Joubert syndrome: a model for untangling recessive disorders with extreme genetic heterogeneity.

BACKGROUND: Joubert syndrome (JS) is a recessive neurodevelopmental disorder characterised 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 algorithm with an optimised 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. CONCLUSIONS: 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.

Correlates of recreational physical activity in early pregnancy.

OBJECTIVE: Despite the well-documented benefits of a physically active lifestyle, over 25% of American adults report that they never engage in regular recreational physical activity. Little is known about the determinants of physical activity among pregnant women. We investigated the predictors of physical activity in 386 normotensive pregnant women. METHODS: Participants provided information about the type, frequency and duration of each physical activity performed during the first 20 weeks of pregnancy. We calculated odd ratios (OR) for active compared with inactive women using logistic regression models. RESULTS: Approximately 61% of women reported participating in some regular physical activity during pregnancy. Walking, swimming, gardening and jogging were the most common activities. Physical activity as an adolescent (OR 4.0) and during the year before pregnancy (OR 48.9) were the strongest predictors of physical activity in pregnancy. Active women who continued to exercise during pregnancy decreased the average intensity of their exercise and the weekly duration of exercise compared with the year before pregnancy. Nulliparas were twice as likely to engage in physical activity as compared with multiparas. Education and income were positively related with physical activity. Non-White women were 40-60% less likely to engage in physical activity as compared with White women. Smokers were also less likely to engage in physical activity. High protein intake was positively associated with physical activity, while the opposite was true for high carbohydrate intake. CONCLUSIONS: The identification of determinants of physical activity in pregnancy has important implications for developing strategies aimed at promoting a physically active lifestyle among young women.

A practical E-PERM (electret passive environmental radon monitor) system for indoor 222Rn measurement.

The technical and scientific basis for the measurement of indoor 222Rn concentration using an E-PERM (Electret passive environmental radon monitor) has been described in our earlier work. The purpose of this paper is to describe further development of a practical and convenient system that can be used routinely for indoor 222Rn measurement. The ion chamber is now made of electrically conducting plastic to minimize the response from natural gamma radiation. A spring-loaded shutter method is used to cover and uncover the electret from outside the chamber. The electret voltage reader has been modified to improve the accuracy and the ease in operation. The calibration, performance, error analysis, and lower limits of detection for these standardized versions of E-PERMs are also described.

An electret passive environmental 222Rn monitor based on ionization measurement.

The electret passive environmental 222Rn monitor (E-PERM) is an extension of electret dosimeters used for measurement of x and gamma radiation. An E-PERM consists of a small cup or canister, having an electret at the bottom, and a filtered inlet at the top. The 222Rn gas entering through the filter and the decay products formed inside the cup generate ions which are collected by the electret. The reduction of charge (or surface potential) on the electret is a measure of time integrated 222Rn exposure. An E-PERM of 220-mL volume with an electret of 0.23 cm thickness gave a surface potential drop of 2.5 V for 37 Bq m-3 d (1 pCi L-1 d). The electret voltage was measured with a specially built surface potential voltmeter. This sensitivity was found adequate for a 1-wk measurement of 222Rn in homes. For longer term measurements, an E-PERM of 40-mL volume and an electret of 51-micron thickness was developed which gave a surface potential drop of 2.6 V for 37 Bq m-3 y (1 pCi L-1 y). Other combinations of chamber volume and electret thicknesses gave responses between these two values. The surface potential of electrets made from Teflon FEP were shown to stay stable even under extreme conditions of relative humidity. The ion collection process in E-PERMs was also shown to be independent of humidity down to an electret surface potential of 100 V.