Flexible Gel-Free Multi-Modal Wireless Sensors With Edge Deep Learning for Detecting and Alerting Freezing of Gait Symptom.

Freezing of gait (FoG) is a debilitating symptom of Parkinson's disease (PD). This work develops flexible wearable sensors that can detect FoG and alert patients and companions to help prevent falls. FoG is detected on the sensors using a deep learning (DL) model with multi-modal sensory inputs collected from distributed wireless sensors. Two types of wireless sensors are developed, including: 1) a C-shape central node placed around the patient's ears, which collects electroencephalogram (EEG), detects FoG using an on-device DL model, and generates auditory alerts when FoG is detected; 2) a stretchable patch-type sensor attached to the patient's legs, which collects electromyography (EMG) and movement information from accelerometers. The patch-type sensors wirelessly send collected data to the central node through low-power ultra-wideband (UWB) transceivers. All sensors are fabricated on flexible printed circuit boards. Adhesive gel-free acetylene carbon black and polydimethylsiloxane electrodes are fabricated on the flexible substrate to allow conformal wear over the long term. Custom integrated circuits (IC) are developed in 180 nm CMOS technology and used in both types of sensors for signal acquisition, digitization, and wireless communication. A novel lightweight DL model is trained using multi-modal sensory data. The inference of the DL model is performed on a low-power microcontroller in the central node. The DL model achieves a high detection sensitivity of 0.81 and a specificity of 0.88. The developed wearable sensors are ready for clinical experiments and hold great promise in improving the quality of life of patients with PD. The proposed design methodologies can be used in wearable medical devices for the monitoring and treatment of a wide range of neurodegenerative diseases.

Multi-Gene Panel Testing of 23,179 Individuals for Hereditary Cancer Risk Identifies Pathogenic Variant Carriers Missed by Current Genetic Testing Guidelines.

Recent advancements in next-generation sequencing have greatly expanded the use of multi-gene panel testing for hereditary cancer risk. Although genetic testing helps guide clinical diagnosis and management, testing recommendations are based on personal and family history of cancer and ethnicity, and many carriers are being missed. Herein, we report the results from 23,179 individuals who were referred for 30-gene next-generation sequencing panel testing for hereditary cancer risk, independent of current testing guidelines-38.7% of individuals would not have met National Comprehensive Cancer Network criteria for genetic testing. We identified a total of 2811 pathogenic variants in 2698 individuals for an overall pathogenic frequency of 11.6% (9.1%, excluding common low-penetrance alleles). Among individuals of Ashkenazi Jewish descent, three-quarters of pathogenic variants were outside of the three common BRCA1 and BRCA2 founder alleles. Across all ethnic groups, pathogenic variants in BRCA1 and BRCA2 occurred most frequently, but the contribution of pathogenic variants in other genes on the panel varied. Finally, we found that 21.7% of individuals with pathogenic variants in genes with well-established genetic testing recommendations did not meet corresponding National Comprehensive Cancer Network criteria. Taken together, the results indicate that more individuals are at genetic risk for hereditary cancer than are identified by current testing guidelines and/or use of single-gene or single-site testing.

Mitochondrial tRNA-serine (AGY) m.C12264T mutation causes severe multisystem disease with cataracts.

Progressive multisystem disease should invoke consideration of potential mitochondrial etiologies. Mitochondrial disease can affect any organ system at any time, particularly involving neurologic, cardiac, muscular, gastroenterologic, and/or ophthalmologic manifestations. We report here a 19-year-old Caucasian man who was followed since birth in multiple pediatric subspecialty clinics for myelomeningocele complications. However, he progressively developed a host of additional problems that were not readily attributable to his neural tube defect involving developmental, ophthalmologic, cardiac, muscular, endocrine, and intermediary metabolic manifestations. Clinical diagnostic testing limited to analysis for common point mutations and deletions in his blood mitochondrial DNA (mtDNA) was not revealing. Skeletal muscle biopsy revealed abnormal mitochondrial morphology and immunostaining, mitochondrial proliferation, and mildly reduced respiratory chain complex I-III activity. Whole mitochondrial genome sequencing analysis in muscle identified an apparently homoplasmic, novel, m.12264C>T transition in the tRNA serine (AGY) gene. The pathogenicity of this mutation was supported by identification of it being present at low heteroplasmy load in his blood (34%) as well as in blood from his maternal grandmother (1%). The proband developed severe nuclear cataracts that proved to be homoplasmic for the pathogenic mtDNA m.12264C>T mutation. This case highlights the value of pursuing whole mitochondrial genome sequencing in symptomatic tissues in the diagnostic evaluation of suspected mitochondrial disease. Furthermore, it is the first report to directly implicate a single mtDNA mutation in the pathogenesis of ocular cataracts and clearly illustrates the important contribution of normal metabolic activity to the function of the ocular lens.

A novel c.592-4_c.592-3delTT mutation in DGUOK gene causes exon skipping.

Deoxyguanosine kinase (DGUOK) catalyzes the first step of the mitochondrial deoxypurine salvage pathway, the phosphorylation of purine deoxyribonucleosides. Mutations in the DGUOK gene have been linked to inherited mtDNA depletion syndromes, neonatal liver failure, nystagmus, and hypotonia. Previously, we reported the first case of a heterozygous unclassified c.592-4_c.592-3delTT alteration in a patient with DGUOK deficiency without the demonstration of its pathogenicity (Dimmock et al., 2008). This alteration was predicted to cause aberrant splicing based upon two computer algorithms. We now report a homozygous c.592-4_c.592-3delTT mutation found in two affected siblings of asymptomatic consanguineous parents. The proband presented with symptoms of idiopathic hepatitis, liver dysfunction, nystagmus, and retinal blindness. This individual died at 6months of age due to liver failure. This individual's affected sibling presented similarly and has remarkable elevations of tyrosine, methionine, and alanine. Many organic acids were elevated in urine, including lactic acid, Krebs cycle intermediates, and para-hydroxy compounds; ketone bodies were also present. RNA studies support aberrant splicing. Sequencing of cDNA detected exon 5 skipping in the two affected siblings, but not in the normal control. These results indicate that the homozygous c.592-4_c.592-3delTT is deleterious and responsible for the DGUOK deficiency. The parents were subsequently confirmed to be carriers of this mutation. In summary, we have demonstrated that c.592-4_c.592-3delTT is a pathogenic splice acceptor site mutation leading to DGUOK deficiency.