Finding new causes of monogenic diabetes helps understand glycaemic regulation in humans. To find novel genetic causes of maturity-onset diabetes of the young (MODY), we sequenced MODY cases with unknown aetiology and compared variant frequencies to large public databases. From 36 European patients, we identify two probands with novel RFX6 heterozygous nonsense variants. RFX6 protein truncating variants are enriched in the MODY discovery cohort compared to the European control population within ExAC (odds ratio = 131, P = 1 × 10−4). We find similar results in non-Finnish European (n = 348, odds ratio = 43, P = 5 × 10−5) and Finnish (n = 80, odds ratio = 22, P = 1 × 10−6) replication cohorts. RFX6 heterozygotes have reduced penetrance of diabetes compared to common HNF1A and HNF4A-MODY mutations (27, 70 and 55% at 25 years of age, respectively). The hyperglycaemia results from beta-cell dysfunction and is associated with lower fasting and stimulated gastric inhibitory polypeptide (GIP) levels. Our study demonstrates that heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance.

Heart rate variability (HRV) has been widely used as a measure of vagal activation in physiological, psychological, and clinical examinations. We studied the within-subject quantitative relationship between HRV and vagal effects on the heart in different body postures during a gradually decreasing vagal blockade. Electrocardiogram and respiratory frequency were measured in subjects (8 endurance athletes and 10 participants of nonendurance sports) in supine, sitting, and standing postures before the blockade, under vagal blockade (atropine sulfate, 0.04 mg/kg), and four times during a 150-min recovery from the blockade. Fast Fourier transform was used to calculate low-frequency power (LFP, 0.04-0.15 Hz), high-frequency power (HFP, 0.15-0.40 Hz), and total power (TP, 0.04-0.40 Hz). A within-subject linear regression analysis of recovery time on each HRV index was conducted. Complete vagal blockade decreased all HRV significantly, particularly HFP (P < 0.001). A linear fit explained a large portion of the within-subject variance between recovery time and natural log-transformed (ln) HRV indexes in every posture, with coefficients of determination (R2) in the supine posture [means (SD)]: 98 (SD 2)% for mean R-R interval, 87 (SD 10)% for lnLFP, 87 (SD 13)% for lnHFP, and 91 (SD 10)% for lnTP. Neither body posture nor endurance-training background had an impact on R2 values. There was marked between-subject variation in the R2 values, slopes, and intercepts. In conclusion, all HRV, particularly HFP, is predominantly under vagal control. Within subjects, lnLFP, lnHFP, and lnTP increased linearly with the gradually decreasing vagal blockade in all postures.

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