Clin Genet. 2023 Apr 13. doi: 10.1111/cge.14338. Online ahead of print. ABSTRACT This study presents 46 patients from 23 unrelated Egyptian families with ALS2-related disorders without evidence of lower motor neuron involvement. Age at onset ranged from 10 months to 2.5 years, featuring progressive upper motor neuron signs. Detailed clinical phenotypes demonstrated inter- and intrafamilial variability. We identified 16 homozygous disease-causing ALS2 variants; sorted as splice-site, missense, frameshift, nonsense and in-frame in eight, seven, four, three, and one families, respectively. Seven of these variants were novel, expanding the mutational spectrum of the ALS2 gene. As expected, clinical severity was positively correlated with disease onset (p = 0.004). This work provides clinical and molecular profiles of a large single ethnic cohort of patients with ALS2 mutations, and suggests that infantile ascending hereditary spastic paralysis (IAHSP) and juvenile primary lateral sclerosis (JPLS) are belonged to one entity with no phenotype-genotype correlation. PMID:37055917 DOI:10.1111/cge.14338

Methods Mol Biol. 2023;2621:217-239. doi: 10.1007/978-1-0716-2950-5_12. ABSTRACT Upon admission to intensive care units (ICU), the differential diagnosis of almost all infants with diseases of unclear etiology includes single locus genetic diseases. Rapid whole genome sequencing (rWGS), including sample preparation, short-read sequencing-by-synthesis, informatics pipelining, and semiautomated interpretation, can now identify nucleotide and structural variants associated with most genetic diseases with robust analytic and diagnostic performance in as little as 13.5 h. Early diagnosis of genetic diseases transforms medical and surgical management of infants in ICUs, minimizing both the duration of empiric treatment and the delay to start of specific treatment. Both positive and negative rWGS tests have clinical utility and can improve outcomes. Since first described 10 years ago, rWGS has evolved considerably. Here we describe our current methods for routine diagnostic testing for genetic diseases by rWGS in as little as 18 h. PMID:37041447 DOI:10.1007/978-1-0716-2950-5_12

JACC Case Rep. 2023 Feb 22;11:101790. doi: 10.1016/j.jaccas.2023.101790. eCollection 2023 Apr 5. ABSTRACT We present a 22-week fetus with isolated absent aortic valve and inverse circular shunt. The pregnancy was interrupted. Here, echocardiography and pathology images demonstrate this rare entity. Whole genome sequencing revealed a potentially disease-causing variant in the APC gene. Whole genome sequencing should be considered in severe and rare fetal diseases. (Level of Difficulty: Advanced.). PMID:37077433 DOI:10.1016/j.jaccas.2023.101790

Mov Disord Clin Pract. 2023 Apr 4;10(5):748-755. doi: 10.1002/mdc3.13728. eCollection 2023 May. ABSTRACT BACKGROUND: The International Parkinson and Movement Disorders Society (MDS) set up a working group on pediatric movement disorders (MDS Task Force on Pediatrics) to generate recommendations to guide the transition process from pediatrics to adult health care systems in patients with childhood-onset movement disorders. METHODS: To develop recommendations for transitional care for childhood onset movement disorders, we used a formal consensus development process, using a multi-round, web-based Delphi survey. The Delphi survey was based on the results of the scoping review of the literature and the results of a survey of MDS members on transition practices. Through iterative discussions, we generated the recommendations included in the survey. The MDS Task Force on Pediatrics were the voting members for the Delphi survey. The task force members comprise 23 child and adult neurologists with expertise in the field of movement disorders and from all regions of the world. RESULTS: Fifteen recommendations divided across four different areas were made pertaining to: (1) team composition and structure, (2) planning and readiness, (3) goals of care, and (4) administration and research. All recommendations achieved consensus with a median score of 7 or greater. CONCLUSION: Recommendations on providing transitional care for patients with childhood onset movement disorders are provided. Nevertheless several challenges remain in the implementation of these recommendations, related to health infrastructure and the distribution of health resources, and the availability of knowledgeable and interested practitioners. Research on the influence of transitional care programs on outcomes in childhood onset movement disorders is much needed. PMID:37205244 PMC:PMC10186998

Genome Med. 2023 Mar 16;15(1):18. doi: 10.1186/s13073-023-01166-7. ABSTRACT BACKGROUND: Rapidly and efficiently identifying critically ill infants for whole genome sequencing (WGS) is a costly and challenging task currently performed by scarce, highly trained experts and is a major bottleneck for application of WGS in the NICU. There is a dire need for automated means to prioritize patients for WGS. METHODS: Institutional databases of electronic health records (EHRs) are logical starting points for identifying patients with undiagnosed Mendelian diseases. We have developed automated means to prioritize patients for rapid and whole genome sequencing (rWGS and WGS) directly from clinical notes. Our approach combines a clinical natural language processing (CNLP) workflow with a machine learning-based prioritization tool named Mendelian Phenotype Search Engine (MPSE). RESULTS: MPSE accurately and robustly identified NICU patients selected for WGS by clinical experts from Rady Children’s Hospital in San Diego (AUC 0.86) and the University of Utah (AUC 0.85). In addition to effectively identifying patients for WGS, MPSE scores also strongly prioritize diagnostic cases over non-diagnostic cases, with projected diagnostic yields exceeding 50% throughout the first and second quartiles of score-ranked patients. CONCLUSIONS: Our results indicate that an automated pipeline for selecting acutely ill infants in neonatal intensive care units (NICU) for WGS can meet or exceed diagnostic yields obtained through current selection procedures, which require time-consuming manual review of clinical notes and histories by specialized personnel. PMID:36927505 DOI:10.1186/s13073-023-01166-7

Front Pediatr. 2023 Mar 14;11:1157630. doi: 10.3389/fped.2023.1157630. eCollection 2023. ABSTRACT BACKGROUND: Congenital heart defects (CHD) and congenital anomalies of the kidney and urinary tract (CAKUT) account for significant morbidity and mortality in childhood. Dozens of monogenic causes of anomalies in each organ system have been identified. However, even though 30% of CHD patients also have a CAKUT and both organs arise from the lateral mesoderm, there is sparse overlap of the genes implicated in the congenital anomalies for these organ systems. We sought to determine whether patients with both CAKUT and CHD have a monogenic etiology, with the long-term goal of guiding future diagnostic work up and improving outcomes. METHODS: Retrospective review of electronic medical records (EMR), identifying patients admitted to Rady Children’s Hospital between January 2015 and July 2020 with both CAKUT and CHD who underwent either whole exome sequencing (WES) or whole genome sequencing (WGS). Data collected included demographics, presenting phenotype, genetic results, and mother’s pregnancy history. WGS data was reanalyzed with a specific focus on the CAKUT and CHD phenotype. Genetic results were reviewed to identify causative, candidate, and novel genes for the CAKUT and CHD phenotype. Associated additional structural malformations were identified and categorized. RESULTS: Thirty-two patients were identified. Eight patients had causative variants for the CAKUT/CHD phenotype, three patients had candidate variants, and three patients had potential novel variants. Five patients had variants in genes not associated with the CAKUT/CHD phenotype, and 13 patients had no variant identified. Of these, eight patients were identified as having possible alternative causes for their CHD/CAKUT phenotype. Eighty-eight percent of all CAKUT/CHD patients had at least one additional organ system with a structural malformation. CONCLUSIONS: Overall, our study demonstrated a high rate of monogenic etiologies in hospitalized patients with both CHD and CAKUT, with a diagnostic rate of 44%. Thus, physicians should have a high suspicion for genetic disease in this population. Together, these data provide valuable information on how to approach acutely ill patients with CAKUT and CHD, including guiding diagnostic work up for associated phenotypes, as well as novel insights into the genetics of CAKUT and CHD overlap syndromes in hospitalized children. PMID:36999085 DOI:10.3389/fped.2023.1157630

Clin Lab Med. 2023 Mar;43(1):127-143. doi: 10.1016/j.cll.2022.09.023. Part of special issue: Artificial Intelligence in the Clinical Laboratory: Current Practice and Emerging Opportunities PMID:36764805 DOI:10.1016/j.cll.2022.09.023

NPJ Genom Med. 2023 Feb 14;8(1):5. doi: 10.1038/s41525-023-00349-w. ABSTRACT Universal newborn screening (NBS) is a highly successful public health intervention. Archived dried bloodspots (DBS) collected for NBS represent a rich resource for population genomic studies. To fully harness this resource in such studies, DBS must yield high-quality genomic DNA (gDNA) for whole genome sequencing (WGS). In this pilot study, we hypothesized that gDNA of sufficient quality and quantity for WGS could be extracted from archived DBS up to 20 years old without PCR (Polymerase Chain Reaction) amplification. We describe simple methods for gDNA extraction and WGS library preparation from several types of DBS. We tested these methods in DBS from 25 individuals who had previously undergone diagnostic, clinical WGS and 29 randomly selected DBS cards collected for NBS from the California State Biobank. While gDNA from DBS had significantly less yield than from EDTA blood from the same individuals, it was of sufficient quality and quantity for WGS without PCR. All samples DBS yielded WGS that met quality control metrics for high-confidence variant calling. Twenty-eight variants of various types that had been reported clinically in 19 samples were recapitulated in WGS from DBS. There were no significant effects of age or paper type on WGS quality. Archived DBS appear to be a suitable sample type for WGS in population genomic studies. PMID:36788231 DOI:10.1038/s41525-023-00349-w

JAMA Netw Open. 2023 Feb 1;6(2):e2254069. doi: 10.1001/jamanetworkopen.2022.54069. ABSTRACT IMPORTANCE: Understanding the causes of infant mortality shapes public health, surveillance, and research investments. However, the association of single-locus (mendelian) genetic diseases with infant mortality is poorly understood. OBJECTIVE: To determine the association of genetic diseases with infant mortality. DESIGN, SETTING, AND PARTICIPANTS: This cohort study was conducted at a large pediatric hospital system in San Diego County (California) and included 546 infants (112 infant deaths [20.5%] and 434 infants [79.5%] with acute illness who survived; age, 0 to 1 year) who underwent diagnostic whole-genome sequencing (WGS) between January 2015 and December 2020. Data analysis was conducted between 2015 and 2022. EXPOSURE: Infants underwent WGS either premortem or postmortem with semiautomated phenotyping and diagnostic interpretation. MAIN OUTCOMES AND MEASURES: Proportion of infant deaths associated with single-locus genetic diseases. RESULTS: Among 112 infant deaths (54 girls [48.2%]; 8 [7.1%] African American or Black, 1 [0.9%] American Indian or Alaska Native, 8 [7.1%] Asian, 48 [42.9%] Hispanic, 1 [0.9%] Native Hawaiian or Pacific Islander, and 34 [30.4%] White infants) in San Diego County between 2015 and 2020, single-locus genetic diseases were the most common identifiable cause of infant mortality, with 47 genetic diseases identified in 46 infants (41%). Thirty-nine (83%) of these diseases had been previously reported to be associated with childhood mortality. Twenty-eight death certificates (62%) for 45 of the 46 infants did not mention a genetic etiology. Treatments that can improve outcomes were available for 14 (30%) of the genetic diseases. In 5 of 7 infants in whom genetic diseases were identified postmortem, death might have been avoided had rapid, diagnostic WGS been performed at time of symptom onset or regional intensive care unit admission. CONCLUSIONS AND RELEVANCE: In this cohort study of 112 infant deaths, the association of genetic diseases with infant mortality was higher than previously recognized. Strategies to increase neonatal diagnosis of genetic diseases and immediately implement treatment may decrease infant mortality. Additional study is required to explore the generalizability of these findings and measure reduction in infant mortality. PMID:36757698 DOI:10.1001/jamanetworkopen.2022.54069