Genetic Analysis of Neural Tube and Orofacial Cleft Defects in the Irish Population

In a collaborative effort with the Health Research Board, the national organization for medical research in the Republic of Ireland, individuals with neural tube defects (NTDs) or facial cleft defects and their parents will be studied. With the exception of a few well-described syndromes most cases of NTDs and facial clefts are not inherited in a Mendelian fashion. Nearly all incident cases occur in families with no prior history of the defects. The observed recurrence risk in families with an NTD child is 10-12 fold higher than the general population suggesting that inherited factors modify this risk. Historically, the incidence of NTDs in Ireland was 5-8 fold higher than the USA. The aim of this study is to identify the gene(s) involved in these defects using standard genetic epidemiology approaches, transmission disequilibrium testing and gene mapping strategies. We will initially evaluate genes known to be involved in folate metabolism and pattern formation (development of the body). The major outcomes measured will be aggregate allele frequencies in case groups compared to controls. Biochemical parameters in red cells and plasma will also be measured. Comparisons will be made between the presence of genetics variants, biochemical parameters and clinical phenotype. Characterizing the genes associated with these defects should provide insight into the etiology and metabolic processes that may be involved, furthering prevention and intervention efforts.

Study Overview

• Status: Terminated
• Conditions: Hereditary Oral Clefts; Neural Tube Defects (NTDs); Facial Cleft Defect

Detailed Description

In a collaborative effort with the Health Research Board, the national organization for medical research in the Republic of Ireland, individuals with neural tube defects (NTDs) or facial cleft defects and their parents will be studied. With the exception of a few well-described syndromes most cases of NTDs and facial clefts are not inherited in a Mendelian fashion. Nearly all incident cases occur in families with no prior history of the defects. However, the observed recurrence risk in families with an NTD child is 10-20 fold higher than the general population incidence suggesting that inherited factors modify this risk. Historically, the incidence of NTDs in Ireland was 5-8 fold higher than the USA. The aim of this study is to identify the gene(s) involved in these defects using standard genetic epidemiology approaches, transmission disequilibrium testing and gene mapping strategies. We will initially evaluate genes known to be involved in folate metabolism and pattern formation (development of the body). The major outcomes measured will be aggregate allele frequencies in case groups compared to controls. Biochemical parameters in red blood cells and plasma will also be measured. Comparisons will be made between the presence of genetics variants, biochemical parameters and clinical phenotype. Characterizing the genes associated with these defects should provide insight into the etiology and metabolic processes that may be involved, furthering prevention and intervention efforts.

• Study Type: Observational
• Enrollment (Actual): 7451

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Human Genome Research Institute (NHGRI), 9000 Rockville Pike

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 85 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

• INCLUSION CRITERIA:

Eligible participants are children and adults with an NTD and their parents residing in the Republic of Ireland, Northern Ireland and the United Kingdom

NTDs are defined to include all forms of spina bifida aperta (meningocele, meningomyelocele), encephalocele, anencephaly, rachischisis, iniencephaly and lipomeningocele. Hydrocephalus, hydranencephaly, dermal sinus and spina bifida occulta do not qualify as NTDs.

For oral clefts, eligible participants are children and adults with a facial cleft in Ireland and their parents.

All families with NTDs or clefts will be recruited for the study.

EXCLUSION CRITERIA:

Those with known syndromes will be excluded or analyzed separately.

Cases for whom both biologic parents are not available will be excluded from some components of triad (case, mother and father) analysis, although the data from the NTD case may be useful for other study components.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Cleft; children and adults with a cleft lip and/or cleft palate and their parents residing in the Republic of Ireland, Northern Ireland and the United Kingdom
NTD; children and adults with an NTD (neural tube defects) and their parents residing in the Republic of Ireland, Northern Ireland and the United Kingdom

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Develop list of candidate genes for these disorders	Develop list of candidate genes for these disorders	Ongoing
Identify intronic and coding polymorphisms in candidate genes	Identify intronic and coding polymorphisms in candidate genes	ongoing
Score collected samples for association and/or linkage between specific alleles and disease status	Score collected samples for association and/or linkage between specific alleles and disease status	ongoing

Collaborators and Investigators

• Sponsor: National Human Genome Research Institute (NHGRI)
• Investigators: Principal Investigator: Lawrence C Brody, Ph.D., National Human Genome Research Institute (NHGRI)

Study record dates

Study Major Dates

• Study Start: January 1, 2000
• Study Completion: December 2, 2019

Study Registration Dates

• First Submitted: June 19, 2006
• First Submitted That Met QC Criteria: June 19, 2006
• First Posted (Estimate): June 21, 2006

Study Record Updates

• Last Update Posted (Actual): December 5, 2019
• Last Update Submitted That Met QC Criteria: December 4, 2019
• Last Verified: December 2, 2019

More Information

Terms related to this study

• Keywords: Birth Defects; Folic Acid; Cleft Lip; Gene-Environment Interactions; Neural Tube Defects
• Additional Relevant MeSH Terms: Nervous System Diseases; Congenital Abnormalities; Nervous System Malformations; Neural Tube Defects; Spinal Dysraphism
• Other Study ID Numbers: 999999053; OH99-HG-N053