Comparative assessment of gene-specific variant distribution in prenatal and postnatal cohorts tested for Noonan syndrome and related conditions.

PURPOSE: To compare the pattern of gene-specific involvement and the spectrum of variants observed in prenatal and postnatal (mean ± SD, 8.9 ± 9.4 years) cohorts tested for Noonan syndrome and related conditions. METHODS: Outcomes of sequencing panel testing were compared between prenatal (n = 845) and postnatal (n = 409) cohorts. RESULTS: PTPN11 and SOS1 harbored the majority of observed variants in both prenatal and postnatal cohorts, and BRAF, HRAS, KRAS, MAP2K1, MAP2K2, RAF1, and SHOC2 had similarities in their pattern of involvement in both cohorts. PTPN11 was the largest contributor of pathogenic variants and had the lowest frequency of variants of uncertain significance (VUS). SOS1 had the highest VUS frequency in both cohorts. The overall VUS frequency was twice as high in prenatal specimens (58.1 vs. 29.3%). PTPN11 and SOS1 had a 1.5-fold higher VUS frequency in the prenatal cohort (10.7 vs. 7.4% and 95 vs. 61.1%, respectively). The diagnostic yield was 3.7% for prenatal samples, with a higher yield of 12.3% in fetuses with cystic hygroma as a sole finding, and 21.3% for postnatal. CONCLUSION: Comparison of prenatal versus postnatal specimens demonstrates that the pattern of specific gene involvement is similar, whereas the classification spectrum of observed variants differs considerably.

Correction: Comparative assessment of gene-specific variant distribution in prenatal and postnatal cohorts tested for Noonan syndrome and related conditions.

The original version of this Article contained an error in the spelling of the author N. T. Leach, which was incorrectly given as N. L. Leach. This has been corrected in both the PDF and HTML versions of the Article.

Relative contributions of insulin deficiency and insulin resistance in maturity-onset diabetes.

The effects of raised insulin resistance and decreased beta-cell function on basal plasma glucose and insulin concentrations have been estimated by means of a mathematical model which uses the available data on control of glucose and insulin flux. The model shows that near-normal basal plasma insulin levels could be maintained by means of basal hyperglycaemia when beta-cell function is deficient. The hyperglycaemia does not become pronounced until more than 80% of beta-cell function has been lost. However, when only 5-10% of beta-cell remains, plasma insulin levels fall in spite of hyperglycaemic stimulation. Conversely, raised insulin resistance in the absence of decreased beta-cell function induces only a small rise in basal plasma glucose concentrations, which stimulates a compensatory increase in basal plasma insulin concentrations from a normal beta-cell capacity. However, if the beta-cell dysfunction is sufficient to induce a basal plasma glucose concentration of 5-6 mmol/l, a slight rise in insulin resistance causes pronounced basal hyperglycaemia.

Effects of pre and perinatal malnutrition on muscle fibres from fast and slow rat muscles.

Pre and perinatal malnutrition of rats was effected by means of limiting the mothers' food intake by 50% during pregnancy and lactation. Male offspring were sacrificed at 36 weeks of age and the anterior tibialis (ANTIB) and soleus (SOL) muscles were prepared for histochemical demonstration of Type I, IIA and IIB muslce fibre types using myosin ATPase and succinic dehydrogenase activity. Muscle weights and mean muscle fibre area determinations showed greater decreases in ANTIB than SOL, SOL muscle fibre areas being relatively unaffected by the undernutrition regimen. The proportions present of the muscle fibre types differed in ANTIB and to a small extent on SOL. In the former muscle, some decreases in area in certain of the fibres were associated with increases in the percentages present, showing a tendency to maintain the physiological cross-sectional area of the muscle.