Population-based description of familial clustering of Chiari malformation Type I.
OBJECTIVE A population-based genealogical resource with linked medical data was used to define the observed familial clustering of Chiari malformation Type I (CM-I). METHODS All patients with CM-I were identified from the 2 largest health care providers in Utah; those patients with linked genealogical data were used to test hypotheses regarding familial clustering. Relative risks (RRs) in first-, second-, and third-degree relatives were estimated using internal cohort-specific CM-I rates; the Genealogical Index of Familiality (GIF) test was used to test for an excess of relationships between all patients with CM-I compared with the expected distribution of relationships for matched control sets randomly selected from the resource. Pedigrees with significantly more patients with CM-I than expected (p < 0.05) based on internal rates were identified. RESULTS A total of 2871 patients with CM-I with at least 3 generations of genealogical data were identified. Significantly increased RRs were observed for first- and third-degree relatives (RR 4.54, p < 0.001, and RR 1.36, p < 0.001, respectively); the RR for second-degree relatives was elevated, but not significantly (RR 1.20, p = 0.13). Significant excess pairwise relatedness was observed among the patients with CM-I (p < 0.001), and borderline significant excess pairwise relatedness was observed when all relationships closer than first cousins were ignored (p = 0.051). Multiple extended high-risk CM-I pedigrees with closely and distantly related members were identified. CONCLUSIONS This population-based description of the familial clustering of 2871 patients with CM-I provided strong evidence for a genetic contribution to a predisposition to CM-I.
1Division of Genetic Epidemiology, Department of Internal Medicine, and.
Diana
D
Abbott
2Department of Neurosurgery, Clinical Neurosciences Center, University of Utah School of Medicine; and.
Douglas
D
Brockmeyer
1Division of Genetic Epidemiology, Department of Internal Medicine, and.
Deborah W
DW
Neklason
1Division of Genetic Epidemiology, Department of Internal Medicine, and.
Craig
C
Teerlink
1Division of Genetic Epidemiology, Department of Internal Medicine, and.|3George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, Utah.
Lisa A
LA
Cannon-Albright
D000328:Adult; D000368:Aged; D001139:Arnold-Chiari Malformation / Q000453:epidemiology* / Q000235:genetics*; D016000:Cluster Analysis; D015331:Cohort Studies; D005190:Family; D005260:Female; D018703:Founder Effect; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D038801:International Classification of Diseases; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D018570:Risk Assessment; D012307:Risk Factors; D014589:Utah / Q000453:epidemiology
CI = confidence interval; CM-I = Chiari malformation Type I; Chiari malformation; GIF = Genealogical Index of Familiality; RR = relative risk; UPDB; UPDB = Utah Population Database; dGIF = distant GIF; familiality; relative risk; skull base