Genotype-Phenotype Correlation in NF1: Evidence for a More Severe Phenotype Associated with Missense Mutations Affecting NF1 Codons 844–848

Neurofibromatosis type 1 (NF1), a common genetic disorder with a birth incidence of 1:2,000–3,000, is characterized by a highly variable clinical presentation. To date, only two clinically relevant intragenic genotype-phenotype correlations have been reported for NF1 missense mutations affecting p.Arg1809 and a single amino acid deletion p.Met922del. Both variants predispose to a distinct mild NF1 phenotype with neither externally visible cutaneous/plexiform neurofibromas nor other tumors. Here, we report 162 individuals (129 unrelated probands and 33 affected relatives) heterozygous for a constitutional missense mutation affecting one of five neighboring NF1 codons—Leu844, Cys845, Ala846, Leu847, and Gly848—located in the cysteine-serine-rich domain (CSRD). Collectively, these recurrent missense mutations affect ∼0.8% of unrelated NF1 mutation-positive probands in the University of Alabama at Birmingham (UAB) cohort. Major superficial plexiform neurofibromas and symptomatic spinal neurofibromas were more prevalent in these individuals compared with classic NF1-affected cohorts (both p < 0.0001). Nearly half of the individuals had symptomatic or asymptomatic optic pathway gliomas and/or skeletal abnormalities. Additionally, variants in this region seem to confer a high predisposition to develop malignancies compared with the general NF1-affected population (p = 0.0061). Our results demonstrate that these NF1 missense mutations, although located outside the GAP-related domain, may be an important risk factor for a severe presentation. A genotype-phenotype correlation at the NF1 region 844–848 exists and will be valuable in the management and genetic counseling of a significant number of individuals

Global injury morbidity and mortality from 1990 to 2017 : results from the Global Burden of Disease Study 2017

Correction:Background Past research in population health trends has shown that injuries form a substantial burden of population health loss. Regular updates to injury burden assessments are critical. We report Global Burden of Disease (GBD) 2017 Study estimates on morbidity and mortality for all injuries. Methods We reviewed results for injuries from the GBD 2017 study. GBD 2017 measured injury-specific mortality and years of life lost (YLLs) using the Cause of Death Ensemble model. To measure non-fatal injuries, GBD 2017 modelled injury-specific incidence and converted this to prevalence and years lived with disability (YLDs). YLLs and YLDs were summed to calculate disability-adjusted life years (DALYs). Findings In 1990, there were 4 260 493 (4 085 700 to 4 396 138) injury deaths, which increased to 4 484 722 (4 332 010 to 4 585 554) deaths in 2017, while age-standardised mortality decreased from 1079 (1073 to 1086) to 738 (730 to 745) per 100 000. In 1990, there were 354 064 302 (95% uncertainty interval: 338 174 876 to 371 610 802) new cases of injury globally, which increased to 520 710 288 (493 430 247 to 547 988 635) new cases in 2017. During this time, age-standardised incidence decreased non-significantly from 6824 (6534 to 7147) to 6763 (6412 to 7118) per 100 000. Between 1990 and 2017, age-standardised DALYs decreased from 4947 (4655 to 5233) per 100 000 to 3267 (3058 to 3505). Interpretation Injuries are an important cause of health loss globally, though mortality has declined between 1990 and 2017. Future research in injury burden should focus on prevention in high-burden populations, improving data collection and ensuring access to medical care.Peer reviewe

Molecular characterization and reclassification of a 1.18 Mbp DMD duplication following positive carrier screening for Duchenne/Becker muscular dystrophy

Abstract A 2‐month‐old male patient harboring a duplication of DMD exons 1–7 classified as pathogenic by an outside institution presented with mildly elevated creatine phosphokinase (CK); molecular breakpoint analysis by our laboratory reclassified the duplication as likely benign. To date, proband continues to develop normally with decreased CK, further supporting our reclassification

Laskutusohje asiakasorganisaatioille case: KuntaPro Oy

Tässä opinnäytetyössä käsiteltiin ohjeen luomista KuntaPro Oy:n asiakasorganisaatioiden käyttöön. Työn tavoitteena oli luoda ohje joka kattaa laskun teon kaikki vaiheet sekä on helppolukuinen ja toimiva laskuttajien näkökulmasta. Ohje luotiin Kuntax-ohjelmistoon. Opinnäytetyö oli luonteeltaan toiminnallinen. Teoriaosuudessa esiteltiin työn toimeksiantaja,Kuntax -ohjelmisto, Microsoft Dynamics AX -ohjelma, josta Kuntax on muokattu, myyntilaskuprosessi ja se millainen on hyvä ohje, koska opinnäytetyön aiheena oli ohje myyntilaskujen luomista varten. Kuntax -ohjelmisto on KuntaPro Oy:n ja Mepco Oy:n yhteistyössä kehittämä talouden- ja toiminnanohjausjärjestelmä. Ohjelmisto otettiin käyttöön tammikuussa 2013 yhdellä KuntaPro Oy:n asiakasorganisaatiolla. Koska kyseessä oli aivan uusi ohjelmisto, piti ohjeet luoda alusta alkaen.Toiminnallinen osio opinnäytetyössä sisältää laskutusohjeen. Ohjeen sisältämän luottamuksellisen materiaalin vuoksi ohje suunniteltiin erilliseksi julkaisuksi. Opinnäytetyöraportissa on kerrottu lopullisen ohjeen muotoiluihin ja rakenteeseen vaikuttaneista päätöksistä