The Epilepsy Phenome/Genome Project

Abstract

Background

Epilepsy is a common neurological disorder that affects approximately 50 million people worldwide. Both risk of epilepsy and response to treatment partly depend on genetic factors, and gene identification is a promising approach to target new prediction, treatment, and prevention strategies. However, despite significant progress in the identification of genes causing epilepsy in families with a Mendelian inheritance pattern, there is relatively little known about the genetic factors responsible for common forms of epilepsy and so-called epileptic encephalopathies.

Study design

The Epilepsy Phenome/Genome Project (EPGP) is a multi-institutional, retrospective phenotype–genotype study designed to gather and analyze detailed phenotypic information and DNA samples on 5250 participants, including probands with specific forms of epilepsy and, in a subset, parents of probands who do not have epilepsy.

Results

EPGP is being executed in four phases: study initiation, pilot, study expansion/establishment, and close-out. This article discusses a number of key challenges and solutions encountered during the first three phases of the project, including those related to (1) study initiation and management, (2) recruitment and phenotyping, and (3) data validation. The study has now enrolled 4223 participants.

Conclusions

EPGP has demonstrated the value of organizing a large network into cores with specific roles, managed by a strong Administrative Core that utilizes frequent communication and a collaborative model with tools such as study timelines and performance-payment models. The study also highlights the critical importance of an effective informatics system, highly structured recruitment methods, and expert data review.

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References

Linehan

Kerr

. Epidemiology of epilepsy in developed countries. In Benbadis

Beran

Berg

. (eds). Atlas of Epilepsies. Springer, London, 2010, pp. 51–56.

Diagana

Bhalla

Ngoungou

Preux

. Epidemiology of epilepsy in resource poor countries. In Benbadis

Beran

Berg

. (eds). Atlas of Epilepsies. Springer, London, 2010, pp. 57–63.

Hesdorffer

Logroscino

Benn

. Estimating risk for developing epilepsy: A population-based study in Rochester, Minnesota. Neurology 76(1): 23–27.

Begley

Famulari

Annegers

. The cost of epilepsy in the United States: An estimate from population-based clinical and survey data. Epilepsia 2000; 41(3): 342–51.

Berg

. Understanding the delay before epilepsy surgery: Who develops intractable focal epilepsy and when? CNS Spectr 2004; 9(9): 136–44.

Wirrell

Camfield

. Long-term psychosocial outcome in typical absence epilepsy. Sometimes a wolf in sheeps’ clothing. Arch Pediatr Adolesc Med 1997; 151(2): 152–58.

Annegers

Hauser

Anderson

Kurland

. The risks of seizure disorders among relatives of patients with childhood onset epilepsy. Neurology 1982; 32(2): 174–79.

Ottman

Annegers

Risch

Hauser

Susser

. Relations of genetic and environmental factors in the etiology of epilepsy. Ann Neurol 1996; 39(4): 442–49.

Bianchi

Viaggi

Chiossi

. Family study of epilepsy in first degree relatives: Data from the Italian Episcreen Study. Seizure 2003; 12(4): 203–10.

10.

Hemminki

Johansson

Sundquist

. Familial risks for epilepsy among siblings based on hospitalizations in Sweden. Neuroepidemiology 2006; 27(2): 67–73.

11.

Vadlamudi

Andermann

Lombroso

. Epilepsy in twins: Insights from unique historical data of William Lennox. Neurology 2004; 62(7): 1127–33.

12.

Berkovic

Howell

Hay

Hopper

. Epilepsies in twins: Genetics of the major epilepsy syndromes. Ann Neurol 1998; 43(4): 435–45.

13.

Corey

Berg

Pellock

. The occurrence of epilepsy and febrile seizures in Virginian and Norwegian twins. Neurology 1991; 41(9): 1433–36.

14.

Kjeldsen

Corey

Christensen

Friis

. Epileptic seizures and syndromes in twins: The importance of genetic factors. Epilepsy Res 2003; 55(1–2): 137–46.

15.

Ottman

Hirose

Jain

Lerche

Lopes-Cendes

. Genetic testing in the epilepsies – Report of the ILAE Genetics Commission. Epilepsia 2010; 51(4): 655–70.

16.

Reid

Berkovic

Petrou

. Mechanisms of human inherited epilepsies. Prog Neurobiol 2009; 87(1): 41–57.

17.

Helbig

Scheffer

Mulley

Berkovic

. Navigating the channels and beyond: Unravelling the genetics of the epilepsies. Lancet Neurol 2008; 7(3): 231–45.

18.

Ottman

. Analysis of genetically complex epilepsies. Epilepsia 2005; 46(Suppl. 10): 7–14.

19.

Chakravarti

. To a future of genetic medicine. Nature 2001; 409(6822): 822–23.

20.

Lander

. The new genomics: Global views of biology. Science 1996; 274(5287): 536–39.

21.

Singleton

Hardy

Traynor

Houlden

. Towards a complete resolution of the genetic architecture of disease. Trends Genet 2010; 26(10): 438–42.

22.

Cavalleri

Weale

Shianna

. Multicentre search for genetic susceptibility loci in sporadic epilepsy syndrome and seizure types: A case-control study. Lancet Neurol 2007; 6(11): 970–80.

23.

Kasperaviciute

Catarino

Heinzen

. Common genetic variation and susceptibility to partial epilepsies: A genome-wide association study. Brain 2010; 133(Pt 7): 2136–47.

24.

Goldstein

. Common genetic variation and human traits. N Engl J Med 2009; 360(17): 1696–98.

25.

Manolio

Collins

Cox

. Finding the missing heritability of complex diseases. Nature 2009; 461(7265): 747–53.

26.

De Kovel

Trucks

Helbig

. Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies. Brain 2010; 133(Pt 1): 23–32.

27.

Heinzen

Radtke

Urban

. Rare deletions at 16p13.11 predispose to a diverse spectrum of sporadic epilepsy syndromes. Am J Hum Genet 2010; 86(5): 707–18.

28.

Helbig

Mefford

Sharp

. 15q13.3 microdeletions increase risk of idiopathic generalized epilepsy. Nat Genet 2009; 41(2): 160–62.

29.

Mefford

Muhle

Ostertag

. Genome-wide copy number variation in epilepsy: Novel susceptibility loci in idiopathic generalized and focal epilepsies. PLoS Genet 2010; 6(5): e1000962.

30.

Scheffer

Berkovic

. Copy number variants – An unexpected risk factor for the idiopathic generalized epilepsies. Brain 2010; 133(Pt 1): 7–8.

31.

Kearney

Wiste

Stephani

. Recurrent de novo mutations of SCN1A in severe myoclonic epilepsy of infancy. Pediatr Neurol 2006; 34(2): 116–20.

32.

Claes

Del-Favero

Ceulemans

. De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy. Am J Hum Genet 2001; 68(6): 1327–32.

33.

Pereira

Vieira

Barroca

. Severe epilepsy, retardation, and dysmorphic features with a 2q deletion including SCN1A and SCN2A. Neurology 2004; 63(1): 191–92.

34.

Villard

Nguyen

Cardoso

. A locus for bilateral perisylvian polymicrogyria maps to Xq28. Am J Hum Genet 2002; 70(4): 1003–08.

35.

Jansen

Andermann

. Genetics of the polymicrogyria syndromes. J Med Genet 2005; 42(5): 369–78.

36.

Leeflang

Marsh

Parrini

. Patient with bilateral periventricular nodular heterotopia and polymicrogyria with apparently balanced reciprocal translocation t(1;6)(p12;p12.2) that interrupts the mannosidase alpha, class 1A, and glutathione S-transferase A2 genes. J Med Genet 2003; 40(12): e128.

37.

Saitsu

Kato

Mizuguchi

. De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy. Nat Genet 2008; 40: 782–88.

38.

Mencarelli

Spanhol-Rosseto

Artuso

. Novel FOXG1 mutations associated with the congenital variant of Rett syndrome. J Med Genet 2010; 47: 49–53.

39.

Bahi-Buisson

Kaminska

Boddaert

. The three stages of epilepsy in patients with CDKL5 mutations. Epilepsia 2008; 49: 1027–37.

40.

Sherr

. The ARX story (epilepsy, mental retardation, autism, and cerebral malformations): One gene leads to many phenotypes. Curr Opin Pediatr 2003; 15(6): 567–71.

41.

Nesbitt

McKenna

Mays

. The Epilepsy Phenome/Genome Project (EPGP) informatics platform. Int J Med Inform 2012.