Standardized practices for RNA diagnostics using clinically accessible specimens reclassifies 75% of putative splicing variants.

Purpose: Genetic variants causing aberrant premessenger RNA splicing are increasingly being recognized as causal variants in genetic disorders. In this study, we devise standardized practices for polymerase chain reaction (PCR)-based RNA diagnostics using clinically accessible specimens (blood, fibroblasts, urothelia, biopsy).

Methods: A total of 74 families with diverse monogenic conditions (31% prenatal-congenital onset, 47% early childhood, and 22% teenage-adult onset) were triaged into PCR-based RNA testing, with comparative RNA sequencing for 19 cases.

A novel RLIM/RNF12 variant disrupts protein stability and function to cause severe Tonne-Kalscheuer syndrome.

Tonne-Kalscheuer syndrome (TOKAS) is an X-linked intellectual disability syndrome associated with variable clinical features including craniofacial abnormalities, hypogenitalism and diaphragmatic hernia. TOKAS is caused exclusively by variants in the gene encoding the E3 ubiquitin ligase gene RLIM, also known as RNF12. Here we report identification of a novel RLIM missense variant, c.

Clinical Spectrum and Functional Consequences Associated with Bi-Allelic Pathogenic Variants.

(PNPase-polynucleotide phosphorylase) is involved in multiple RNA processing functions in the mitochondria. Bi-allelic pathogenic variants cause heterogeneous clinical phenotypes affecting multiple organs without any established genotype-phenotype correlations. Defects in PNPase can cause variable combined respiratory chain complex defects.

Nemaline myopathy and distal arthrogryposis associated with an autosomal recessive TNNT3 splice variant.

A male neonate presented with severe weakness, hypotonia, contractures and congenital scoliosis. Skeletal muscle specimens showed marked atrophy and degeneration of fast fibers with striking nemaline rods and hypertrophy of slow fibers that were ultrastructurally normal. A neuromuscular gene panel identified a homozygous essential splice variant in TNNT3 (chr11:1956150G > A, NM_006757.

Whole-exome sequencing identifies novel variants in PNPT1 causing oxidative phosphorylation defects and severe multisystem disease.

Recent advances in next-generation sequencing strategies have led to the discovery of many novel disease genes. We describe here a non-consanguineous family with two affected boys presenting with early onset of severe axonal neuropathy, optic atrophy, intellectual disability, auditory neuropathy and chronic respiratory and gut disturbances. Whole-exome sequencing (WES) was performed on all family members and we identified compound heterozygous variants (c.

The Impact of Neurofibromatosis Type 1 on the Health and Wellbeing of Australian Adults.

The complications of neurofibromatosis type 1 (NF1) are widespread, unpredictable and variable and each person's experience of this disorder is unique. However, few studies have addressed the impact of NF1 from an individual's perspective. This qualitative study aims to identify the ways in which NF1 impacts upon affected Australian adults.

Curation, integration and visualization of bacterial virulence factors in PATRIC.

Motivation: We've developed a highly curated bacterial virulence factor (VF) library in PATRIC (Pathosystems Resource Integration Center, www.patricbrc.org) to support infectious disease research.

Germline CBL mutation associated with a noonan-like syndrome with primary lymphedema and teratoma associated with acquired uniparental isodisomy of chromosome 11q23.

Germline mutations in the gene CBL (Casitas B-lineage lymphoma), involved in the RAS-MAPK signaling pathway, have been found as a rare cause of the neuro-cardio-facial-cutaneous syndromes. Somatically acquired homozygous CBL mutations were initially identified in association with myeloproliferative disorders, particularly juvenile myelomonocytic leukemia (JMML). We describe a girl with a Noonan-like phenotype of bilateral ptosis, lymphedema of the lower limbs and moderate intellectual disability, due to a de novo heterozygous mutation in CBL.

PATRIC, the bacterial bioinformatics database and analysis resource.

The Pathosystems Resource Integration Center (PATRIC) is the all-bacterial Bioinformatics Resource Center (BRC) (http://www.patricbrc.org).

Evolution of drug resistance in multiple distinct lineages of H5N1 avian influenza.

Some predict that influenza A H5N1 will be the cause of a pandemic among humans. In preparation for such an event, many governments and organizations have stockpiled antiviral drugs such as oseltamivir (Tamiflu). However, it is known that multiple lineages of H5N1 are already resistant to another class of drugs, adamantane derivatives, and a few lineages are resistant to oseltamivir.

Neonatal severe hyperparathyroidism: an important clue to the aetiology.

Neonatal severe hyperparathyroidism is a rare condition that presents as striking hyperparathyroidism, hypercalcaemia, and metabolic bone disease. The aetiology needs to be determined soon after diagnosis to direct appropriate management and to determine an accurate prognosis. Taking a family history is a valuable clinical tool in paediatric medicine.