The fundamental need for unifying phenotypes in sudden unexpected pediatric deaths

A definitive, authoritative approach to evaluate the causes of unexpected, and ultimately unexplained, pediatric deaths remains elusive, relegating final conclusions to diagnoses of exclusion in the vast majority of cases. Research into unexplained pediatric deaths has focused primarily on sudden infant deaths (under 1 year of age) and led to the identification of several potential, albeit incompletely understood, contributory factors: nonspecific pathology findings, associations with sleep position and environment that may not be uniformly relevant, and the elucidation of a role for serotonin that is practically difficult to estimate in any individual case. Any assessment of progress in this field must also acknowledge the failure of current approaches to substantially decrease mortality rates in decades. Furthermore, potential commonalities with pediatric deaths across a broader age spectrum have not been widely considered. Recent epilepsy-related observations and genetic findings, identified post-mortem in both infants and children who died suddenly and unexpectedly, suggest a role for more intense and specific phenotyping efforts as well as an expanded role for genetic and genomic evaluation. We therefore present a new approach to reframe the phenotype in sudden unexplained deaths in the pediatric age range, collapsing many distinctions based on arbitrary factors (such as age) that have previously guided research in this area, and discuss its implications for the future of postmortem investigation

A 19-year-old at 37 weeks gestation with an acute acetylsalicylic acid overdose

Acute salicylate overdose in pregnancy is potentially fatal for both the mother and fetus and presents a unique challenge in intensive care management. While suggested thresholds exist for hemodialysis in adults with toxic salicylate ingestion, it is unclear if these thresholds remain appropriate for the gravid patient, particularly given that medications such as acetylsalicylic acid may cross the placental barrier and accumulate in the fetal bloodstream. We describe a case of a gravid patient at ∼37 weeks gestational age with a self-reported acetylsalicylic acid ingestion of 32.5 g and review prior cases of both acute and chronic salicylate ingestion in pregnancy in order to determine the clinical precedent for hemodialysis in this situation

AXIN2-related oligodontia-colorectal cancer syndrome with cleft palate as a possible new feature

Background: Pathogenic variants in AXIN2 have been associated with tooth agenesis, colon polyps, and colon cancer. Given the rare nature of this phenotype, we set out to collect additional genotypic and phenotypic information. Methods: Data were collected via a structured questionnaire. Sequencing was performed in these patients mostly due to diagnostic purpose. A little more than half of the AXIN2 variant carriers were identified by NGS; other six were family members. Results: Here, we report 13 individuals with a heterozygous AXIN2 pathogenic/likely pathogenic variant who have a variable expression of oligodontia-colorectal cancer syndrome (OMIM 608615) or oligodontia-cancer predisposition syndrome (ORPHA 300576). Three individuals from one family also had cleft palate, which might represent a new clinical feature of AXIN2 phenotype, also given the fact that AXIN2 polymorphisms have been found in association with oral clefting in population studies. AXIN2 has already been added to multigene cancer panel tests; further research should be conducted to determine whether it should be added to cleft lip/palate multigene panels. Conclusion: More clarity about oligodontia-colorectal cancer syndrome, about the variable expression, and associated cancer risks is needed to improve clinical management and to establish guidelines for surveillance. We collected information about the surveillance that was advised, which might support clinical management of these patients.</p

Multicenter Consensus Approach to Evaluation of Neonatal Hypotonia in the Genomic Era: A Review

IMPORTANCE: Infants with hypotonia can present with a variety of potentially severe clinical signs and symptoms and often require invasive testing and multiple procedures. The wide range of clinical presentations and potential etiologies leaves diagnosis and prognosis uncertain, underscoring the need for rapid elucidation of the underlying genetic cause of disease. OBSERVATIONS: The clinical application of exome sequencing or genome sequencing has dramatically improved the timely yield of diagnostic testing for neonatal hypotonia, with diagnostic rates of greater than 50% in academic neonatal intensive care units (NICUs) across Australia, Canada, the UK, and the US, which compose the International Precision Child Health Partnership (IPCHiP). A total of 74% (17 of 23) of patients had a change in clinical care in response to genetic diagnosis, including 2 patients who received targeted therapy. This narrative review discusses the common causes of neonatal hypotonia, the relative benefits and limitations of available testing modalities used in NICUs, and hypotonia management recommendations. CONCLUSIONS AND RELEVANCE: This narrative review summarizes the causes of neonatal hypotonia and the benefits of prompt genetic diagnosis, including improved prognostication and identification of targeted treatments which can improve the short-term and long-term outcomes. Institutional resources can vary among different NICUs; as a result, consideration should be given to rule out a small number of relatively unique conditions for which rapid targeted genetic testing is available. Nevertheless, the consensus recommendation is to use rapid genome or exome sequencing as a first-line testing option for NICU patients with unexplained hypotonia. As part of the IPCHiP, this diagnostic experience will be collected in a central database with the goal of advancing knowledge of neonatal hypotonia and improving evidence-based practice

Genome sequencing identifies a homozygous inversion disrupting QDPR as a cause for dihydropteridine reductase deficiency

Background: Dihydropteridine reductase (DHPR) is one of the key enzymes for maintaining in the organism the supply of tetrahydrobiopterin (BH4 ), an essential cofactor for aromatic amino acid hydroxylases. Its dysfunction causes the condition of hyperphenylalaninemia together with the lack of neurotransmitters. Methods: We report a patient with biochemically diagnosed DHPR deficiency, with extensive molecular investigations undertaken to detect variations in quinoid dihydropteridine reductase (QDPR) gene. Sanger sequencing of QDPR coding regions, exome sequencing, QDPR mRNA PCR, and karyotyping were followed by trio genome sequencing. Results: Short-read genome sequencing revealed a homozygous 9-Mb inversion disrupting QDPR. Structural variant breakpoints in chromosome 4 were located to intron 2 of QDPR at Chr4(GRCh38):g.17505522 and in intron 8 of the ACOX3 gene, Chr4(GRCh38):g.8398067). Both nonrelated parents carried the variant in heterozygous state. The inversion was not present in gnomAD structural variant database. Conclusion: Identification of the exact breakpoints now allows further straightforward molecular genetic testing of potential carriers of the inversion. This study extends the pathogenic variant spectrum of DHPR deficiency and highlights the role of structural variants in recessive metabolic disorders. To our knowledge, this is the first report on a large, canonical (rather than complex) homozygous pathogenic inversion detected by genome sequencing. Keywords: QDPR gene; dihydropteridine reductase deficiency; genome sequencing; inversion; tetrahydrobiopterin deficiencies

Distinct effects on mRNA export factor GANP underlie neurological disease phenotypes and alter gene expression depending on intron content

Defects in the mRNA export scaffold protein GANP, encoded by the MCM3AP gene, cause autosomal recessive early-onset peripheral neuropathy with or without intellectual disability. We extend here the phenotypic range associated with MCM3AP variants, by describing a severely hypotonic child and a sibling pair with a progressive encephalopathic syndrome. In addition, our analysis of skin fibroblasts from affected individuals from seven unrelated families indicates that disease variants result in depletion of GANP except when they alter critical residues in the Sac3 mRNA binding domain. GANP depletion was associated with more severe phenotypes compared with the Sac3 variants. Patient fibroblasts showed transcriptome alterations that suggested intron content-dependent regulation of gene expression. For example, all differentially expressed intronless genes were downregulated, including ATXN7L3B, which couples mRNA export to transcription activation by association with the TREX-2 and SAGA complexes. Our results provide insight into the molecular basis behind genotype-phenotype correlations in MCM3AP-associated disease and suggest mechanisms by which GANP defects might alter RNA metabolism.Peer reviewe

Beyond the Exome: What’s Next in Diagnostic Testing for Mendelian Conditions

Despite advances in clinical genetic testing, including the introduction of exome sequencing (ES), more than 50% of individuals with a suspected Mendelian condition lack a precise molecular diagnosis. Clinical evaluation is increasingly undertaken by specialists outside of clinical genetics, often occurring in a tiered fashion and typically ending after ES. The current diagnostic rate reflects multiple factors, including technical limitations, incomplete understanding of variant pathogenicity, missing genotype-phenotype associations, complex gene-environment interactions, and reporting differences between clinical labs. Maintaining a clear understanding of the rapidly evolving landscape of diagnostic tests beyond ES, and their limitations, presents a challenge for non-genetics professionals. Newer tests, such as short-read genome or RNA sequencing, can be challenging to order, and emerging technologies, such as optical genome mapping and long-read DNA sequencing, are not available clinically. Furthermore, there is no clear guidance on the next best steps after inconclusive evaluation. Here, we review why a clinical genetic evaluation may be negative, discuss questions to be asked in this setting, and provide a framework for further investigation, including the advantages and disadvantages of new approaches that are nascent in the clinical sphere. We present a guide for the next best steps after inconclusive molecular testing based upon phenotype and prior evaluation, including when to consider referral to research consortia focused on elucidating the underlying cause of rare unsolved genetic disorders

Implementation of rapid genomic sequencing in safety-net neonatal intensive care units: protocol for the VIrtual GenOme CenteR (VIGOR) proof-of-concept study.

INTRODUCTION: Rapid genomic sequencing (rGS) in critically ill infants with suspected genetic disorders has high diagnostic and clinical utility. However, rGS has primarily been available at large referral centres with the resources and expertise to offer state-of-the-art genomic care. Critically ill infants from racial and ethnic minority and/or low-income populations disproportionately receive care in safety-net and/or community settings lacking access to state-of-the-art genomic care, contributing to unacceptable health equity gaps. VIrtual GenOme CenteR is a \u27proof-of-concept\u27 implementation science study of an innovative delivery model for genomic care in safety-net neonatal intensive care units (NICUs). METHODS AND ANALYSIS: We developed a virtual genome centre at a referral centre to remotely support safety-net NICU sites predominantly serving racial and ethnic minority and/or low-income populations and have limited to no access to rGS. Neonatal providers at each site receive basic education about genomic medicine from the study team and identify eligible infants. The study team enrols eligible infants (goal n of 250) and their parents and follows families for 12 months. Enrolled infants receive rGS, the study team creates clinical interpretive reports to guide neonatal providers on interpreting results, and neonatal providers return results to families. Data is collected via (1) medical record abstraction, (2) surveys, interviews and focus groups with neonatal providers and (3) surveys and interviews with families. We aim to examine comprehensive implementation outcomes based on the Proctor Implementation Framework using a mixed methods approach. ETHICS AND DISSEMINATION: This study is approved by the institutional review board of Boston Children\u27s Hospital (IRB-P00040496) and participating sites. Participating families are required to provide electronic written informed consent and neonatal provider consent is implied through the completion of surveys. The results will be disseminated via peer-reviewed publications and data will be made accessible per National Institutes of Health (NIH) policies. TRIAL REGISTRATION NUMBER: NCT05205356/clinicaltrials.gov