A comprehensive approach to identification of pathogenic FANCA variants in Fanconi anemia patients and their families

Fanconi anemia (FA) is a rare recessive DNA repair deficiency resulting from mutations in one of at least 22 genes. Two‐thirds of FA families harbor mutations in FANCA. To genotype patients in the International Fanconi Anemia Registry (IFAR) we employed multiple methodologies, screening 216 families for FANCA mutations. We describe identification of 57 large deletions and 261 sequence variants, in 159 families. All but seven families harbored distinct combinations of two mutations demonstrating high heterogeneity. Pathogenicity of the 18 novel missense variants was analyzed functionally by determining the ability of the mutant cDNA to improve the survival of a FANCA‐null cell line when treated with MMC. Overexpressed pathogenic missense variants were found to reside in the cytoplasm, and nonpathogenic in the nucleus. RNA analysis demonstrated that two variants (c.522G > C and c.1565A > G), predicted to encode missense variants, which were determined to be nonpathogenic by a functional assay, caused skipping of exons 5 and 16, respectively, and are most likely pathogenic. We report 48 novel FANCA sequence variants. Defining both variants in a large patient cohort is a major step toward cataloging all FANCA variants, and permitting studies of genotype–phenotype correlations.     

The role of FISH and cytology in upper urinary tract surveillance after radical cystectomy for bladder cancer

ObjectivesCytology and fluorescence in situ hybridization (FISH) (Urovysion) assay are often used during upper urinary tract surveillance in patients following radical cystectomy with urinary diversion, without much available data regarding efficacy in this population. Here, we evaluate the value of FISH and cytology in detecting upper tract recurrence in the face of a urinary diversion.Materials and methodsA review of our cystectomy database revealed 270 patients who had at least one FISH and/or cytology assay performed during surveillance after radical cystectomy. Workup included upper tract imaging in all patients and upper tract endoscopy as indicated. A total of 163 FISH assays and 474 urinary cytology examinations were included in the analysis. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of FISH and cytology were assessed.ResultsTen patients (3.4%) developed upper tract recurrence after a median follow-up time of 31 months (2–202). All but 1 patient presented either with gross hematuria or positive finding on imaging; 6 had positive FISH and cytology, and 2 had positive cytology only (no FISH done). For detection of upper tract recurrence, sensitivity, specificity, PPV, and NPV of cytology were 80.0%, 85.6%, 10.7%, and 99.5%, respectively; and that for FISH were 85.7%, 86.5%, 23.1%, and 99.2%, respectively.ConclusionsThe FISH assay and urinary cytology both demonstrate high rates of false positivity and are useful mainly for their negative predictive ability in patients with a urinary diversion. Unless prospective trials show otherwise, both—or at least the more expensive test—can be omitted from surveillance strategies.     

Suicide risk and prevalence of major depressive disorder (MDD) among individuals infected with HIV-1 subtype C versus B in Southern Brazil

Major depressive disorder (MDD) is among the most prevalent neuropsychiatric disorders associated with HIV infection; however, its risks and neurobiologic correlates in diverse cultures are poorly understood. This study aimed to examine the frequency of MDD among HIV+ participants in southern Brazil. We hypothesized that the frequency and severity of MDD would be higher among individuals with HIV+ compared with HIV? and higher in HIV subtype B compared with C. Individuals with HIV (n?=?39) as well as seronegative controls (n?=?22) were enrolled in a cross-sectional, prospective, observational study. Current and lifetime history of MDD was diagnosed by MINI-Plus; symptom severity was assessed by Beck Depression Inventory-II (BDI-II). Current and past episodes of MDD were significantly more frequent in the HIV+ versus HIV? group: current MDD, 15 (38.5 %) vs. 0 (0 %), p?=?0.0004; past MDD, 24 (61.5 %) vs. 3 (13.6 %), p?=?0.0004. The median BDI-II score in the HIV+ group was significantly higher than that in the HIV? (13 (8–27.5) vs. 2.5 (1–5.5); p?<?0.0001). Current suicide risk, defined as during the last month, was found in 18 % of participants in the HIV-positive and none in the HIV-negative group. Neither current MDD frequency (8 (57.1 %) vs. 6 (40 %), p?=?0.47) nor BDI-II score differed across subtypes B and C. HIV+ group may be more likely to experience current MDD than HIV?. This was the first study to compare the frequency and severity of MDD in HIV subtypes B and C; we found no difference between HIV subtypes B and C.