The cytotoxicity of DNA-protein crosslinks (DPCs) is largely ascribed to their ability to block the progression of DNA replication. DPCs frequently occur in cells, either as a consequence of ...metabolism or exogenous agents, but the mechanism of DPC repair is not completely understood. Here, we characterize SPRTN as a specialized DNA-dependent and DNA replication-coupled metalloprotease for DPC repair. SPRTN cleaves various DNA binding substrates during S-phase progression and thus protects proliferative cells from DPC toxicity. Ruijs-Aalfs syndrome (RJALS) patient cells with monogenic and biallelic mutations in SPRTN are hypersensitive to DPC-inducing agents due to a defect in DNA replication fork progression and the inability to eliminate DPCs. We propose that SPRTN protease represents a specialized DNA replication-coupled DPC repair pathway essential for DNA replication progression and genome stability. Defective SPRTN-dependent clearance of DPCs is the molecular mechanism underlying RJALS, and DPCs are contributing to accelerated aging and cancer.
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•DNA-protein crosslinks (DPCs) stall DNA replication and induce genomic instability•SPARTAN (SPRTN) is a DNA replication-coupled metalloprotease which proteolyses DPCs•SPRTN metalloprotease is a fundamental enzyme in DPC repair pathway•Ruijs-Aalfs syndrome is caused by a defect in DPC repair due to mutations in SPRTN
Monogenic mutations in SPRTN cause genomic instability, premature aging, and hepatocellular carcinoma. The molecular mechanism of how SPRTN protects genome stability and prevents accelerated aging and cancer is not clear. Vaz, Popovic, et al. show that SPRTN is a DNA replication-coupled metalloprotease for DNA-protein crosslink repair in proliferative human cells.
As the use of genomic sequencing (GS) in the prenatal setting becomes more widespread, laboratories and clinicians will be tasked with making decisions about whether to offer incidental and secondary ...findings to expectant parents and, if so, which ones. Unfortunately, few guidelines or position statements issued by professional bodies address the return of secondary findings specifically in the context of prenatal GS, nor do they offer clear guidance on whether, and which types of incidental findings should be reported. Laboratories and clinicians will also need to navigate other challenges, such as how to obtain sufficiently informed consent, workload burdens for both laboratories and clinicians, and funding. Here we discuss these, and other challenges associated with offering incidental and secondary findings in the context of prenatal GS. We outline existing guidelines for return of these findings, prenatally and in children. We review the existing literature on stakeholder perspectives on return of incidental and secondary findings and discuss the main practical and ethical challenges that require consideration. We then propose a framework to help guide decision‐making, suggesting a baseline routine analysis, with additional layers of analysis that could be offered, according to local laboratory policy, with additional opt‐in consent from the parents.
Key points
What's already known about this topic?
The use of genomic sequencing (GS) in the prenatal setting is becoming more widespread.
Few guidelines or position statements from professional bodies address returning secondary findings in the context of prenatal GS.
What does this review add?
We summarize existing guidelines and literature on the topic.
We discuss practical and ethical challenges that require consideration.
We propose a framework to guide decision‐making, suggesting baseline routine analysis, with additional layers of analysis that could be offered, with opt‐in parental consent.
Bloom syndrome is a recessive human genetic disorder with features of genome instability, growth deficiency and predisposition to cancer. The only known causative gene is the BLM helicase that is a ...member of a protein complex along with topoisomerase III alpha, RMI1 and 2, which maintains replication fork stability and dissolves double Holliday junctions to prevent genome instability. Here we report the identification of a second gene, RMI2, that is deleted in affected siblings with Bloom-like features. Cells from homozygous individuals exhibit elevated rates of sister chromatid exchange, anaphase DNA bridges and micronuclei. Similar genome and chromosome instability phenotypes are observed in independently derived RMI2 knockout cells. In both patient and knockout cell lines reduced localisation of BLM to ultra fine DNA bridges and FANCD2 at foci linking bridges are observed. Overall, loss of RMI2 produces a partially active BLM complex with mild features of Bloom syndrome.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Genomic technologies such as next-generation sequencing (NGS) are revolutionizing molecular diagnostics and clinical medicine. However, these approaches have proven inefficient at identifying ...pathogenic repeat expansions. Here, we apply a collection of bioinformatics tools that can be utilized to identify either known or novel expanded repeat sequences in NGS data. We performed genetic studies of a cohort of 35 individuals from 22 families with a clinical diagnosis of cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS). Analysis of whole-genome sequence (WGS) data with five independent algorithms identified a recessively inherited intronic repeat expansion (AAGGG)exp in the gene encoding Replication Factor C1 (RFC1). This motif, not reported in the reference sequence, localized to an Alu element and replaced the reference (AAAAG)11 short tandem repeat. Genetic analyses confirmed the pathogenic expansion in 18 of 22 CANVAS-affected families and identified a core ancestral haplotype, estimated to have arisen in Europe more than twenty-five thousand years ago. WGS of the four RFC1-negative CANVAS-affected families identified plausible variants in three, with genomic re-diagnosis of SCA3, spastic ataxia of the Charlevoix-Saguenay type, and SCA45. This study identified the genetic basis of CANVAS and demonstrated that these improved bioinformatics tools increase the diagnostic utility of WGS to determine the genetic basis of a heterogeneous group of clinically overlapping neurogenetic disorders.
More than 7 million individuals have been conceived by Assisted Reproductive Technologies (ART) and there is clear evidence that ART is associated with a range of adverse early life outcomes, ...including rare imprinting disorders. The periconception period and early embryogenesis are associated with widespread epigenetic remodeling, which can be influenced by ART, with effects on the developmental trajectory in utero, and potentially on health throughout life. Here we profile genome-wide DNA methylation in blood collected in the newborn period and in adulthood (age 22-35 years) from a unique longitudinal cohort of ART-conceived individuals, previously shown to have no differences in health outcomes in early adulthood compared with non-ART-conceived individuals. We show evidence for specific ART-associated variation in methylation around birth, most of which occurred independently of embryo culturing. Importantly, ART-associated epigenetic variation at birth largely resolves by adulthood with no direct evidence that it impacts on development and health.
The search for causation is a key component of the assessment of the child with intellectual disability. Historically, a specific diagnosis has been achievable in only a small minority of these ...children, but over the last decade, this has changed dramatically such that a specific diagnosis is now possible in about half of all children with intellectual disability. This improvement has been driven by major advances in genetic‐testing technologies, the most important of which are chromosome microarray and whole exome sequencing. Simultaneously, these technological advances have revealed many new genetic syndromes that had previously escaped clinical recognition, and demonstrated that the majority of severe intellectual disability is caused by pathogenic gene variants that arise de novo in the child. Although access to genomic testing is currently limited, evidence from health economic studies suggests that this testing is most cost effective when performed early in the patient's diagnostic journey.
Aim
To investigate parents' preferences and motivations for receiving and discussing prognostic genetic test results.
Method
We used a cross‐sectional, interpretive description qualitative study ...design. We collected data through semi‐structured interviews with Australian parents, which we analysed using reflexive thematic analysis.
Results
Parents (n = 32) had a child or children with a genetic neurodevelopmental condition, such as fragile X syndrome, DiGeorge (22q11.2 deletion) syndrome, or Angelman syndrome. Parents of mildly impacted or older children were tolerant to prognostic uncertainty. Parents found conversations about their child's prognosis emotional and preferred to discuss their child's potential strengths and challenges. While most were enthusiastic about prognostic tests and described many motivations for testing, the potential for prognostic information to contribute to a loss of hope and stigmatizing societal views were also discussed.
Interpretation
Parents had mixed preferences and motivations for acquiring prognostic genetic information about their child, contrasting evidence in other contexts such as cancer where parents typically have minimal tolerance of uncertainty. Health professionals should consider strength‐based framing of prognostic information gained from current and emerging technologies when returning results to families.
What this paper adds
Parents had varied views about receiving prognostic information on their children's neurodevelopmental condition.
Some parents preferred prognostic uncertainty about their children's genetic neurodevelopmental condition.
What this paper adds
Parents had varied views about receiving prognostic information on their children's neurodevelopmental condition.
Some parents preferred prognostic uncertainty about their children's genetic neurodevelopmental condition.
This original article is commented on by Tyynismaa on pages 828–829 of this issue.
This study aimed to evaluate the association between human chorionic gonadotropin and adverse pregnancy outcomes.
Medline, Embase, PubMed, and Cochrane were searched in November 2021 using Medical ...Subject Headings (MeSH) and relevant key words.
This analysis included published full-text studies of pregnant women with serum human chorionic gonadotropin testing between 8 and 28 weeks of gestation, investigating fetal outcomes (fetal death in utero, small for gestational age, preterm birth) or maternal factors (hypertension in pregnancy: preeclampsia, pregnancy-induced hypertension, placental abruption, HELLP syndrome, gestational diabetes mellitus).
Studies were extracted using REDCap software. The Newcastle–Ottawa scale was used to assess for risk of bias. Final meta-analyses underwent further quality assessment using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) method.
A total of 185 studies were included in the final review, including the outcomes of fetal death in utero (45), small for gestational age (79), preterm delivery (62), hypertension in pregnancy (107), gestational diabetes mellitus (29), placental abruption (17), and HELLP syndrome (2). Data were analyzed separately on the basis of categorical measurement of human chorionic gonadotropin and human chorionic gonadotropin measured on a continuous scale. Eligible studies underwent meta-analysis to generate a pooled odds ratio (categorical human chorionic gonadotropin level) or difference in medians (human chorionic gonadotropin continuous scale) between outcome groups. First-trimester low human chorionic gonadotropin levels were associated with preeclampsia and fetal death in utero, whereas high human chorionic gonadotropin levels were associated with preeclampsia. Second-trimester high human chorionic gonadotropin levels were associated with fetal death in utero and preeclampsia.
Human chorionic gonadotropin levels are associated with placenta-mediated adverse pregnancy outcomes. Both high and low human chorionic gonadotropin levels in the first trimester of pregnancy can be early warning signs of adverse outcomes. Further analysis of human chorionic gonadotropin subtypes and pregnancy outcomes is required to determine the diagnostic utility of these findings in reference to specific cutoff values.
An association between assisted reproduction technologies (ART) and abnormal genomic imprinting in humans has been recognized for several years; however, the magnitude of this risk and the spectrum ...of imprinting syndromes to which the risk applies remains unknown. Nine human imprinting syndromes have been identified but current evidence links ART with only three: Beckwith–Wiedemann syndrome, Angelman syndrome and the newly described maternal hypomethylation syndrome. There is currently a lack of evidence linking ART with the remaining six imprinting syndromes: Prader–Willi syndrome, Russell–Silver syndrome, maternal and paternal uniparental disomy of chromosome 14, pseudohypoparathyroidism type 1b and transient neonatal diabetes. Evidence from clinical reports suggests that the association between imprinting syndromes and ART may be restricted to syndromes where the imprinting change takes the form of hypomethylation on the maternal allele. In contrast, studies of gametes and early embryos suggest that ART can be associated with hypermethylation as well as hypomethylation, with imprinting changes occurring on paternal as well as maternal alleles. The health effects of ART-associated imprinting changes may also extend beyond the nine recognized imprinting syndromes.
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