Epistasis and the sensitivity of phenotypic screens for beta thalassaemia

Genetic disorders of haemoglobin, particularly the sickle cell diseases and the alpha and beta thalassaemias, are the commonest inherited disorders worldwide. The majority of affected births occur in low-income and lower-middle income countries. Screening programmes are a vital tool to counter these haemoglobinopathies by: (i) identifying individual carriers and allowing them to make informed reproductive choices, and (ii) generating population level gene-frequency estimates, to help ensure the optimal allocation of public health resources. For both of these functions it is vital that the screen performed is suitably sensitive. One popular first-stage screening option to detect carriers of beta thalassaemia in low-income countries is the One Tube Osmotic Fragility Test (OTOFT). Here we introduce a population genetic framework within which to quantify the likely sensitivity and specificity of the OTOFT in different epidemiological contexts. We demonstrate that interactions between the carrier states for beta thalassaemia and alpha thalassaemia, glucose-6-phosphate dehydrogenase deficiency and Southeast Asian Ovalocytosis have the potential to reduce the sensitivity of OTOFTs for beta thalassaemia heterozygosity to below 70%. Our results therefore caution against the widespread application of OTOFTs in regions where these erythrocyte variants co-occur

Assessing and measuring chronic multimorbidity in the older population: a proposal for its operationalization

Background Although the definition of multimorbidity as “the simultaneous presence of two or more chronic diseases” is well established, its operationalization is not yet agreed. This study aims to provide a clinically driven comprehensive list of chronic conditions to be included when measuring multimorbidity. Methods Based on a consensus definition of chronic disease, all four-digit level codes from the International Classification of Diseases, 10th revision (ICD-10) were classified as chronic or not by an international and multidisciplinary team. Chronic ICD-10 codes were subsequently grouped into broader categories according to clinical criteria. Last, we showed proof of concept by applying the classification to older adults from the Swedish National study of Aging and Care in Kungsholmen (SNAC-K) using also inpatient data from the Swedish National Patient Register. Results A disease or condition was considered to be chronic if it had a prolonged duration and either (a) left residual disability or worsening quality of life or (b) required a long period of care, treatment, or rehabilitation. After applying this definition in relation to populations of older adults, 918 chronic ICD-10 codes were identified and grouped into 60 chronic disease categories. In SNAC-K, 88.6% had =2 of these 60 disease categories, 73.2% had =3, and 55.8% had =4. Conclusions This operational measure of multimorbidity, which can be implemented using either or both clinical and administrative data, may facilitate its monitoring and international comparison. Once validated, it may enable the advancement and evolution of conceptual and theoretical aspects of multimorbidity that will eventually lead to better care

Mutation update for the SATB2 gene

SATB2-associated syndrome (SAS) is an autosomal dominant neurodevelopmental disorder caused by alterations in the SATB2 gene. Here we present a review of published pathogenic variants in the SATB2 gene to date and report 38 novel alterations found in 57 additional previously unreported individuals. Overall, we present a compilation of 120 unique variants identified in 155 unrelated families ranging from single nucleotide coding variants to genomic rearrangements distributed throughout the entire coding region of SATB2. Single nucleotide variants predicted to result in the occurrence of a premature stop codon were the most commonly seen (51/120=42.5%) followed by missense variants (31/120=25.8%). We review the rather limited functional characterization of pathogenic variants and discuss current understanding of the consequences of the different molecular alterations. We present an expansive phenotypic review along with novel genotype-phenotype correlations. Lastly, we discuss current knowledge on animal models and present future prospects. This review should help provide better guidance for the care of individuals diagnosed with SAS

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Effect of strenuous maternal exercise before and during pregnancy on rat progeny renal function

The effects of strenuous exercise before and during pregnancy on the renal function and morphological alterations of the progeny were determined in a study on female Wistar rats. This research was done based on a previous study carried out in our laboratory, which showed morphological alterations in rats submitted to this kind of exercise. As the form is related to the function, the physiological relevance of submitting a pregnant female to a high-intensity exercise training regimen could be explained by the fact that morphological alterations can influence kidney function. The animals were assigned to one of two groups: control animals that did not exercise during pregnancy and trained animals that swam for 120 min 5 days a week for 8 weeks before pregnancy and daily for 60 min over a period of 8 weeks starting on the second day of pregnancy. Seven rats of each group were analyzed for morphological alterations and for renal function. The progeny of the rats used for morphological evaluation were born by cesarean section and the progeny of the animals used to evaluate renal function were born normally. The progeny were two months old when renal function was evaluated. Fertility and morbidity were the same for both groups. Strenuous maternal exercise had no significant influence on glomerular filtration rate (GFR) but renal plasma flow was lower in the progeny of the trained group (mean ± SD, 16.65 ± 3.77 ml min-1 kg-1) compared to the progeny of the control group (33.42 ± 2.56 ml min-1 kg-1). Antidiuretic and antinatriuretic effects on the progeny of the trained group were observed, since urine flow as percentage of GFR and the fraction of urinary sodium excretion were lower in this group (1.38 ± 0.10 and 0.60 ± 0.04%, respectively) compared to the progeny of the control group (2.36 ± 0.11 and 1.55 ± 0.20%, respectively). Moreover, in this exercise program, fetuses from trained animals were small-sized (2.45 ± 0.19 vs 4.66 ± 2.45 g for control animals) and showed lower differentiation compared to fetuses from the control group. These effects were probably caused by caloric restriction, hypoxia and reduction of umbilical cord length