INTRODUCTION TO GENETIC COUNSELING€¦ · • Mendelian or chromosomal disorders: a gene or...
Transcript of INTRODUCTION TO GENETIC COUNSELING€¦ · • Mendelian or chromosomal disorders: a gene or...
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Your ERN logo here 3 August 2020
Co-founded by the EU1
INTRODUCTION TO GENETIC COUNSELINGfor epileptic disorders
Gaëtan LESCA,Lyon University Hospital, France
6th August 2020
EpiCARE ERN EDUCATIONAL WEBINARS
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Genetic counseling: definition
• Process by which the patients, or relatives at risk of an inherited disorder, are advised of:– the consequences and nature of the disorder– the probability of developing or transmitting it– the options open to them in management and
family planning• Accurate genetic counseling is based on the
identification of disease causing genetic or chromosomal variants
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Procreation options for families affected with Mendelian epilepsies
with severe outcome
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Prenatal diagnosis
11 weeks of amenorrhea
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Prenatal diagnosis
11 weeks of amenorrhea 15 weeks of amenorrhea
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Prenatal diagnosis
11 weeks of amenorrhea 15 weeks of amenorrhea
Requires definite genetic diagnosis in the index case and determination of parental status
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Prenatal diagnosis
10 weeks of gestation
Ø For X-linked disorders it is possible to perform fetal sex determination in maternal blood before PND
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Preimplantation genetic diagnosis
• In vitro fertilization• Genetic study in 1
blastocyst cell• Same conditions as
PND but only for inherited diseases
• Mother < 40 years of age
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Favorable situations for PND/PID
• Mendelian or chromosomal disorders: a gene or chromosomal variant is highly related to disease
• Best configuration:– High penetrance– Homogeneous expressivity– Good genotype phenotype correlations– X-linked recessive disorder (females not usually
affected)
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The two main categories of genetic factors
Strong influence of a major gene
Mendelian epilepsies--------
High amplitude effect, high risk of disease
Limited influence of a given gene
Multifactorial epilepsies--------
Risk factors, neither necessary nor sufficient
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“Idiopathic”/genetic generalized epilepsy
• Often familial occurrence• Higher risk to be have epilepsy for 1st degree
relatives of patients• But rarely consistent with a Mendelian mode
of inheritance• Usually multifactorial inheritance with several
genetic risk factors and environmental factors
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Genetic risk factors and GGE
• Female, 2 years: absence epilepsy with falls -> remission (valproate discontinued)
• 6 years: childhood absence epilepsy -> remission (stop discontinued)• 13 years: myoclonia at awakening, 2 GTCS• No cognitive impairment• No family history of epilepsy
15q13.3 microdeletion
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Variability of clinical expression of the 15q13.3 microdeletion
Intellectual disability, autism, GGE(0.3% cases, 0% controls)
Schizophrenia(0.2% cases,
0,01% controls)
GGE(1% cases,
<0,02% controls)
Odds ratio : 68 [29 – 181] Inherited in 80% of cases (half of them unaffected)
15q13.3
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High genetic heterogeneity of Mendelian epilepsies
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Autosomal recessive disorders
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• Multifocal seizures, day 1• Drug resistant (> 100
seizures/day)• EEG: migrating partial
seizures• 2 inherited variants in
SLC12A5• Encodes the K+/Cl-
transporter KCC2 • Functional studies may
help to understand the pathological consequences
Early-onset DEE with autosomal recessive inheritance
c.349T>A p.Phe117Ile
c.1258C>T p.Arg420Cys
c.349T>A p.Phe117Ile
c.1258C>T p.Arg420Cys
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X-linked disorders
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X-linked (recessive) epileptic disorders
• Christianson’s syndrome with ESES• Intragenic deletion of SLC9A6
?
?
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X-linked (recessive) epileptic disorders
• Boy with epilepsy and intellectual disability
• No family history• Normal brain MRI• No dysmorphic feature• p.(Ser918Thr) of CASK
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X-linked (recessive) epileptic disorders
• Boy with epilepsy and intellectual disability
• No family history• Normal brain MRI• No dysmorphic feature• p.(Ser918Thr) of CASK
Moog et al., Orphanet J Rare Dis 2015
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X-linked (recessive) epileptic disorders
• Boy with epilepsy and intellectual disability
• No family history• Normal brain MRI• No dysmorphic feature• p.(Ser918Thr) of CASK
Role in disease ?
Moog et al., Orphanet J Rare Dis 2015
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Segregation study for X-linked disorders
p.(Ser918Thr)
p.(Ser918Thr)/wt
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p.(Ser918Thr)
p.(Ser918Thr)/wt wt
wt
p.(Ser918Thr)/wt
Segregation study for X-linked disorders
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p.(Ser918Thr)
p.(Ser918Thr)
p.(Ser918Thr)
p.(Ser918Thr)/wt wt
wt
p.(Ser918Thr) /wt
Segregation study for X-linked disorders
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X-linked disorders and variable expressivity in females (KIAA2022)
Males• Inherited loss of function
mutations• Severe intellectual disability,
microcephaly, autistic features• Generalized epilepsy in some
Van Maldergem et al., 2013
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X-linked disorders and variable expressivity in females (KIAA2022)
Males• Inherited loss of function
mutations• Severe intellectual disability,
microcephaly, autistic features• Generalized epilepsy in some
Females• De novo loss of function
mutations• Mild to severe intellectual
deficiency• Intractable myoclonic epilepsy
Van Maldergem et al., 2013
Females
Males
De Lange et al., 2013
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PCDH19 and epilepsy in females
Ø Female-restricted epilepsy and mental retardation (Dibbens et al., 2008)
Ø Dravet-like syndrome (Depienne et al., 2009)
Cellular interference
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Autosomal dominant disorders
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Self-limiting epilepsies in infancy(Benign familial epilepsies)
Benign Familial Neonatal Epilepsy
Benign Familial Neonatal Infantile Epilepsy
Benign Familial Infantile Epilepsy
1 day
3 months
1 year
KCNQ2> KCNQ3
SCN2A
PRRT2
Cognitive impairment
No(only if homozygous)
No
Rare (5%), variable severity
SCN2A
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Genetic febrile seizures plus (GEFS+) and phenotypic variability
Febrile and non febrile seizures
Febrile and non febrile seizures + mild intellectual disability
Dravet syndrome
M/-M/-
M/-M Missense variant of SCN1A
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GRIN2A and Landau-Kleffner syndrome / focal epilepsy with CSWS
Lesca et al., 2013
• High variability of cognitive impairment in patients with LOF variants of GRIN2A
• Incomplete penetrance in some individuals (parents)
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Picard et al., 2014
DEPDC5 nonsense
variant (stop)
DEPDC5 focal epilepsy
• Nocturnal > diurnal seizures, since the age of 2• Several episodes per night, drug resistant • Incomplete penetrance (50%)
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DEPDC5 and lesionnal focal epilepsies
• FCD IIa -> hemimegalencephaly
• 2nd hit = somatic mutation in dysplastic tissue ? (Baulac et al., 2015)
Scheffer et al., 2014
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De novo (autosomal dominant) variants
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KCNQ2-related epilepsies(Millichap et al., 2016)
Self-limiting epilepsy(Benin Familial Neonatal Epilepsy)
Early-onset developmental epileptic encephalopathy
Loss-of-function variantsMissense variants Missense variants
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Genes involved in both mild and severe phenotypes
Gene Mild phenotype (usually inherited) Severe phenotype (usually de novo)
SCN1A GEFS+ Dravet syndrome
SCN1B GEFS+ Dravet syndrome (homozygous mutations)
SCN2A Benign Familial neonatal-infantile Epilepsy
EOEE
SCN8A Benign familial infantile epilepsy and paroxysmal choreoathetosis
EOEE
KCNQ2 Benign familial neonatal epilepsy EOEE
SLC2A1 Refractory generalized or focal epilepsy (early absence epilepsy)
De Vivo syndrome
GABRA1 Idiopathic generalized epilepsy EOEE
GABRG2 GEFS+ EOEE
GRIN2A Epilepsy-aphasia syndrome EOEEModified from Helbig and Abou Tayoum, 2016
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« Sporadic » cases and genetic risk
ØAny recurrence risk ?
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« Sporadic » cases and genetic risk
• de novo mutation ?• X -Linked ?• Autosomal dominant with incomplete
penetrance ?• Mitochondrial inheritance ?• Chromosomal inheritance ?
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« Sporadic » cases and genetic risk
• de novo mutation ?• X -Linked ?• Autosomal dominant with incomplete
penetrance ?• Mitochondrial inheritance ?• Chromosomal inheritance ?
The lack of family history does not exclude a Mendelian disorder… and recurrence risk for the family between 1 and 50%
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Dravet syndrome
• Onset at 9 months• Febrile and non febrile
seizures• Drug-resistant epilepsy• Intellectual disability• EEG normal at onset,
then slowing of background and multifocal anomalies
SCN1A pathogenic variant not found in
blood-extracted DNA from the parents
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Family recurrence of Dravet syndrome
• Recurrence in a half-brother• Parental germline/somatic mosaicism in 9% of patients
with Dravet syndrome (Depienne et al., 2011)
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de novo variants and et germline mosaicism
Mutation
Mutated cells
Oocyte / sperm
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de novo variants and et germline mosaicism
Mutation
Mutated cells
Oocyte / sperm
• Risk for all de novo gene variant or chromosomal anomaly• PND can be proposed for future pregnancies of the parents
(even if separated)
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Conclusion
• Should be offered to most families after genetic diagnosis, even when the disease-causing variant had occurred de novo
• Mandatory for family planning (prenatal/ premplanation diagnosis) -> when possible before a pregnancy !
• Should be based on acurate genetic diagnosis• Simple and more complex situations