ClinGen Dosage Sensitivity Curation Page

8p23.1 region (DEFB gene cluster)

  • Curation Status: Complete


Location Information

Select assembly: (NC_000008.10) ()
  • Haploinsufficiency score: Haploinsufficiency unlikely
  • Strength of Evidence (disclaimer): Haploinsufficiency unlikely

Haploinsufficiency phenotype comments:

The beta-defensin gene cluster on 8p23.1 (including DEFB4, DEFB103, DEFB104,DEFB105,DEFB106,and DEFB107) is polymorphic in copy number among individuals. Individuals have between 2 to 12 copies per diploid genome. Copy numbers between 2 and 6 are common, and all populations examined the modal copy number is 4 per diploid genome (reviewed in Hollox 2008, PMID:19287149). Fellermann et al. (2006) found an association between fewer copies of the DEFB4 gene and risk for Crohn disease (CD) (PMID:16909382). From OMIM (entry 602215): "They showed that healthy individuals, as well as patients with ulcerative colitis, have a median of 4 (range 2-10) copies of the DEFB4 gene per genome. In a surgical cohort with ileal or colonic Crohn disease and in a second large cohort with inflammatory bowel diseases, those with ileal resections/disease exhibited a normal median copy number of 4 for the DEFB4 gene, whereas those with colonic Crohn disease had a median of only 3 copies per genome (P = 0.008 for the surgical cohort; P = 0.032 for the second cohort). Overall, the copy number distribution in colonic Crohn disease was shifted to lower numbers compared with controls. Individuals with 3 copies or fewer had a significantly higher risk of developing colonic Crohn disease than did individuals with 4 or more copies (odds ratio 3.06). A gene copy number of less than 4 for the DEFB4 gene was associated with diminished mucosal mRNA expression (P = 0.033)." Fernandez-Jiminez et al. (2010) (PMID: 20483368) had similar findings. They performed "polymerase chain reaction (PCR) in 376 CD patients and 376 controls...Beta-defensin clusters varied between 2 and 9 copies per genome, and when grouped into bins, high copy numbers (>4) were underrepresented among patients (p = 0.023; odds ratio = 0.69, 95% CI = 0.50-0.96), suggesting that increased copy numbers could protect from CD..." Though evidence such as that cited above suggest an association between copy number variation in the beta-defensin gene cluster and risk for various auto-immune and inflammatory disorders, this evidence does not suggest that copy number variation in this area is CAUSATIVE of these phenotypes. Additionally, these types of phenotypes are not typically those for which clinical cytogenomic microarray testing is ordered. Because of this, we are designating this region "dosage sensitivity unlikely."

  • Triplosensitivity score: Triplosensitivity unlikely
  • Strength of Evidence (disclaimer): Triplosensitivity unlikely

Triplosensitivity phenotype comment:

The beta-defensin gene cluster on 8p23.1 (including DEFB4, DEFB103, DEFB104,DEFB105,DEFB106,and DEFB107) is polymorphic in copy number among individuals. Individuals have between 2 to 12 copies per diploid genome. Copy numbers between 2 and 6 are common, and all populations examined the modal copy number is 4 per diploid genome (reviewed in Hollox 2008, PMID:19287149). "Triplosensitive" not really accurate here; but there is a significant linear increase in relative risk of psoriasis with increasing copy number (Hollox et al., 2008; PMID 18059266). Using multiplex amplifiable probe hybridization (MAPH) and paralog ratio test (PRT), Hollox et al. (2008) reported an association between increased copy number variation at the beta-defensin gene cluster and psoriasis among 179 Dutch patients and 272 controls (P = 7.8 x 10(-5)). A second cohort of 319 German patients and 305 controls assayed using PRT confirmed the finding (P = 2.95 x 10(-5)). Hollox et al. (2008) suggested that high levels of beta-defensins may result in an inappropriate inflammatory response after minor skin injury in patients with psoriasis. The specific values given in the paper are: Copy number /Relative Risk 2 / 0.31 3 / 0.51 4 / 0.84 5 / 1.08 >6 / 1.69 Though evidence such as that cited above suggest an association between copy number variation in the beta-defensing gene cluster and risk for various auto-immune and inflammatory disorders, this evidence does not suggest that copy number variation in this area is CAUSATIVE of these phenotypes. Additionally, these types of phenotypes are not typically those for which clinical cytogenomic microarray testing is ordered. Because of this, we are designating this region "dosage sensitivity unlikely."