Expanding the phenotype of HNRNPU-related disorders to include brief, resolved, unexplained events (BRUE)

hnRNP-U deficiency is caused by pathogenic variants in HNRNPU, which encodes the heterogeneous nuclear ribonucleoprotein U (HNRNPU), a highly conserved protein responsible for assisting spliceosomes in mediating transcription and alternative splicing activity. HnRNPs are responsible for the regulation of translation at the presynaptic sites as well as the transportation of stabilized mRNAs along the axonal cytoskeleton. Here, we report a 2-year-old-male with a HNRNPU variant with a new presentation of apparent recurrent apneic spells with an underlying epileptic origin. These were described as apnea followed by desaturation and tachycardia in the 180\u27s-200 range prior to resolution of symptoms. He also had autistiform behaviors, hypotonia, global developmental delay, heart defects, and unique facial features. The anesthetist professional parents describe multiple BRUE. At 26 months, he presented to the hospital with hypotonia and unique facial features, global developmental delay, autistiform behaviors, dyspraxia with cognitive disability and a change in mental status. On physical exam, the proband had telecanthus, a broad nasal bridge, short palpebral fissures, mild nevus flammeus changes on his face, a single right palmar crease, and a modified single crease on the left. EKG showed a sinus rhythm with intermittent 1st degree AV block, blocked premature atrial contractions, left axis deviation, right bundle branch block, and an ejection fraction of 67%. Echocardiography re-identified an atrial septal defect. Brain MRI showed a T2/FLAIR hyperintense signal in the white matter of the parietal lobes, left greater than right. EEG identified generalized slowing indicative of a mild nonspecific encephalopathy. History of episodes were determined to be consistent with partial onset seizures with eye opening, deviation, and tachycardia with apnea and medical treatment ensued. Genetic testing including microarray and an epilepsy panel that identified no genomic dosage anomalies and a de novo nonsense mutation (c.803+2T\u3eC; p. unknown in HNRNPU), classified as pathogenic. The study of hnRNP complexes have gained momentum in neurodegenerative and tumorigenesis disease research. hnRNPs have a key role in mediating transcription, alternative splicing, and translation activity. Recently, Durkin et al, 2020 (PMID: 32319732) reported 21 previously unreported probands; nearly doubling the recorded patient population. Probands in the literature to date have had variable presentation, but usually with hypotonia, global developmental delays, and seizures. This suggests the addition of HNRNPU to all seizure-related diagnostic panels. We would also recommend including the HNRNPU-related disorders in a differential diagnosis of BRUE and recurrent apneic episodes as any underlying clonic activity may be profoundly subtle.https://digitalcommons.unmc.edu/chri_forum/1018/thumbnail.jp

Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic Medicine

Despite rapid technical progress and demonstrable effectiveness for some types of diagnosis and therapy, much remains to be learned about clinical genome and exome sequencing (CGES) and its role within the practice of medicine. The Clinical Sequencing Exploratory Research (CSER) consortium includes 18 extramural research projects, one National Human Genome Research Institute (NHGRI) intramural project, and a coordinating center funded by the NHGRI and National Cancer Institute. The consortium is exploring analytic and clinical validity and utility, as well as the ethical, legal, and social implications of sequencing via multidisciplinary approaches; it has thus far recruited 5,577 participants across a spectrum of symptomatic and healthy children and adults by utilizing both germline and cancer sequencing. The CSER consortium is analyzing data and creating publically available procedures and tools related to participant preferences and consent, variant classification, disclosure and management of primary and secondary findings, health outcomes, and integration with electronic health records. Future research directions will refine measures of clinical utility of CGES in both germline and somatic testing, evaluate the use of CGES for screening in healthy individuals, explore the penetrance of pathogenic variants through extensive phenotyping, reduce discordances in public databases of genes and variants, examine social and ethnic disparities in the provision of genomics services, explore regulatory issues, and estimate the value and downstream costs of sequencing. The CSER consortium has established a shared community of research sites by using diverse approaches to pursue the evidence-based development of best practices in genomic medicine

Ethical Considerations for Equitable Access to Genomic Sequencing for Critically Ill Neonates in the United States

Rare diseases impact all socio-economic, geographic, and racial groups indiscriminately. Newborn screening (NBS) is an exemplary international public health initiative that identifies infants with rare conditions early in life to reduce morbidity and mortality. NBS theoretically promotes equity through universal access, regardless of financial ability. There is however heterogeneity in access to newborn screening and conditions that are screened throughout the world. In the United States and some other developed countries, NBS is provided to all babies, subsidized by the local or federal government. Although NBS is an equitable test, infants admitted to neonatal intensive care units (NICUs) may not receive similar benefits to healthier infants. Newborns in the NICU may receive delayed and/or multiple newborn screens due to known limitations in interpreting the results with prematurity, total parenteral nutrition, blood transfusions, infection, and life support. Thus, genomic technologies might be needed in addition to NBS for equitable care of this vulnerable population. Whole exome (WES) and genome sequencing (WGS) have been recently studied in critically ill newborns across the world and have shown promising results in shortening diagnostic odysseys and providing clinical utility. However, in certain circumstances several barriers might limit access to these tests. Here, we discuss some of the existing barriers to genomic sequencing in NICUs in the United States, explore the ethical implications related to low access, consider ways to increase access to genomic testing, and offer some suggestions for future research in these areas

Knowledge, motivations, expectations, and traits of an African, African-American, and Afro-Caribbean sequencing cohort and comparisons to the original ClinSeq

PURPOSE: Racial minority populations are underrepresented in genomics research. This study enrolled African-descended individuals in a sequencing study and reported their characteristics. METHODS: We purposively recruited 467 individuals self-identified as African, African American, or Afro-Caribbean to the ClinSeq RESULTS: Recruitment took five years and 83% of enrollees completed the survey. Participants had modest knowledge about benefits and limitations of sequencing (x̅s = 5.1, ranges: 0-10), and less than the original cohort (x̅ = 7.5 and 7.7, respectively). Common motivations to enroll were learning information relevant to personal health (49%) or family members\u27 health (33%), and most had realistic expectations of sequencing. Like the original cohort, they had high levels of optimism, openness, and resilience. CONCLUSION: Early adopters may have relatively consistent personality traits irrespective of majority/minority status and recruitment methods, but high levels of genomics knowledge are not universal. Research should determine whether recruitment and consent procedures provide adequate education to promote informed choices and realistic expectations, which are vital to ethical research and increasing genomics research participation in underrepresented communities