Extreme Growth Failure is a Common Presentation of Ligase IV Deficiency

Ligase IV syndrome is a rare differential diagnosis for Nijmegen breakage syndrome owing to a shared predisposition to lympho‐reticular malignancies, significant microcephaly, and radiation hypersensitivity. Only 16 cases with mutations in LIG4 have been described to date with phenotypes varying from malignancy in developmentally normal individuals, to severe combined immunodeficiency and early mortality. Here, we report the identification of biallelic truncating LIG4 mutations in 11 patients with microcephalic primordial dwarfism presenting with restricted prenatal growth and extreme postnatal global growth failure (average OFC ?10.1 s.d., height ?5.1 s.d.). Subsequently, most patients developed thrombocytopenia and leucopenia later in childhood and many were found to have previously unrecognized immunodeficiency following molecular diagnosis. None have yet developed malignancy, though all patients tested had cellular radiosensitivity. A genotype–phenotype correlation was also noted with position of truncating mutations corresponding to disease severity. This work extends the phenotypic spectrum associated with LIG4 mutations, establishing that extreme growth retardation with microcephaly is a common presentation of bilallelic truncating mutations. Such growth failure is therefore sufficient to consider a diagnosis of LIG4 deficiency and early recognition of such cases is important as bone marrow failure, immunodeficiency, and sometimes malignancy are long term sequelae of this disorder.     

Genetic Variations and Diseases in UniProtKB/Swiss‐Prot: The Ins and Outs of Expert Manual Curation

During the last few years, next‐generation sequencing (NGS) technologies have accelerated the detection of genetic variants resulting in the rapid discovery of new disease‐associated genes. However, the wealth of variation data made available by NGS alone is not sufficient to understand the mechanisms underlying disease pathogenesis and manifestation. Multidisciplinary approaches combining sequence and clinical data with prior biological knowledge are needed to unravel the role of genetic variants in human health and disease. In this context, it is crucial that these data are linked, organized, and made readily available through reliable online resources. The Swiss‐Prot section of the Universal Protein Knowledgebase (UniProtKB/Swiss‐Prot) provides the scientific community with a collection of information on protein functions, interactions, biological pathways, as well as human genetic diseases and variants, all manually reviewed by experts. In this article, we present an overview of the information content of UniProtKB/Swiss‐Prot to show how this knowledgebase can support researchers in the elucidation of the mechanisms leading from a molecular defect to a disease phenotype.     

Screening polypectomy rates below quality benchmarks: A prospective study

AIM:To estimate and compare sex-specific screening polypectomy rates to quality benchmarks of 40%in men and 30%in women.METHODS:A prospective cohort study was undertaken of patients aged 50-75,scheduled for colonoscopy,and covered by the Québec universal health insurance plan.Endoscopist and patient questionnaires were used to obtain screening and non-screening colonoscopy indications.Patient self-report was used to obtain history of gastrointestinal conditions/symptoms and prior colonoscopy.Sex-specific polypectomy rates(PRs)and95%CI were calculated using Bayesian hierarchical logistic regression.RESULTS:In total,45 endoscopists and 2134(mean age=61,50%female)of their patients participated.According to patients,screening PRs in males and females were 32.4%(95%CI:23.8-41.8)and19.4%(95%CI:13.1-25.4),respectively.According to endoscopists,screening PRs in males and females were 30.2%(95%CI:27.0-41.9)and 16.6%(95%CI:16.3-28.6),respectively.Sex-specific PRs did not meet quality benchmarks at all ages except for:males aged65-69(patient screening indication),and males aged70-74(endoscopist screening indication).For all patients aged 50-54,none of the CI included the quality benchmarks.CONCLUSION:Most sex-specific screening PRs in Québec were below quality benchmarks;PRs were especially low for all 50-54 year olds.