COL11A2 as a candidate gene for vertebral malformations and congenital scoliosis.

Human vertebral malformations (VMs) have an estimated incidence of 1/2000 and are associated with significant health problems including congenital scoliosis (CS) and recurrent organ system malformation syndromes such as VACTERL (vertebral anomalies; anal abnormalities; cardiac abnormalities; tracheo-esophageal fistula; renal anomalies; limb anomalies). The genetic cause for the vast majority of VMs are unknown. In a CS/VM patient cohort, three COL11A2 variants (R130W, R1407L and R1413H) were identified in two patients with cervical VM. A third patient with a T9 hemivertebra and the R130W variant was identified from a separate study. These substitutions are predicted to be damaging to protein function, and R130 and R1407 residues are conserved in zebrafish Col11a2. To determine the role for COL11A2 in vertebral development, CRISPR/Cas9 was used to create a nonsense mutation (col11a2L642*) as well as a full gene locus deletion (col11a2del) in zebrafish. Both col11a2L642*/L642* and col11a2del/del mutant zebrafish exhibit vertebral fusions in the caudal spine, which form due to mineralization across intervertebral segments. To determine the functional consequence of VM-associated variants, we assayed their ability to suppress col11a2del VM phenotypes following transgenic expression within the developing spine. While wildtype col11a2 expression suppresses fusions in col11a2del/+ and col11a2del/del backgrounds, patient missense variant-bearing col11a2 failed to rescue the loss-of-function phenotype in these animals. These results highlight an essential role for COL11A2 in vertebral development and support a pathogenic role for two missense variants in CS.

Cost-Effectiveness Analysis of the Introduction of HPV Vaccination of 9-Year-Old-Girls in Iran.

OBJECTIVES: To estimate the cost effectiveness of introducing the quadrivalent human papillomavirus (HPV) vaccine into the national immunization program of Iran. METHODS: The CERVIVAC cost-effectiveness model was used to calculate incremental cost per averted disability-adjusted life-year by vaccination compared with no vaccination from both governmental and societal perspectives. Calculations were based on epidemiologic parameters from the Iran National Cancer Registry and other national data sources as well as from literature review. We estimated all direct and indirect costs of cervical cancer treatment and vaccination program. All future costs and benefits were discounted at 3% per year and deterministic sensitivity analysis was used. RESULTS: During a 10-year period, HPV vaccination was estimated to avert 182 cervical cancer cases and 20 deaths at a total vaccination cost of US $23,459,897; total health service cost prevented because of HPV vaccination was estimated to be US $378,646 and US $691,741 from the governmental and societal perspective, respectively. Incremental cost per disability-adjusted life-year averted within 10 years was estimated to be US $15,205 and US $14,999 from the governmental and societal perspective, respectively, and both are higher than 3 times the gross domestic product per capita of Iran (US $14,289). Sensitivity analysis showed variation in vaccine price, and the number of doses has the greatest volatility on the incremental cost-effectiveness ratio. Using a two-dose vaccination program could be cost-effective from the societal perspective (incremental cost-effectiveness ratio = US $11,849). CONCLUSIONS: Introducing a three-dose HPV vaccination program is currently not cost-effective in Iran. Because vaccine supplies cost is the most important parameter in this evaluation, considering a two-dose schedule or reducing vaccine prices has an impact on final conclusions.