Integrated multi-omics for rapid rare disease diagnosis on a national scale.

Critically ill infants and children with rare diseases need equitable access to rapid and accurate diagnosis to direct clinical management. Over 2 years, the Acute Care Genomics program provided whole-genome sequencing to 290 families whose critically ill infants and children were admitted to hospitals throughout Australia with suspected genetic conditions. The average time to result was 2.9 d and diagnostic yield was 47%. We performed additional bioinformatic analyses and transcriptome sequencing in all patients who remained undiagnosed. Long-read sequencing and functional assays, ranging from clinically accredited enzyme analysis to bespoke quantitative proteomics, were deployed in selected cases. This resulted in an additional 19 diagnoses and an overall diagnostic yield of 54%. Diagnostic variants ranged from structural chromosomal abnormalities through to an intronic retrotransposon, disrupting splicing. Critical care management changed in 120 diagnosed patients (77%). This included major impacts, such as informing precision treatments, surgical and transplant decisions and palliation, in 94 patients (60%). Our results provide preliminary evidence of the clinical utility of integrating multi-omic approaches into mainstream diagnostic practice to fully realize the potential of rare disease genomic testing in a timely manner.

De novo mutations in GRIN1 cause extensive bilateral polymicrogyria.

Polymicrogyria is a malformation of cortical development. The aetiology of polymicrogyria remains poorly understood. Using whole-exome sequencing we found de novo heterozygous missense GRIN1 mutations in 2 of 57 parent-offspring trios with polymicrogyria. We found nine further de novo missense GRIN1 mutations in additional cortical malformation patients. Shared features in the patients were extensive bilateral polymicrogyria associated with severe developmental delay, postnatal microcephaly, cortical visual impairment and intractable epilepsy. GRIN1 encodes GluN1, the essential subunit of the N-methyl-d-aspartate receptor. The polymicrogyria-associated GRIN1 mutations tended to cluster in the S2 region (part of the ligand-binding domain of GluN1) or the adjacent M3 helix. These regions are rarely mutated in the normal population or in GRIN1 patients without polymicrogyria. Using two-electrode and whole-cell voltage-clamp analysis, we showed that the polymicrogyria-associated GRIN1 mutations significantly alter the in vitro activity of the receptor. Three of the mutations increased agonist potency while one reduced proton inhibition of the receptor. These results are striking because previous GRIN1 mutations have generally caused loss of function, and because N-methyl-d-aspartate receptor agonists have been used for many years to generate animal models of polymicrogyria. Overall, our results expand the phenotypic spectrum associated with GRIN1 mutations and highlight the important role of N-methyl-d-aspartate receptor signalling in the pathogenesis of polymicrogyria.

Acute Endophthalmitis Caused by Leuconostoc spp. following Intravitreal Bevacizumab Injection.

We present a case of acute endophthalmitis caused by Leuconostoc spp. following intravitreal bevacizumab injection. An 86-year-old immunocompetent female developed acute endophthalmitis after intravitreal injection of bevacizumab for neovascular age-related macular degeneration. The patient presented with pain, visual acuity of hand motions, hypopyon, and dense vitritis 96 h after treatment. She was treated with vitreous and anterior chamber tap followed by intravitreal injections of 1 mg vancomycin, 2.25 mg ceftazidime, and 400 µg dexamethasone. Cultures revealed growth of Leuconostoc spp., a genus of gram-positive bacteria that is inherently resistant to vancomycin. Due to persistent inflammation, pars plana vitrectomy (PPV) with intravitreal injection of 0.4 mg amikacin was performed 16 days later, followed by resolution of endophthalmitis and return of vision to 20/40. In conclusion, the management of acute endophthalmitis caused by Leuconostoc spp., a gram-positive coccobacillus, can be particularly challenging due to its inherent resistance to vancomycin. PPV with intravitreal amikacin led to resolution of endophthalmitis. Our case expands the number of cases of endophthalmitis caused by Leuconostoc spp. and highlights the possibility of Leuconostoc-related endophthalmitis in an outpatient setting in an immunocompetent host.

Concomitant Intravitreal Ganciclovir and Dexamethasone Therapy in the Management of Acute Retinal Necrosis in a Patient Previously Treated with Oral Famciclovir.

Several treatments have been reported for acute retinal necrosis (ARN). We report a case of treatment with intravitreal injection of ganciclovir and dexamethasone in addition to oral valacyclovir in a patient who was previously treated with oral famciclovir for ipsilateral herpes zoster ophthalmicus (HZO).

High-resolution MR imaging of the orbit in patients with retinoblastoma.

Retinoblastoma is the most common intraocular childhood malignancy, with a prevalence of one in 18,000 children younger than 5 years old in the United States. In 80% of patients, retinoblastoma is diagnosed before the age of three, and in 95% of patients, retinoblastoma is diagnosed before the age of five. Although reports exist of retinoblastoma in adults, onset beyond 6 years of age is rare. Broadly, retinoblastoma may be classified into two groups: sporadic and heritable. In either case, the origin of the tumor is a biallelic mutation in primitive neuroepithelial cells. Although their details vary, several staging schemes are used to describe the extent of retinoblastoma according to the following four general criteria: intraocular location, extraocular (extraorbital) location, central nervous system disease, and systemic metastases. In the past decade, substantial changes have taken place in terms of staging and monitoring treatment in patients with retinoblastoma. Diagnosis and treatment of retinoblastoma involve a multidisciplinary approach, for which imaging is a vital component. Increasing awareness and concerns about the effects of radiation in patients with retinoblastoma have led to a shift away from external-beam radiation therapy and toward chemotherapy and locoregional treatment, as well as the establishment of magnetic resonance imaging as the most important imaging modality for diagnosis, staging, and treatment monitoring.

Traffic law knowledge disparity between Hispanics and non-Hispanic whites in California.

BACKGROUND: The Hispanic population is one group that is involved in a disproportionately high percentage of fatal motor vehicle collisions in the United States. STUDY OBJECTIVES: This study investigated demographic factors contributing to a lack of knowledge and awareness of traffic laws among Hispanic drivers involved in motor vehicle collisions (MVCs) in southern California. METHODS: The cross-sectional study enrolled adults (n = 190) involved in MVCs presenting to a Level I trauma center in southern California over a 7-month period. Subjects completed a survey about California traffic law knowledge (TLK) consisting of eight multiple-choice questions. The mean number of questions answered correctly was compared between groups defined by demographic data. RESULTS: The mean number of TLK questions answered correctly by Hispanic and non-Hispanic white groups were significantly different at 4.13 and 4.62, respectively (p = 0.005; 95% confidence interval -0.83 to -0.15). Scores were significantly lower in subjects who were not fluent in English, had less than a high school education, did not possess a current driver's license, and received their TLK from sources other than a driver's education class or Department of Motor Vehicle materials. Analysis of variance showed that the source of knowledge was the strongest predictor of accurate TLK. CONCLUSION: Source of TLK is a major contributing factor to poor TLK in Hispanics. An emphasis on culturally specific traffic law education is needed.

The foot and ankle: MR imaging of uniquely pediatric disorders.

MR imaging of the foot and ankle in children poses unique challenges, not only because of technical issues, but also because of the variations produced by age related changes. However, because of its excellent soft tissue contrast (especially helpful in delineating cartilage related abnormalities), MR imaging offers a distinct advantage over other imaging modalities. This article discusses MR imaging techniques for examining the pediatric foot and ankle, and reviews some common conditions encountered in a child's foot and ankle. This includes lesions such as osteochondritis dissecans; tarsal coalition; soft tissue and bony tumors of the foot and ankle; infection; and clubfoot.