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Genomic rearrangements involving AUTS2 (7q11.22) are associated with autism and intellectual disability (ID), although evidence for causality is limited. By combining the results of diagnostic testing of 49,684 individuals, we identified 24 microdeletions that affect at least one exon of AUTS2, as well as one translocation and one inversion each with a breakpoint within the AUTS2 locus. Comparison of 17 well-characterized individuals enabled identification of a variable syndromic phenotype including ID, autism, short stature, microcephaly, cerebral palsy, and facial dysmorphisms. The dysmorphic features were more pronounced in persons with 3'AUTS2 deletions. This part of the gene is shown to encode a C-terminal isoform (with an alternative transcription start site) expressed in the human brain. Consistent with our genetic data, suppression of auts2 in zebrafish embryos caused microcephaly that could be rescued by either the full-length or the C-terminal isoform of AUTS2. Our observations demonstrate a causal role of AUTS2 in neurocognitive disorders, establish a hitherto unappreciated syndromic phenotype at this locus, and show how transcriptional complexity can underpin human pathology. The zebrafish model provides a valuable tool for investigating the etiology of AUTS2 syndrome and facilitating gene-function analysis in the future.

High-risk human papillomavirus (hrHPV) testing has a higher sensitivity but lower specificity than cytology for detection of high-grade intraepithelial neoplasia (CIN). To avoid over-referral to colposcopy and overtreatment, hrHPV-positive women require triage testing and/or followup. A total of 25,658 women (30-60 years) enrolled in a population-based cohort study had an adequate baseline Pap smear and hrHPV test. The end-point was cumulative two-year risk of CIN grade 3 or worse (CIN31). In a post-hoc analysis, fourteen triage/followup strategies for hrHPV-positive women (n 5 1,303) were evaluated for colposcopy referral rate, positive (PPV) and negative predictive value (NPV). Five strategies involved triage testing without a repeat test and nine strategies involved triage testing followed by one repeat testing. The tests were cytology, hrHPV, HPV16/ 18 genotyping and HPV16/18/31/33/45 genotyping. Results were adjusted for women in the cohort study who did not attend repeat testing. Of the strategies without repeat testing, combined cytology and HPV16/18/31/33/45 genotyping gave the highest NPV of 98.9% (95%CI 97.6-99.5%). The corresponding colposcopy referral rate was 58.1% (95%CI 55.4-60.8%). Eight of the nine strategies with retesting had an estimated NPV of at least 98%. Of those, cytology triage followed by cytology at 12 months had a markedly lower colposcopy referral rate of 33.4% (95%CI 30.2-36.7%) than the other strategies. The NPV of the latter strategy was 99.3% (95%CI 98.1-99.8%). Triage hrHPV-positive women with cytology, followed by repeat cytology testing yielded a high NPV and modest colposcopy referral rate and appear to be the most feasible management strategy.Strong evidence is now available that testing for high-risk human papillomavirus (hrHPV) infection is more sensitive than cytology in detecting high-grade cervical intraepithelial neoplasia (CIN). 1-7 However, hrHPV testing also detects more transient hrHPV infections than cytology, 1,8 which may lead to over-referral for colposcopy and thus overtreatment. 5 Management of hrHPV-positive women is, therefore, of major concern. In particular, in countries with an efficient cytology-based screening program and a moderate colposcopy referral rate such as The Netherlands and the United Kingdom, the increased burden on healthcare resources upon introduction of a less-specific screening test may be Key words: human papillomavirus, uterine cervical neoplasms, cervical intraepithelial neoplasia, colposcopy, early detection of cancer CJLM was the project leader, designed the study with SB, LR and PJFS and had access to all data. DCR, together with JB, CJLM, FJvK, VC and PJFS, drafted the manuscript. DCR, JB and VC were responsible for data analysis. ATH, DAMH CJLM and PJFS were responsible for HPV testing and HPV genotyping. LR was responsible for database management. DCR and WMV were responsible for the logistics. RHMV was responsible for communication with gynaecologists. FJvK and LR were responsible for cytology testing. All authors critically...

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Aim: To describe the effect of introducing the CISOE-A framework for reporting cervical cytology results, including changes in repeat and referral advice in the Netherlands, on the efficacy of the screening programme. Changes in the distribution of cytological results, the detection rate of cervical intraepithelial neoplasia (CIN) lesions, and the detection rate of squamous cervical carcinoma are reported. Methods:The results of all gynaecology cytological and histological examinations, as registered in the nationwide database for histopathology and cytopathology (PALGA) from 1990 to 2000, were retrieved from seven laboratories in the greater Amsterdam area.

We assessed clearance rates of 14 high-risk human papillomavirus (hrHPV) types in hrHPV-positive women with normal cytology and borderline/mild dyskaryosis (BMD) in a population-based cervical screening cohort of 44 102 women. The 6-month hrHPV type-specific clearance rates, that is, clearance of the same type as detected at baseline, in women with normal and BMD smears were 43% (95% confidence interval (CI) 39 -47) and 29% (95% CI 24 -34), respectively. Corresponding 18-month clearance rates were markedly higher, namely 65% (95% CI 60 -69) and 41% (95% CI 36 -47), respectively. The lowest clearance rates in women with normal cytology were observed for HPV16, HPV18, HPV31, and HPV33. Significantly reduced 18-month clearance rates at a significance level of 1% were observed for HPV16 (49%, 95% CI 41 -59) and HPV31 (50%, 95% CI 39 -63) in women with normal cytology, and for HPV16 (19%, 95% CI 12 -29) in women with BMD. Among women who did not clear hrHPV, women with HPV16 persistence displayed an increased detection rate of XCIN3 (normal Po0.0001; BMD, P ¼ 0.005). The type-specific differences in clearance rates indicate the potential value of hrHPV genotyping in screening programs. Our data support close surveillance (i.e. referral directly, or within 6 months) of women with HPV16 and are inconclusive for surveillance of women with HPV18, HPV31, and HPV33. For the other hrHPV-positive women, it seems advisable to adopt a conservative management with a long waiting period, as hrHPV clearance is markedly higher after 18 months than after 6 months and the risk for XCIN3 is low.

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We present the type-distribution of high-risk human papillomavirus (HPV) types in women with normal cytology (n ¼ 1467), adenocarcinoma in situ (ACIS) (n ¼ 61), adenocarcinoma (n ¼ 70), and squamous cell carcinoma (SCC) (n ¼ 83). Cervical adenocarcinoma and ACIS were significantly more frequently associated with HPV18 (OR MH 15.0; 95% CI 8.6 -26.1 and 21.8; 95% CI 11.9 -39.8, respectively) than normal cytology. Human papillomavirus16 was only associated with adenocarcinoma and ACIS after exclusion of HPV18-positive cases (OR MH 6.6; 95% CI 2.8 -16.0 and 9.4; 95% CI 2.8 -31.2, respectively). For SCC, HPV16 prevalence was elevated (OR MH 7.0; 95% CI 3.9 -12.4) compared to cases with normal cytology, and HPV18 prevalence was only increased after exclusion of HPV16-positive cases (OR MH 4.3; 95% CI 1.6 -11.6). These results suggest that HPV18 is mainly a risk factor for the development of adenocarcinoma whereas HPV16 is associated with both SCC and adenocarcinoma. (Walboomers et al, 1999). Testing for hrHPV types combined with cervical cytology becomes increasingly attractive as data accumulate that a combined test increases the efficacy of cervical screening programmes and triage policies for women with both equivocal and normal cervical smears (Cuzick et al, 2003;Khan et al, 2005). Possibly, even more efficient screening strategies can be developed by selecting hrHPV types conferring a preferential risk for the development of cervical cancer, and treat these infections more aggressively. In order to assess the preferential risk for cervical cancer and its precursors, typespecific prevalence of hrHPV types in cancer cases should be compared to type-specific prevalence in women without cancer. In a meta-analysis of cervical squamous cell carcinomas (SCCs) compared to high-grade squamous intraepithelial lesions, HPV16, HPV18 and HPV45 appeared to display an elevated prevalence in cervical cancer (Clifford et al, 2003a). A second meta-analysis revealed that HPV16 and HPV18 are more prevalent in SCC than in low-grade SIL (Clifford et al, 2005). However, a comparison with hrHPV prevalence in women with normal cytology was not made, hampering the translation of these findings to implementation of type-specific hrHPV testing in population-based screening.Recently in a cross-sectional study, we have demonstrated that among the hrHPV types, HPV16 and HPV33 were significantly more common in women with cervical intraepithelial neoplasia grade 2 or more (XCIN2) than in women with normal cytology. However in that study, cases of XCIN2 were retrieved from population-based screening, and consequently, the prevalence of invasive carcinomas as well as adenocarcinoma in situ (ACIS) was low.In order to obtain a more comprehensive view on the change in distribution from hrHPV infections without cytological abnormalities to hrHPV prevalence in cervical cancer, we compared crosssectional screening data of women with normal cytology to retrospectively collected cases of SCC, adenocarcinoma (AdCx) and ACIS. MATERIALS AND METHODS Women wi...