A genealogical assessment of familial clustering of anorectal malformations


Familial recurrence of anorectal malformations (ARMs) has been reported in single institution case series and in two population-based studies. Here, we investigate the familial aggregation of ARMs using well-established, unbiased methods in a population genealogy of Utah. Study subjects included 255 ARM cases identified from among the two largest healthcare providers in Utah with linked genealogy data using International Classification of Diseases, Ninth Revision (ICD-9) diagnosis codes. The genealogical index of familiality (GIF) statistic, which compares the average pair-wise relatedness of cases to sets of matched controls, was used to test excess familial clustering. We also estimated relative risks (RRs) for ARM and associated phenotypes in relatives of cases adjusting for age-, sex-, and birthplace. Significant excess familial clustering was observed for all ARM subjects (GIF p < 1e-3). Significant RR estimates for ARM (RR = 15.6, p = 3.3e-6), and for almost all co-morbid birth defects previously associated with ARM, were observed among first-degree relatives of ARM case subjects. This genealogically-based population survey of familial aggregation of ARMs confirms the presence of a heritable component to ARMs and provides unbiased risk estimates to relatives of cases, which may have clinical utility.

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  1. 1.

    Mundt E, Bates MD. Genetics of Hirschsprung’s disease and anorectal malformations. Semin Pediatr Surg. 2010;19:107–17.

    Article  PubMed  Google Scholar 

  2. 2.

    Wijers CHW, van Rooij I, Macelis C, Brunner H, de Blaauw I, Roeleveld N. Genetic and non-genetic etiology of nonsyndromic anorectal malformations: a systematic review. Birth Defects Res C Embryo Today. 2014;102:382–400.

    Article  PubMed  CAS  Google Scholar 

  3. 3.

    Quan L, Smith DW. The VATER association. Vertebral defects, anal atresia, T-E fistula, with esophageal atresia, radial and renal dysplasia: a spectrum of association defects. J Pediatr. 1973;82:104–7.

    Article  PubMed  CAS  Google Scholar 

  4. 4.

    Solomon BD. VACTERL/VATER Association. Orphanet J Rare Dis. 2011;6:56.

    Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Oyen N, Boyd HA, Poulsen G, Wohlfahrt J, Melbye M. Familial recurrence of midline birth defects – a nationwide Danish cohort study. Am J Epidemiol. 2009;170:46–52.

    Article  PubMed  Google Scholar 

  6. 6.

    Falcone RA, Levitt MA, Pena A, Bates M. Increased heritability of certain types of anorectal malformations. J Ped Surg. 2007;42:124–8.

    Article  Google Scholar 

  7. 7.

    Solomon BD, Pineda-Alvarez DE, Raam MS, Cummings DAT. Evidence for inheritance in patients with VACTERL association. Hum Genet. 2010;127:731–3.

    Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Skolnick MH. The Utah genealogical database: a resource for genetic epidemiology. In: Cairns J, Lyon JL, Skolnick M, editors. Banbury report No. 4: cancer incidence in defined populations. New York, NY: Cold Spring Harbor Laboratories; 1980. p. 285–97.

    Google Scholar 

  9. 9.

    Albright F, Teerlink C, Werner TL, Cannon-Albright LA. Significant evidence for a heritable contribution to cancer predisposition: A review of cancer familiality by site. BMC Cancer. 2012;12:138.

    Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Kauwe JSK, Ridge PG, Foster NL, Cannon-Albright LA. Strong evidence for a genetic contribution to late-onset Alzheimer’s Disease mortality: a population-based study. PLoS ONE. 2013;8:e77087.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. 11.

    Yates WR, Johnson C, McKee P, Cannon-Albright LA. Genetic analysis of low BMI phenotype in the Utah population database. PLoS ONE. 2013;8:e80287.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. 12.

    Teerlink CC, Albright FS, Lins L, Cannon-Albright LA. A comprehensive survey of cancer risks in extended families. Genet Med. 2012;14:107–14.

    Article  PubMed  Google Scholar 

  13. 13.

    Albright F, Stephenson RA, Agarwal N, Teerlink CC, Lowrance WT, Farnham JM, et al. Prostate cancer risk prediction based on complete prostate cancer family history. Prostate. 2015;75:390–8.

    Article  PubMed  Google Scholar 

  14. 14.

    Marcelis C, de Blaauw I, Brunner H. Chromosomal anomalies in the etiology of anorectal malformations: A review. Am J Med Genet Part A. 2011;155:2692–704.

    Article  CAS  Google Scholar 

  15. 15.

    de Blaauw I,Wijers CHW, Schmiedeke E, Holland-Cunz S, Gambaf P, Marcelis CLM, Reutter H, Aminoff D, Schipper M, Schwarzer N, Grasshoff-Derrm S, Midrio P, Jenetzky E, van Rooij IALM. First results of a European multi-center registry of patients with anorectal malformations. J Ped Surg. 2013;48:2530–5.

    Article  Google Scholar 

  16. 16.

    Hofmann AD, Puri P. Association of Hirschsprung’s disease and anorectal malformation: a systematic review. Pediatr Surg Int. 2013;29:913–7.

    Article  PubMed  Google Scholar 

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Partial support for all data sets within the Utah Population Database (UPDB) was provided by Huntsman Cancer Institute, Huntsman Cancer Foundation, University of Utah, and the Huntsman Cancer Institute’s Cancer Center Support grant, P30 CA42014 from National Cancer Institute. Financial support for data analysis was provided by Primary Children’s Foundation, Salt Lake City, UT, USA.

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Correspondence to Michael D. Rollins.

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Teerlink, C.C., Bernhisel, R., Cannon-Albright, L.A. et al. A genealogical assessment of familial clustering of anorectal malformations. J Hum Genet 63, 1029–1034 (2018). https://doi.org/10.1038/s10038-018-0487-y

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