Abstract
Congenital diaphragmatic hernia (CDH) is a developmental defect of the diaphragm that causes high newborn mortality. Isolated or non-syndromic CDH is considered a multifactorial disease, with strong evidence implicating genetic factors. As low heritability has been reported in isolated CDH, family-based genetic methods have yet to identify the genetic factors associated with the defect. Using the Utah Population Database, we identified distantly related patients from several extended families with a high incidence of isolated CDH. Using high-density genotyping, seven patients were analyzed by homozygosity exclusion rare allele mapping (HERAM) and phased haplotype sharing (HapShare), two methods we developed to map shared chromosome regions. Our patient cohort shared three regions not previously associated with CDH, that is, 2q11.2-q12.1, 4p13 and 7q11.2, and two regions previously involved in CDH, that is, 8p23.1 and 15q26.2. The latter regions contain GATA4 and NR2F2, two genes implicated in diaphragm formation in mice. Interestingly, three patients shared the 8p23.1 locus and one of them also harbored the 15q26.2 segment. No coding variants were identified in GATA4 or NR2F2, but a rare shared variant was found in intron 1 of GATA4. This work shows the role of heritability in isolated CDH. Our family-based strategy uncovers new chromosomal regions possibly associated with disease, and suggests that non-coding variants of GATA4 and NR2F2 may contribute to the development of isolated CDH. This approach could speed up the discovery of the genes and regulatory elements causing multifactorial diseases, such as isolated CDH.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 3137-3147 |
| Number of pages | 11 |
| Journal | American Journal of Medical Genetics, Part A |
| Volume | 158 A |
| Issue number | 12 |
| DOIs | |
| State | Published - Jan 1 2012 |
| Externally published | Yes |
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Keywords
- Congenital diaphragmatic hernia
- GATA4
- NR2F2
- Shared segment analysis
- Utah population database
ASJC Scopus subject areas
- Genetics
- Genetics(clinical)
Cite this
A family-based paradigm to identify candidate chromosomal regions for isolated congenital diaphragmatic hernia. / Arrington, Cammon B.; Bleyl, Steven B.; Matsunami, Nori; Bowles, Neil E.; Leppert, Tami I.; Demarest, Bradley L.; Osborne, Karen; Yoder, Bradley A.; Byrne, Janice L.; Schiffman, Joshua D.; Null, Donald; Digeronimo, Robert; Rollins, Michael; Faix, Roger; Comstock, Jessica; Camp, Nicola J.; Leppert, Mark F.; Yost, H. Joseph; Brunelli, Luca.
In: American Journal of Medical Genetics, Part A, Vol. 158 A, No. 12, 01.01.2012, p. 3137-3147.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - A family-based paradigm to identify candidate chromosomal regions for isolated congenital diaphragmatic hernia
AU - Arrington, Cammon B.
AU - Bleyl, Steven B.
AU - Matsunami, Nori
AU - Bowles, Neil E.
AU - Leppert, Tami I.
AU - Demarest, Bradley L.
AU - Osborne, Karen
AU - Yoder, Bradley A.
AU - Byrne, Janice L.
AU - Schiffman, Joshua D.
AU - Null, Donald
AU - Digeronimo, Robert
AU - Rollins, Michael
AU - Faix, Roger
AU - Comstock, Jessica
AU - Camp, Nicola J.
AU - Leppert, Mark F.
AU - Yost, H. Joseph
AU - Brunelli, Luca
PY - 2012/1/1
Y1 - 2012/1/1
N2 - Congenital diaphragmatic hernia (CDH) is a developmental defect of the diaphragm that causes high newborn mortality. Isolated or non-syndromic CDH is considered a multifactorial disease, with strong evidence implicating genetic factors. As low heritability has been reported in isolated CDH, family-based genetic methods have yet to identify the genetic factors associated with the defect. Using the Utah Population Database, we identified distantly related patients from several extended families with a high incidence of isolated CDH. Using high-density genotyping, seven patients were analyzed by homozygosity exclusion rare allele mapping (HERAM) and phased haplotype sharing (HapShare), two methods we developed to map shared chromosome regions. Our patient cohort shared three regions not previously associated with CDH, that is, 2q11.2-q12.1, 4p13 and 7q11.2, and two regions previously involved in CDH, that is, 8p23.1 and 15q26.2. The latter regions contain GATA4 and NR2F2, two genes implicated in diaphragm formation in mice. Interestingly, three patients shared the 8p23.1 locus and one of them also harbored the 15q26.2 segment. No coding variants were identified in GATA4 or NR2F2, but a rare shared variant was found in intron 1 of GATA4. This work shows the role of heritability in isolated CDH. Our family-based strategy uncovers new chromosomal regions possibly associated with disease, and suggests that non-coding variants of GATA4 and NR2F2 may contribute to the development of isolated CDH. This approach could speed up the discovery of the genes and regulatory elements causing multifactorial diseases, such as isolated CDH.
AB - Congenital diaphragmatic hernia (CDH) is a developmental defect of the diaphragm that causes high newborn mortality. Isolated or non-syndromic CDH is considered a multifactorial disease, with strong evidence implicating genetic factors. As low heritability has been reported in isolated CDH, family-based genetic methods have yet to identify the genetic factors associated with the defect. Using the Utah Population Database, we identified distantly related patients from several extended families with a high incidence of isolated CDH. Using high-density genotyping, seven patients were analyzed by homozygosity exclusion rare allele mapping (HERAM) and phased haplotype sharing (HapShare), two methods we developed to map shared chromosome regions. Our patient cohort shared three regions not previously associated with CDH, that is, 2q11.2-q12.1, 4p13 and 7q11.2, and two regions previously involved in CDH, that is, 8p23.1 and 15q26.2. The latter regions contain GATA4 and NR2F2, two genes implicated in diaphragm formation in mice. Interestingly, three patients shared the 8p23.1 locus and one of them also harbored the 15q26.2 segment. No coding variants were identified in GATA4 or NR2F2, but a rare shared variant was found in intron 1 of GATA4. This work shows the role of heritability in isolated CDH. Our family-based strategy uncovers new chromosomal regions possibly associated with disease, and suggests that non-coding variants of GATA4 and NR2F2 may contribute to the development of isolated CDH. This approach could speed up the discovery of the genes and regulatory elements causing multifactorial diseases, such as isolated CDH.
KW - Congenital diaphragmatic hernia
KW - GATA4
KW - NR2F2
KW - Shared segment analysis
KW - Utah population database
UR - http://www.scopus.com/inward/record.url?scp=84870242761&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84870242761&partnerID=8YFLogxK
U2 - 10.1002/ajmg.a.35664
DO - 10.1002/ajmg.a.35664
M3 - Article
C2 - 23165927
AN - SCOPUS:84870242761
VL - 158 A
SP - 3137
EP - 3147
JO - American Journal of Medical Genetics
JF - American Journal of Medical Genetics
SN - 1552-4825
IS - 12
ER -