Mutations in RPSA and NKX2-3 link development of the spleen and intestinal vasculature.

Idiopathic intestinal varicosis is a developmental disorder defined by dilated and convoluted submucosal veins in the colon or small bowel. A limited number of families with idiopathic intestinal varices has been reported, but the genetic cause has not yet been identified. We performed whole-exome and targeted Sanger sequencing of candidate genes in five intestinal varicosis families. In four families, mutations in the RPSA gene were found, a gene previously linked to congenital asplenia. Individuals in these pedigrees had intestinal varicose veins and angiodysplasia, often in combination with asplenia. In a further four-generation pedigree that only showed intestinal varicosities, the RPSA gene was normal. Instead, a nonsense mutation in the homeobox gene NKX2-3 was detected which cosegregated with the disease in this large family with a LOD (logarithm of the odds) score of 3.3. NKX2-3 is a component of a molecular pathway underlying spleen and gut vasculature development in mice. Our results provide a molecular basis for familial idiopathic intestinal varices. We provide evidence for a relationship between the molecular pathways underlying the development of the spleen and intestinal mucosal vasculature that is conserved between humans and mice. We propose that clinical management of intestinal varices, should include assessment of a functional spleen.

Exome sequencing in routine diagnostics: a generic test for 254 patients with primary immunodeficiencies.

BACKGROUND: Diagnosis of primary immunodeficiencies (PIDs) is complex and cumbersome yet important for the clinical management of the disease. Exome sequencing may provide a genetic diagnosis in a significant number of patients in a single genetic test. METHODS: In May 2013, we implemented exome sequencing in routine diagnostics for patients suffering from PIDs. This study reports the clinical utility and diagnostic yield for a heterogeneous group of 254 consecutively referred PID patients from 249 families. For the majority of patients, the clinical diagnosis was based on clinical criteria including rare and/or unusual severe bacterial, viral, or fungal infections, sometimes accompanied by autoimmune manifestations. Functional immune defects were interpreted in the context of aberrant immune cell populations, aberrant antibody levels, or combinations of these factors. RESULTS: For 62 patients (24%), exome sequencing identified pathogenic variants in well-established PID genes. An exome-wide analysis diagnosed 10 additional patients (4%), providing diagnoses for 72 patients (28%) from 68 families altogether. The genetic diagnosis directly indicated novel treatment options for 25 patients that received a diagnosis (34%). CONCLUSION: Exome sequencing as a first-tier test for PIDs granted a diagnosis for 28% of patients. Importantly, molecularly defined diagnoses indicated altered therapeutic options in 34% of cases. In addition, exome sequencing harbors advantages over gene panels as a truly generic test for all genetic diseases, including in silico extension of existing gene lists and re-analysis of existing data.

Treatment satisfaction in renal transplant patients taking tacrolimus once daily.

BACKGROUND: Adherence to immunosuppressive therapy, which is important to prevent rejection after organ transplantation, is influenced by satisfaction of patients with their medication regimen. OBJECTIVE: We investigated the effect of introducing a simplified medication regimen for renal transplant patients on treatment satisfaction, in particular, convenience. METHODS: In a prospective cohort study, treatment was switched from tacrolimus twice daily to tacrolimus once daily with a simultaneous change to a once-daily formulation of other drugs when applicable. Treatment satisfaction was measured in 75 participants with the validated Treatment Satisfaction Questionnaire for Medication version II. RESULTS: The treatment convenience score increased from a mean (SD) of 66.0 (14.5) to 78.5 (14.5) (P < 0.001). The mean (SD) daily number of medication ingestion time points diminished from 2.4 (0.7) to 1.6 (0.7) (P < 0.001), and the mean (SD) daily number of tablets decreased from 12.4 (3.3) to 9.1 (2.6) (P < 0.001). The self-reported adherence to the medication regimen increased from 79.7% to 94.6% (P < 0.001). CONCLUSIONS: The introduction of a simplified medication regimen enabled by the use of a once-daily formulation of tacrolimus increases treatment convenience after renal transplantation. This regimen had a beneficial effect on self-reported adherence.