Haploinsufficiency of the E3 ubiquitin-protein ligase gene TRIP12 causes intellectual disability with or without autism spectrum disorders, speech delay, and dysmorphic features.

Impairment of ubiquitin-proteasome system activity involving ubiquitin ligase genes UBE3A, UBE3B, and HUWE1 and deubiquitinating enzyme genes USP7 and USP9X has been reported in patients with neurodevelopmental delays. To date, only a handful of single-nucleotide variants (SNVs) and copy-number variants (CNVs) involving TRIP12, encoding a member of the HECT domain E3 ubiquitin ligases family on chromosome 2q36.3 have been reported. Using chromosomal microarray analysis and whole-exome sequencing (WES), we have identified, respectively, five deletion CNVs and four inactivating SNVs (two frameshifts, one missense, and one splicing) in TRIP12. Seven of these variants were found to be de novo; parental studies could not be completed in two families. Quantitative PCR analyses of the splicing mutation showed a dramatically decreased level of TRIP12 mRNA in the proband compared to the family controls, indicating a loss-of-function mechanism. The shared clinical features include intellectual disability with or without autistic spectrum disorders, speech delay, and facial dysmorphism. Our findings demonstrate that E3 ubiquitin ligase TRIP12 plays an important role in nervous system development and function. The nine presented pathogenic variants further document that TRIP12 haploinsufficiency causes a childhood-onset neurodevelopmental disorder. Finally, our data enable expansion of the phenotypic spectrum of ubiquitin-proteasome dependent disorders.

Renal and Ureteric Stone Composition: A five year retrospective study for Northern Ireland.

INTRODUCTION: The study aimed to present the types of renal and ureteric stones (calculi) present in the population of Northern Ireland. The data may help in future planning treatment of stone services, patient education and prevention. METHODS: Consecutive retrospective renal and ureteric stones analysed over 5.75 years (January 2008 - September 2013) in Northern Ireland. Exclusions included patients < 16 years, and calculi listed as bladder stone. RESULTS: Total of 1618 stones analysed. Male to female calculi ratio 1.93: 1. Age range 16 - 94 years (52.2 mean), most common age for stone analysis 31-60 years. From 2008 to 2012 the number of stones analysed increased by 132.9%. Calcium was demonstrated in 94.5% (1529) of stones, of which 2.5% (40) pure calcium oxalate. Calcium oxalate and phosphate 72.9% (1182) of all stones, male to female ratio 2.4:1. Stones containing uric acid 9.6% (156), with uric acid male to female ratio 4.83:1. Struvite 13.7% (222), male to female ratio 1:1.6. Pure cystine 1.1% (18) of stones, male to female ratio 1:1.3. CONCLUSION: There is a high proportion (94.4%) of stones containing calcium oxalate in Northern Ireland; these patients should be aiming to produce 2L of urine a day to aid prevention. Most common age for stone analysis (31-60) is in keeping with most common age for presentation. The steep increase in calculi analysis of 132.9% must be met with personalised stone treatment and prevention strategies.

Factors influencing the adoption of blood alternatives to minimize allogeneic transfusion: the perspective of eight Ontario hospitals.

OBJECTIVE: To identify and describe the factors influencing the use and nonuse of blood-sparing methods such as preoperative autologous donation, acute normovolemic hemodilution, and the use of cell salvage devices, hemostatic agents and erythropoietin. DESIGN: An interview survey. SETTING: Eight Ontario hospitals. METHOD: Interviews were conducted with chiefs of surgery, orthopedics, cardiac surgery and anesthesia, and with heads of transfusion medicine and pharmacy. Hospitals were selected using the qualitative sampling strategy of maximum variation based on their use of the methods (as reported in a previous mail survey). RESULTS: Use of blood-sparing methods was influenced by diverse factors often operating simultaneously. These included the following: characteristics of the method (e.g., evidence of its effectiveness, ease of use, cost); perceptions and experiences of the potential adopters (experience with the method, perception of the current safety of allogeneic blood, perceived convenience or inconvenience of using the method); aspects of the practice setting (inability to move resources between hospital departments, presence of a local clinical champion); and the external environment (patient and public expectations, funding of the blood system, blood shortages). INTERPRETATION: More rational and evidence-based use of blood-sparing methods could be promoted by the adoption of an interdisciplinary, comprehensive, coordinated approach tailored to each patient's needs.