ABSTRACT
Hearing loss is the most common sensory disorder and because of its high genetic heterogeneity, implementation of Massively Parallel Sequencing (MPS) in diagnostic laboratories is greatly improving the possibilities of offering optimal care to patients. We present the results of a two-year period of molecular diagnosis that included 207 French families referred for non-syndromic hearing loss. Our multi-step strategy involved (i) DFNB1 locus analysis, (ii) MPS of 74 genes, and (iii) additional approaches including Copy Number Variations, in silico analyses, minigene studies coupled when appropriate with complete gene sequencing, and a specific assay for STRC. This comprehensive screening yielded an overall diagnostic rate of 48%, equally distributed between DFNB1 (24%) and the other genes (24%). Pathogenic genotypes were identified in 19 different genes, with a high prevalence of GJB2, STRC, MYO15A, OTOF, TMC1, MYO7A and USH2A. Involvement of an Usher gene was reported in 16% of the genotyped cohort. Four de novo variants were identified. This study highlights the need to develop several molecular approaches for efficient molecular diagnosis of hearing loss, as this is crucial for genetic counselling, audiological rehabilitation and the detection of syndromic forms.
Subject(s)
Connexins/genetics , DNA Copy Number Variations , Hearing Loss/diagnosis , High-Throughput Nucleotide Sequencing/methods , White People/genetics , Cohort Studies , Computer Simulation , Connexin 26 , Early Diagnosis , France , Genetic Predisposition to Disease , Genetic Testing/methods , Hearing Loss/genetics , Humans , Male , Mutation , Sensitivity and Specificity , Sequence Analysis, DNA/methodsABSTRACT
OBJECTIVE: To address whether: (1) bioelectrical impedance analysis (BIA) can provide precise and accurate estimates of total body water (TBW) and extracellular water (ECW) in healthy elderly subjects, that display age-induced changes in body composition, (2) BIA models are improved by introducing variables related to geometrical body-shape and osmolarity. DESIGN: Cross-validation of available BIA models and models developed in the study. SUBJECTS: 58 healthy elderly subjects (31 women, 27 men, 66.8+/-4.7 y, mean +/- s.d.) MEASUREMENTS: BIA at 5, 50 and 100 kHz, 18O labelled water measurements of TBW, Br measurements of ECW, anthropometric variables, plasma osmolarity. RESULTS: Published BIA models for estimating TBW, entail various degrees of bias. Precise models (SEE of the models 0.8 L at 100 kHz, 1.0 L at 50 kHz) involving height2/resistance, weight, gender, circumferences and plasma osmolarity were established with data from 30 subjects chosen at random. Cross-validation of an independent group (n = 28) showed no bias (-1.5+/-3.2 L at 100 kHz, -1.4+/-3.2 L at 50 kHz, P = NS). CONCLUSION: We conclude that BIA models with increased accuracy and precision for predicting ECW and TBW can be derived in healthy elderly subjects. Repeated measures had a mean difference of 0.2+/-1.2 L.
Subject(s)
Aging , Body Water , Electric Impedance , Extracellular Space , Aged , Body Composition , Female , Humans , Male , Middle Aged , Oxygen Isotopes , Regression Analysis , Sensitivity and SpecificityABSTRACT
Total body water (TBW) and body composition are crucial for the estimation of nutritional status in many clinical circumstances. While the measurement of TBW with 18O-enriched water is technically easier than with 2H2O, the cost of 10% 18O-enriched water can be regarded as prohibitive. The aim of this study was to prove that less enriched (i.e. 2%) and cheaper (about 25 ECU per dose per subject, i.e. $30) 18O water can be used to measure TBW. In the 41 subjects studied, isotopic equilibrium was achieved 4 hours after the isotope was administered. Plateau enrichments in urine, saliva, and plasma samples did not differ significantly between 5 and 8 hours after the dose. TBW measurements in 8 of these subjects showed no significant differences, regardless of whether 2% or 10% water was used. We conclude that accurate estimates of TBW and body composition can be obtained with low-cost, 2% 18O-enriched water.
