Search

Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes 1 . Large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here we identify the non-coding RNA RNU4-2 as a syndromic NDD gene. RNU4-2 encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome 2 . We identify an 18 base pair region of RNU4-2 mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and stem III) that is severely depleted of variation in the general population, but in which we identify heterozygous variants in 115 individuals with NDD. Most individuals (77.4%) have the same highly recurrent single base insertion (n.64_65insT). In 54 individuals in whom it could be determined, the de novo variants were all on the maternal allele. We demonstrate that RNU4-2 is highly expressed in the developing human brain, in contrast to RNU4-1 and other U4 homologues. Using RNA sequencing, we show how 5' splice-site use is systematically disrupted in individuals with RNU4-2 variants, consistent with the known role of this region during spliceosome activation. Finally, we estimate that variants in this 18 base pair region explain 0.4% of individuals with NDD. This work underscores the importance of non-coding genes in rare disorders and will provide a diagnosis to thousands of individuals with NDD worldwide., (© 2024. The Author(s).)

Objectives. To assess SARS-CoV-2 transmission within a correctional facility and recommend mitigation strategies. Methods. From April 29 to May 15, 2020, we established the point prevalence of COVID-19 among incarcerated persons and staff within a correctional facility in Arkansas. Participants provided respiratory specimens for SARS-CoV-2 testing and completed questionnaires on symptoms and factors associated with transmission. Results. Of 1647 incarcerated persons and 128 staff tested, 30.5% of incarcerated persons (range by housing unit = 0.0%-58.2%) and 2.3% of staff tested positive for SARS-CoV-2. Among those who tested positive and responded to symptom questions (431 incarcerated persons, 3 staff), 81.2% and 33.3% were asymptomatic, respectively. Most incarcerated persons (58.0%) reported wearing cloth face coverings 8 hours or less per day, and 63.3% reported close contact with someone other than their bunkmate. Conclusions. If testing remained limited to symptomatic individuals, fewer cases would have been detected or detection would have been delayed, allowing transmission to continue. Rapid implementation of mass testing and strict enforcement of infection prevention and control measures may be needed to mitigate spread of SARS-CoV-2 in this setting.

Although ribosomes are ubiquitous and essential for life, recent data indicate that monogenic causes of ribosomal dysfunction can confer a remarkable degree of specificity in terms of human disease phenotype. Box C/D small nucleolar RNAs (snoRNAs) are evolutionarily conserved non-protein-coding RNAs involved in ribosome biogenesis. Here we show that biallelic mutations in the gene SNORD118, encoding the box C/D snoRNA U8, cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts (LCC), presenting at any age from early childhood to late adulthood. These mutations affect U8 expression, processing and protein binding and thus implicate U8 as essential in cerebral vascular homeostasis., Competing Interests: The authors declare that they have no competing financial interests.

Background: Mutations in microtubule-regulating genes are associated with disorders of neuronal migration and microcephaly. Regulation of centriole length has been shown to underlie the pathogenesis of certain ciliopathy phenotypes. Using a next-generation sequencing approach, we identified mutations in a novel centriolar disease gene in a kindred with an embryonic lethal ciliopathy phenotype and in a patient with primary microcephaly., Methods and Results: Whole exome sequencing data from a non-consanguineous Caucasian kindred exhibiting mid-gestation lethality and ciliopathic malformations revealed two novel non-synonymous variants in CENPF, a microtubule-regulating gene. All four affected fetuses showed segregation for two mutated alleles [IVS5-2A>C, predicted to abolish the consensus splice-acceptor site from exon 6; c.1744G>T, p.E582X]. In a second unrelated patient exhibiting microcephaly, we identified two CENPF mutations [c.1744G>T, p.E582X; c.8692 C>T, p.R2898X] by whole exome sequencing. We found that CENP-F colocalised with Ninein at the subdistal appendages of the mother centriole in mouse inner medullary collecting duct cells. Intraflagellar transport protein-88 (IFT-88) colocalised with CENP-F along the ciliary axonemes of renal epithelial cells in age-matched control human fetuses but did not in truncated cilia of mutant CENPF kidneys. Pairwise co-immunoprecipitation assays of mitotic and serum-starved HEKT293 cells confirmed that IFT88 precipitates with endogenous CENP-F., Conclusions: Our data identify CENPF as a new centriolar disease gene implicated in severe human ciliopathy and microcephaly related phenotypes. CENP-F has a novel putative function in ciliogenesis and cortical neurogenesis., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

The ability of spherule-derived coccidioidin containing 0.4 % phenol and 0.0001 % thimerosal in buffered saline to induce delayed-type hypersensitivity (DTH) was evaluated in four separate studies. The skin test antigen was titrated in 20 adult volunteers with a recent history of pulmonary coccidioidomycosis using intradermal doses of 0.4, 0.8, and 1.6 μg of antigen, based on total dry weight. Based on these data, a dose of 1.27 μg was shown to elicit a mean ± SEM induration response of 23.5 ± 2.3 mm at 48 h, similar to the 23.6-mm response after 48 h of the U. S. Reference coccidioidin last tested approximately 13 years ago. The 1.27 μg dose in 0.1 mL of the spherule-derived antigen (Spherusol) was then examined in three separate groups of adult volunteers to determine the sensitivity and specificity of the product. Fifty-nine of 60 individuals living in a non-endemic area for coccidioidomycosis were skin test negative to Spherusol. Twelve subjects with a recent history of pulmonary histoplasmosis were skin test negative to Spherusol. Finally, 51 of 52 individuals with a recent diagnosis of acute pulmonary coccidioidomycosis were skin test positive to Spherusol. Within this group, prior therapy with fluconazole did not appear to reduce the reactivity to Spherusol. No serious adverse events were observed in the four studies. From these data, Spherusol was found to be safe and has an overall observed sensitivity and specificity of ≥ 98 % in detecting DTH in coccidioidomycosis.

Aboriginal and Torres Strait Islander Australians (Indigenous Australians) have more than twice the smoking prevalence of non-Indigenous Australians. Anti-smoking campaigns have demonstrated success in the general population but little is known about their impact among Indigenous people. A total of 143 Indigenous and a comparison group of 156 non-Indigenous smokers from South Australia were shown 10 anti-smoking advertisements representing a range of advertisements typically aired in Australia. Participants rated advertisements on a five-point Likert scale assessing factors including message acceptance and personalized effectiveness. On average, Indigenous people rated the mainstream advertisements higher than non-Indigenous people and were more likely to report that they provided new information. Advertisements with strong graphic imagery depicting the health effects of smoking were rated highest by Indigenous smokers. Advertisements featuring real people describing the serious health consequences of smoking received mixed responses. Those featuring an ill person were rated higher by Indigenous people than those featuring the family of the person affected by a smoking-related disease. With limited Indigenous-specific messages available and given the finite resources of most public health campaigns, exposure to mainstream strong graphic and emotive first-person narratives about the health effects of smoking are likely to be highly motivating for Indigenous smokers.

Familial hypertelorism, characterized by widely spaced eyes, classically shows autosomal dominant inheritance (Teebi type), but some pedigrees are compatible with X-linkage. No mechanism has been described previously, but clinical similarity has been noted to craniofrontonasal syndrome (CFNS), which is caused by mutations in the X-linked EFNB1 gene. Here we report a family in which females in three generations presented with hypertelorism, but lacked either craniosynostosis or a grooved nasal tip, excluding CFNS. DNA sequencing of EFNB1 was normal, but further analysis revealed a duplication of 937 kb including EFNB1 and two flanking genes: PJA1 and STARD8. We found that the X chromosome bearing the duplication produces ∼1.6-fold more EFNB1 transcript than the normal X chromosome and propose that, in the context of X-inactivation, this difference in expression level of EFNB1 results in abnormal cell sorting leading to hypertelorism. To support this hypothesis, we provide evidence from a mouse model carrying a targeted human EFNB1 cDNA, that abnormal cell sorting occurs in the cranial region. Hence, we propose that X-linked cases resembling Teebi hypertelorism may have a similar mechanism to CFNS, and that cellular mosaicism for different levels of ephrin-B1 (as well as simple presence/absence) leads to craniofacial abnormalities., (© 2011 Wiley-Liss, Inc.)

Atopic dermatitis (AD) is a common inflammatory skin disease with recurring episodes of itching and a chronic relapsing course. The prevalence of AD has increased exponentially over the years, along with information on how it may occur. Diagnosis of AD is typically based on physical examination and history and may be confirmed based on chronicity of symptoms, itching, and age-specific morphology. Nonpharmacological approaches include psychological interventions such as behavior modification, stress reduction techniques, and group psychotherapeutic treatments or may also include dietary restrictions, ultraviolet (UV) phototherapy, house dust mite reduction, and avoidance of enzyme-enriched detergents. Herbal therapy has also showed some promise particularly Zemaphyte®, Kamillosan®, and Shiunko®. Pharmacological agents that show great efficacy include emollients, topical corticosteroids, and topical calcineurin inhibitors.

Molecular epidemiologic studies provide evidence of transmission of Mycobacterium tuberculosis within clusters of patients whose isolates share identical IS6110-DNA fingerprint patterns. However, M. tuberculosis transmission among patients whose isolates have similar but not identical DNA fingerprint patterns (i.e., differing by a single band) has not been well documented. We used DNA fingerprinting, combined with conventional epidemiology, to show unsuspected patterns of tuberculosis transmission associated with three public bars in the same city. Among clustered TB cases, DNA fingerprinting analysis of isolates with similar and identical fingerprints helped us discover epidemiologic links missed during routine tuberculosis contact investigations.

Aims: To establish a clinical and molecular diagnosis in a family with late onset lattice corneal dystrophy., Methods: Linkage analysis, single strand conformation polymorphism (SSCP) analysis, and direct sequencing of genomic DNA were performed. A review of the patients' clinical symptoms and signs was undertaken., Results: Linkage to chromosome 9q34 was established and a mutation in the gelsolin gene was found in affected individuals. Numerous symptoms experienced by the patients were attributable to this mutation., Conclusion: A diagnosis of amyloidosis type V (familial amyloidosis, Finnish type, FAF/Meretoja syndrome/gelsolin related amyloidosis) was made. This is the first case of amyloidosis type V described in the UK. This emphasises the importance of recognition of the extraocular manifestations of eye disease both in the diagnosis and management of the patient. In addition, these findings can help molecular geneticists in their search for disease-causing mutations.

Six autosomal dominant corneal dystrophies are caused by mutations in the TGFBI (BIGH3) gene on chromosome 5q31: three types of lattice corneal dystrophy (LCD), including type I and type IIIA, granular, Avellino (ACD), and Reis-Bucklers. Initially an exact genotype-phenotype correlation was reported. We report three families, with differing clinical features, all presenting with "granular" corneal dystrophy. We analysed the TGFBI gene by SSCP analysis and direct sequencing in order to further assess the genotype-phenotype correlation. We describe three separate mutations in TGFBI: one novel, one initially described as causing ACD, and one previously described. The novel mutation, R124S, is at the identical position to the mutation causing LCD type I (CDL1). We review the clinical and histological phenotypes of the corneal dystrophies and hypothesize that the ability of a mutation to cause amyloid deposition depends on the location and nature of the mutation. In addition, we suggest that the classification of the granular corneal dystrophies be revised according to mutation type and that ACD should not be classified as a distinct morphological entity., (Copyright 1999 Wiley-Liss, Inc.)

We report two unrelated patients with Asymmetric Crying Facies (ACF) and 22q11 deletion. In the first case ACF was the presenting feature. Fluorescent In Situ Hybridization (FISH) revealed 22q11 deletion and subsequent echocardiography demonstrated a normal cardiovascular system. The second presented with hypoparathyroidism, shown on FISH to be secondary to 22q11 deletion. Echocardiography was normal and ACF was found incidentally. Deletion of 22q11 has been reported with ACF occurring as part of the Cardiofacial syndrome (CFS) [Giannotti A, Mingarelli R, (1994): Am J Med Genet 53: 303-304] but this is the first report of ACF with 22q11 deletion in the absence of cardiac abnormalities. A review of the literature pertaining to ACF is presented.