In this study, we report the experience of the only reference clinical next-generation sequencing lab in Saudi Arabia with the first 1000 families who span a wide-range of suspected Mendelian phenotypes. A total of 1019 tests were performed in the period of March 2016–December 2016 comprising 972 solo (index only), 14 duo (parents or affected siblings only), and 33 trio (index and parents). Multigene panels accounted for 672 tests, while whole exome sequencing (WES) represented the remaining 347 tests. Pathogenic or likely pathogenic variants that explain the clinical indications were identified in 34% (27% in panels and 43% in exomes), spanning 279 genes and including 165 novel variants. While recessive mutations dominated the landscape of solved cases (71% of mutations, and 97% of which are homozygous), a substantial minority (27%) were solved on the basis of dominant mutations. The highly consanguineous nature of the study population also facilitated homozygosity for many private mutations (only 32.5% of the recessive mutations are founder), as well as the first instances of recessive inheritance of previously assumed strictly dominant disorders (involving ITPR1, VAMP1, MCTP2, and TBP). Surprisingly, however, dual molecular diagnosis was only observed in 1.5% of cases. Finally, we have encountered candidate variants in 75 genes (ABHD6, ACY3, ADGRB2, ADGRG7, AGTPBP1, AHNAK2, AKAP6, ASB3, ATXN1L, C17orf62, CABP1, CCDC186, CCP110, CLSTN2, CNTN3, CNTN5, CTNNA2, CWC22, DMAP1, DMKN, DMXL1, DSCAM, DVL2, ECI1, EP400, EPB41L5, FBXL22, GAP43, GEMIN7, GIT1, GRIK4, GRSF1, GTRP1, HID1, IFNL1, KCNC4, LRRC52, MAP7D3, MCTP2, MED26, MPP7, MRPS35, MTDH, MTMR9, NECAP2, NPAT, NRAP, PAX7, PCNX, PLCH2, PLEKHF1, PTPN12, QKI, RILPL2, RIMKLA, RIMS2, RNF213, ROBO1, SEC16A, SIAH1, SIRT2, SLAIN2, SLC22A20, SMDT1, SRRT, SSTR1, ST20, SYT9, TSPAN6, UBR4, VAMP4, VPS36, WDR59, WDYHV1, and WHSC1) not previously linked to human phenotypes and these are presented to accelerate post-publication matchmaking. Two of these genes were independently mutated in more than one family with similar phenotypes, which substantiates their link to human disease (AKAP6 in intellectual disability and UBR4 in early dementia). If the novel candidate disease genes in this cohort are independently confirmed, the yield of WES will have increased to 83%, which suggests that most “negative” clinical exome tests are unsolved due to interpretation rather than technical limitations.Electronic supplementary materialThe online version of this article (doi:10.1007/s00439-017-1821-8) contains supplementary material, which is available to authorized users.
Adolescent anorexia nervosa, a psychiatric disease with high mortality, is often associated with bradycardia. We studied the vagal control of sinus node function in anorexic subjects, to investigate the mechanism of anorexic bradycardia. Cardiac vagal tone was determined in a group of 11 adolescent anorexic girls and in 11 age- and height-matched controls. Cardiac vagal tone in the anorexic patients was measured as the change in R-R interval in response to complete cholinergic blockade; in addition, non-invasive indices of cardiac vagal tone and baroreflex sensitivity were determined in both anorexic and control subjects. Cardiac vagal tone in anorexic subjects was 465 +/- 52 (SE) ms, about 30% higher than values reported for healthy subjects. Vagal tone values were directly related to percent weight loss (R = 0.69, P = 0.017). Non-invasive indices of both cardiac vagal activity and baroreflex sensitivity were significantly higher in the anorexic group as compared to controls; the percent increase of cardiac vagal tone, however, exceeded the increase of baroreflex sensitivity. Cardiac vagal hyperactivity significantly contributes to the bradycardia of anorexic subjects. The excess vagal activity is only partly explained by enhanced baroreflex sensitivity.
A novel, single stage high resolution mass spectrometry-based method is presented for the population level screening of inborn errors of metabolism. The approach proposed here extends traditional electrospray tandem mass spectrometry screening by introducing nanospray ionization and high resolution mass spectrometry, allowing the selective detection of more than 400 individual metabolic constituents of blood including acylcarnitines, amino acids, organic acids, fatty acids, carbohydrates, bile acids, and complex lipids. Dried blood spots were extracted using a methanolic solution of isotope labeled internal standards, and filtered extracts were electrosprayed using a fully automated chip-based nanospray ion source in both positive and negative ion mode. Ions were analyzed using an Orbitrap Fourier transformation mass spectrometer at nominal mass resolution of 100,000. Individual metabolic constituents were quantified using standard isotope dilution methods. Concentration threshold (cutoff) level-based analysis allows the identification of newborns with metabolic diseases, similarly to the traditional electrospray tandem mass spectrometry (ESI-MS/MS) method; however, the detection of additional known biomarkers (e.g., organic acids) results in improved sensitivity and selectivity. The broad range of detected analytes allowed the untargeted multivariate statistical analysis of spectra and identification of additional diseased states, therapeutic artifacts, and damaged samples, besides the metabolic disease panel.
Gastric proton pump inhibitors are widely used in the treatment of dyspeptic problems and for the eradication of H. pylori infection. Data are not available on whether omeprazole, a representative of proton pump inhibitors, influences the function of osteoclastic H+-pump in children. We studied the impact of short-term omeprazole administration on the biochemical parameters of bone turnover in pediatric patients. Urinary calcium excretion, serum total alkaline phosphatase activity, collagen type 1 crosslinked C-telopeptide, and osteocalcin levels were determined in 34 children [20 girls (9 prepubertal) and 14 boys (6 prepubertal)] before and after 2 weeks of omeprazole treatment at a dose of 20 mg/day. The measured parameters were within the healthy reference range in each patient. None of them altered during the study in any age or in any gender. We conclude that omeprazole, at a dose of 20 mg/day, does not significantly influence the investigated biochemical parameters of osteoclast and osteoblast function in pediatric patients.
Hepatic late adverse effects after antineoplastic treatment for childhood cancer Mulder, Renee L.; van Dalen, Elvira C.; Van den Hof, Malon; Bresters, Dorine; Koot, Bart G. P.; Castellino, Sharon M.; Loke, Yoon; Leclercq, Edith; Post, Piet N.; Caron, Huib N.
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