Identification of rare-disease genes using blood transcriptome sequencing and large control cohorts.

It is estimated that 350 million individuals worldwide suffer from rare diseases, which are predominantly caused by mutation in a single gene1. The current molecular diagnostic rate is estimated at 50%, with whole-exome sequencing (WES) among the most successful approaches2-5. For patients in whom WES is uninformative, RNA sequencing (RNA-seq) has shown diagnostic utility in specific tissues and diseases6-8. This includes muscle biopsies from patients with undiagnosed rare muscle disorders6,9, and cultured fibroblasts from patients with mitochondrial disorders7. However, for many individuals, biopsies are not performed for clinical care, and tissues are difficult to access. We sought to assess the utility of RNA-seq from blood as a diagnostic tool for rare diseases of different pathophysiologies. We generated whole-blood RNA-seq from 94 individuals with undiagnosed rare diseases spanning 16 diverse disease categories. We developed a robust approach to compare data from these individuals with large sets of RNA-seq data for controls (n = 1,594 unrelated controls and n = 49 family members) and demonstrated the impacts of expression, splicing, gene and variant filtering strategies on disease gene identification. Across our cohort, we observed that RNA-seq yields a 7.5% diagnostic rate, and an additional 16.7% with improved candidate gene resolution

TCEAL1 Loss-of-Function Results in an X-Linked Dominant Neurodevelopmental Syndrome and Drives the Neurological Disease Trait in Xq222 Deletions

An Xq22.2 region upstream of PLP1 has been proposed to underly a neurological disease trait when deleted in 46,XX females. Deletion mapping revealed that heterozygous deletions encompassing the smallest region of overlap (SRO) spanning six Xq22.2 genes (BEX3, RAB40A, TCEAL4, TCEAL3, TCEAL1, and MORF4L2) associate with an early-onset neurological disease trait (EONDT) consisting of hypotonia, intellectual disability, neurobehavioral abnormalities, and dysmorphic facial features. None of the genes within the SRO have been associated with monogenic disease in OMIM. Through local and international collaborations facilitated by GeneMatcher and Matchmaker Exchange, we have identified and herein report seven de novo variants involving TCEAL1 in seven unrelated families: three hemizygous truncating alleles; one hemizygous missense allele; one heterozygous TCEAL1 full gene deletion; one heterozygous contiguous deletion of TCEAL1, TCEAL3, and TCEAL4; and one heterozygous frameshift variant allele. Variants were identified through exome or genome sequencing with trio analysis or through chromosomal microarray. Comparison with previously reported Xq22 deletions encompassing TCEAL1 identified a more-defined syndrome consisting of hypotonia, abnormal gait, developmental delay/intellectual disability especially affecting expressive language, autistic-like behavior, and mildly dysmorphic facial features. Additional features include strabismus, refractive errors, variable nystagmus, gastroesophageal reflux, constipation, dysmotility, recurrent infections, seizures, and structural brain anomalies. An additional maternally inherited hemizygous missense allele of uncertain significance was identified in a male with hypertonia and spasticity without syndromic features. These data provide evidence that TCEAL1 loss of function causes a neurological rare disease trait involving significant neurological impairment with features overlapping the EONDT phenotype in females with the Xq22 deletion

Workplace violence in a large correctional health servce in New South Wales, Australia: a retrospective review of incident management records

BackgroundLittle is known about workplace violence among correctional health professionals. This studyaimed to describe the patterns, severity and outcomes of incidents of workplace violenceamong employees of a large correctional health service, and to explore the help-seekingbehaviours of staff following an incident.MethodsThe study setting was Justice Health, a statutory health corporation established to providehealth care to people who come into contact with the criminal justice system in New SouthWales, Australia. We reviewed incident management records describing workplace violenceamong Justice Health staff. The three-year study period was 1/7/2007-30/6/2010.ResultsDuring the period under review, 208 incidents of workplace violence were recorded. Verbalabuse (71%) was more common than physical abuse (29%). The most (44%) incidents ofworkplace violence (including both verbal and physical abuse) occurred in adult maleprisons, although the most (50%) incidents of physical abuse occurred in a forensic hospital.Most (90%) of the victims were nurses and two-thirds were females. Younger employees andmales were most likely to be a victim of physical abuse. Preparing or dispensing medicationand attempting to calm and/or restrain an aggressive patient were identified as ‘high risk’work duties for verbal abuse and physical abuse, respectively. Most (93%) of the incidents ofworkplace violence were initiated by a prisoner/patient. Almost all of the incidents receivedeither a medium (46%) or low (52%) Severity Assessment Code. Few victims of workplaceviolence incurred a serious physical injury – there were no workplace deaths during the studyperiod. However, mental stress was common, especially among the victims of verbal abuse(85%). Few (6%) victims of verbal abuse sought help from a health professional.ConclusionsAmong employees of a large correctional health service, verbal abuse in the workplace wassubstantially more common than physical abuse. The most incidents of workplace violenceoccurred in adult male prisons. Review of the types of adverse health outcomes experiencedby the victims of workplace violence and the assessments of severity assigned to violentincidents suggests that, compared with health care settings in the community, correctionalsettings are fairly safe places in which to practice

The Use of Academic-Community Partnerships in Participant Accrual to an Inherited Cancer Registry

The Use of Academic-Community Partnerships in Participant Accrual to an Inherited Cancer RegistryDevon Bonner, Patrice Fleming, Sue Friedman, Susan Vadaparampil, Veronica Harville, Tuya PalBackground: The development of inherited cancer registries has provided for increased ascertainment of participants into genetic-based cancer research studies. Participants have mainly been recruited through academic-based genetic counseling and testing services. An Inherited Cancer Registry (ICARE) was established at Moffitt Cancer Center and participants were recruited through both an academic-community partnership with Facing Our Risks Empowered (FORCE), a non-profit organization for individuals and families affected by hereditary breast and ovarian cancer, and through academic-based high risk cancer clinics. This study sought to determine the efficacy of both methods in recruiting participants to the ICARE inherited cancer registry. Methods: Data was collected from a pre-existing dataset tracking accrual into the ICARE registry from June 2010 to November 2010. Frequencies were calculated for the number of participants accrued through each recruitment method as well as the number of subjects approached and number of participants consented to the registry through each method. Results: Of the 128 participants enrolled into ICARE, 82% (n=105) were enrolled through the academic-community partnership and 18% (n=23) were enrolled through the academic-based high risk cancer clinics. Of the 148 subjects approached for enrollment, 81% (n=116) were approached through the academic-community partnership and 19% (n=27) were approached through the academic-based high risk cancer clinics. 90.5% of subjects approached through the academic-community partnership were enrolled in the cancer registry while 85% of subjects approached through academic-based high risk cancer clinics enrolled.Conclusions: Although inherited cancer registries have historically recruited heavily through academic-based clinical services, recruitment through academic-community partnerships may prove to be a valuable tool in accruing registry participants as well

The Use of Academic-Community Partnerships in Participant Accrual to an Inherited Cancer Registry

The Use of Academic-Community Partnerships in Participant Accrual to an Inherited Cancer RegistryDevon Bonner, Patrice Fleming, Sue Friedman, Susan Vadaparampil, Veronica Harville, Tuya PalBackground: The development of inherited cancer registries has provided for increased ascertainment of participants into genetic-based cancer research studies. Participants have mainly been recruited through academic-based genetic counseling and testing services. An Inherited Cancer Registry (ICARE) was established at Moffitt Cancer Center and participants were recruited through both an academic-community partnership with Facing Our Risks Empowered (FORCE), a non-profit organization for individuals and families affected by hereditary breast and ovarian cancer, and through academic-based high risk cancer clinics. This study sought to determine the efficacy of both methods in recruiting participants to the ICARE inherited cancer registry. Methods: Data was collected from a pre-existing dataset tracking accrual into the ICARE registry from June 2010 to November 2010. Frequencies were calculated for the number of participants accrued through each recruitment method as well as the number of subjects approached and number of participants consented to the registry through each method. Results: Of the 128 participants enrolled into ICARE, 82% (n=105) were enrolled through the academic-community partnership and 18% (n=23) were enrolled through the academic-based high risk cancer clinics. Of the 148 subjects approached for enrollment, 81% (n=116) were approached through the academic-community partnership and 19% (n=27) were approached through the academic-based high risk cancer clinics. 90.5% of subjects approached through the academic-community partnership were enrolled in the cancer registry while 85% of subjects approached through academic-based high risk cancer clinics enrolled.Conclusions: Although inherited cancer registries have historically recruited heavily through academic-based clinical services, recruitment through academic-community partnerships may prove to be a valuable tool in accruing registry participants as well

A Closer Look at Risk Perception among Black Women at Increased Risk for Hereditary Breast and Ovarian Cancer

Although Caucasian women are diagnosed with breast cancer more often than Black women, Black women are diagnosed at younger ages and experience higher mortality from breast cancer than any other racial/ethnic group

Effective Third-Order Nonlinearities In Metallic Refractory Titanium Nitride Thin Films

Nanophotonic devices offer an unprecedented ability to concentrate light into small volumes which can greatly increase nonlinear effects. However, traditional plasmonic materials suffer from low damage thresholds and are not compatible with standard semiconductor technology. Here we study the nonlinear optical properties in the novel refractory plasmonic material titanium nitride using the Z-scan method at 1550 nm and 780 nm. We compare the extracted nonlinear parameters for TiN with previous works on noble metals and note a similarly large nonlinear optical response. However, TiN films have been shown to exhibit a damage threshold up to an order of magnitude higher than gold films of a similar thickness, while also being robust, cost-efficient, bio- and CMOScompatible. Together, these properties make TiN a promising material for metal-based nonlinear optics

Effective Third-Order Nonlinearities In Refractory Plasmonic Tin Thin Films

Here we study the third-order susceptibility of TiN thin films using the dual-arm Z-scan technique at 780 nm and 1550 nm. Due to its refractory nature, TiN is a promising metallic nonlinear component

Effective Third-Order Nonlinearities In Metallic Refractory Titanium Nitride Thin Films: Publisher\u27S Note

This publisher\u27s note amends the Acknowledgments of [Opt. Mater. Express 5, 2395 (2015)]