Severe cognitive impairment Severe motor difficulties Death by age 5
Who to test? Testing follows MR findings Generalised cortical malformation Bilateral (but not necessarily symmetrical) cortical malformation Lissencephaly PMG Other Sub-cortical band heterotopia Lissencephaly with cerebellar hypoplasia Abnormal BG with absence/dysgenesis of anterior limb IC? microlissencephaly
Cost of test 530.00
Challenges ARX Significance of identified changes
Future developments New genes can be added to the panel However The gene panel is an interim step before whole exome sequencing becomes routine