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Background Joubert syndrome (JS) is a recessive neurodevelopmental disorder characterized by hypotonia, ataxia, cognitive impairment, abnormal eye movements, respiratory control disturbances, and a distinctive mid-hindbrain malformation. JS demonstrates substantial phenotypic variability and genetic heterogeneity. This study provides a comprehensive view of the current genetic basis, phenotypic range and gene-phenotype associations in JS. Methods We sequenced 27 JS-associated genes in 440 affected individuals (375 families) from a cohort of 532 individuals (440 families) with JS, using molecular inversion probe-based targeted capture and next generation sequencing. Variant pathogenicity was defined using the Combined Annotation Dependent Depletion (CADD) algorithm with an optimized score cut-off. Results We identified presumed causal variants in 62% of pedigrees, including the first B9D2 mutations associated with JS. 253 different mutations in 23 genes highlight the extreme genetic heterogeneity of JS. Phenotypic analysis revealed that only 34% of individuals have a “pure JS” phenotype. Retinal disease is present in 30% of individuals, renal disease in 25%, coloboma in 17%, polydactyly in 15%, liver fibrosis in 14% and encephalocele in 8%. Loss of CEP290 function is associated with retinal dystrophy, while loss of TMEM67 function is associated with liver fibrosis and coloboma, but we observe no clear-cut distinction between JS-subtypes. Conclusion This work illustrates how combining advanced sequencing techniques with phenotypic data addresses extreme genetic heterogeneity to provide diagnostic and carrier testing, guide medical monitoring for progressive complications, facilitate interpretation of genome-wide sequencing results in individuals with a variety of phenotypes, and enable gene-specific treatments in the future.

Background Microalbuminuria is a common diagnosis in the clinical care of patients with type 1 diabetes. Long-term outcomes after the development of microalbuminuria are variable. Methods We quantified the incidence of and risk factors for long-term renal outcomes after the development of microalbuminuria in the DCCT/EDIC Study. The DCCT randomly assigned 1441 persons with type 1 diabetes to intensive or conventional diabetes therapy, and participants were subsequently followed during the observational EDIC Study. During DCCT/EDIC, 325 participants developed incident persistent microalbuminuria (albumin excretion rate [AER] ≥ 30 mg/24hr on two consecutive study visits). We assessed their subsequent renal outcomes, including progression to macroalbuminuria (AER ≥ 300 mg/24hr x2), impaired glomerular filtration rate (estimated GFR < 60 mL/min/1.73m2 x2), and end stage renal disease (ESRD), and regression to normoalbuminuria (AER < 30 mg/24hr x2). Results Median follow-up after persistent microalbuminuria diagnosis was 13 years (maximum 23 years). 10-year cumulative incidences of progression to macroalbuminuria, impaired GFR, and ESRD and regression to normoalbuminuria were 28%, 15%, 3%, and 40%, respectively. Albuminuria outcomes were more favorable with intensive diabetes therapy, lower hemoglobin A1c, lack of retinopathy, female gender, lower blood pressure, and lower concentrations of LDL cholesterol and triglyceride. Lower hemoglobin A1c, lack of retinopathy, and lower blood pressure were also associated with decreased risk of impaired GFR. Conclusions After the development of persistent microalbuminuria, progression and regression of kidney disease each occur commonly. Intensive glycemic control, lower blood pressure, and a more favorable lipid profile are associated with improved outcomes.

Rhombencephalosynapsis is a midline brain malformation characterized by missing cerebellar vermis with apparent fusion of the cerebellar hemispheres. Rhombencephalosynapsis can be seen in isolation or together with other central nervous system and extra-central nervous system malformations. Gómez-López-Hernández syndrome combines rhombencephalosynapsis with parietal/temporal alopecia and sometimes trigeminal anaesthesia, towering skull shape and dysmorphic features. Rhombencephalosynapsis can also be seen in patients with features of vertebral anomalies, anal atresia, cardiovascular anomalies, trachea-oesophageal fistula, renal anomalies, limb defects (VACTERL) association. Based on a comprehensive evaluation of neuroimaging findings in 42 patients with rhombencephalosynapsis, we propose a spectrum of severity, ranging from mild (the partial absence of nodulus, anterior and posterior vermis), to moderate (the absence of posterior vermis with some anterior vermis and nodulus present), to severe (the absence of posterior and anterior vermis with some nodulus present), to complete (the absence of the entire vermis including nodulus). We demonstrate that the severity of rhombencephalosynapsis correlates with fusion of the tonsils, as well as midbrain abnormalities including aqueductal stenosis and midline fusion of the tectum. Rhombencephalosynapsis is also associated with multiple forebrain abnormalities including absent olfactory bulbs, dysgenesis of the corpus callosum, absent septum pellucidum and, in rare patients, atypical forms of holoprosencephaly. The frequent association between rhombencephalosynapsis and aqueductal stenosis prompted us to evaluate brain magnetic resonance images in other patients with aqueductal stenosis at our institution, and remarkably, we identified rhombencephalosynapsis in 9%. Strikingly, subjects with more severe rhombencephalosynapsis have more severely abnormal neurodevelopmental outcome, as do subjects with holoprosencephaly and patients with VACTERL features. In summary, our data provide improved diagnostic and prognostic information, and support disruption of dorsal-ventral patterning as a mechanism underlying rhombencephalosynapsis.

Purpose To identify a prognostic gene signature for HPV-negative OSCC patients. Experimental Design Two gene expression datasets were used; a training dataset from the Fred Hutchinson Cancer Research Center (FHCRC) (n=97), and a validation dataset from the MD Anderson Cancer Center (MDACC) (n=71). We applied L1/L2-penalized Cox regression models to the FHCRC data on the 131–gene signature previously identified to be prognostic in OSCC patients to identify a prognostic model specific for high-risk HPV-negative OSCC patients. The models were tested with the MDACC dataset using a receiver operating characteristic analysis. Results A 13-gene model was identified as the best predictor of HPV-negative OSCC-specific survival in the training dataset. The risk score for each patient in the validation dataset was calculated from this model and dichotomized at the median. The estimated 2-year mortality (± SE) of patients with high risk scores was 47.1 (±9.24)% compared with 6.35 (± 4.42)% for patients with low risk scores. ROC analyses showed that the areas under the curve for the age, gender, and treatment modality-adjusted models with risk score (0.78, 95%CI: 0.74-0.86) and risk score plus tumor stage (0.79, 95%CI: 0.75-0.87) were substantially higher than for the model with tumor stage (0.54, 95%CI: 0.48-0.62). Conclusions We identified and validated a 13-gene signature that is considerably better than tumor stage in predicting survival of HPV-negative OSCC patients. Further evaluation of this gene signature as a prognostic marker in other populations of patients with HPV-negative OSCC is warranted.