Population-based description of familial clustering of Chiari malformation Type I

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A population-based genealogical resource with linked medical data was used to define the observed familial clustering of Chiari malformation Type I (CM-I).


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.


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.


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.

ABBREVIATIONS CI = confidence interval; CM-I = Chiari malformation Type I; dGIF = distant GIF; GIF = Genealogical Index of Familiality; RR = relative risk; UPDB = Utah Population Database.

Article Information

Correspondence Lisa Cannon-Albright, 391 Chipeta Way, Ste. D, Salt Lake City, UT 84108-1266. email: lisa.albright@utah.edu.

INCLUDE WHEN CITING Published online February 3, 2017; DOI: 10.3171/2016.9.JNS161274.

Disclosures The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

© AANS, except where prohibited by US copyright law.



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    Contribution to the GIF statistic by pairwise genetic distance for 2871 patients with CM-I compared with matched controls. Pairwise genetic distance: 1 = parent/offspring; 2 = siblings or grandparent/grandchild; 3 = avuncular relatives, for example; 4 = first cousins, for example; 5 = first cousins, once removed; 6 = second cousins, and so forth. Figure is available in color online only.

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    Example of a high-risk CM-I pedigree. The male pedigree founder has 2 wives and over 6500 descendants in the UPDB, including 10 patients with CM-I, with only 4.8 patients with CM-I expected (p = 0.02). Circles are females, squares are males, strikethrough indicates deceased. The horizontal line between male and female indicates mating (marriage); the line descending from that connects to all their offspring. Multiple marriages have a mark on the mating connector (e.g., the female founder of the pedigree had 2 spouses). Solid shape represents a patient with CM-1.



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