Osteopoikilosis and multiple exostoses caused by novel mutations in LEMD3 and EXT1 genes respectively - coincidence within one family

<p>Abstract</p> <p>Background</p> <p>Osteopoikilosis is a rare autosomal dominant genetic disorder, characterised by the occurrence of the hyperostotic spots preferentially localized in the epiphyses and metaphyses of the long bones, and in the carpal and tarsal bones <abbrgrp><abbr bid="B1">1</abbr></abbrgrp>. Heterozygous <it>LEMD3 </it>gene mutations were shown to be the primary cause of the disease <abbrgrp><abbr bid="B2">2</abbr></abbrgrp>. Association of the primarily asymptomatic osteopokilosis with connective tissue nevi of the skin is categorized as Buschke-Ollendorff syndrome (BOS) <abbrgrp><abbr bid="B3">3</abbr></abbrgrp>. Additionally, osteopoikilosis can coincide with melorheostosis (MRO), a more severe bone disease characterised by the ectopic bone formation on the periosteal and endosteal surface of the long bones <abbrgrp><abbr bid="B4">4</abbr><abbr bid="B5">5</abbr><abbr bid="B6">6</abbr></abbrgrp>. However, not all MRO affected individuals carry germ-line <it>LEMD3 </it>mutations <abbrgrp><abbr bid="B7">7</abbr></abbrgrp>. Thus, the genetic cause of MRO remains unknown. Here we describe a familial case of osteopoikilosis in which a novel heterozygous <it>LEMD3 </it>mutation coincides with a novel mutation in <it>EXT1</it>, a gene involved in aetiology of multiple exostosis syndrome. The patients affected with both <it>LEMD3 </it>and <it>EXT1 </it>gene mutations displayed typical features of the osteopoikilosis. There were no additional skeletal manifestations detected however, various non-skeletal pathologies coincided in this group.</p> <p>Methods</p> <p>We investigated <it>LEMD3 </it>and <it>EXT1 </it>in the three-generation family from Poland, with 5 patients affected with osteopoikilosis and one child affected with multiple exostoses.</p> <p>Results</p> <p>We found a novel c.2203C > T (p.R735X) mutation in exon 9 of <it>LEMD3</it>, resulting in a premature stop codon at amino acid position 735. The mutation co-segregates with the osteopoikilosis phenotype and was not found in 200 ethnically matched controls. Another new substitution G > A was found in <it>EXT1 </it>gene at position 1732 (cDNA) in Exon 9 (p.A578T) in three out of five osteopoikilosis affected family members. Evolutionary conservation of the affected amino acid suggested possible functional relevance, however no additional skeletal manifestations were observed other then those specific for osteopoikilosis. Finally in one member of the family we found a splice site mutation in the <it>EXT1 </it>gene intron 5 (IVS5-2 A > G) resulting in the deletion of 9 bp of cDNA encoding three evolutionarily conserved amino acid residues. This child patient suffered from a severe form of exostoses, thus a causal relationship can be postulated.</p> <p>Conclusions</p> <p>We identified a new mutation in <it>LEMD3 </it>gene, accounting for the familial case of osteopoikilosis. In the same family we identified two novel <it>EXT1 </it>gene mutations. One of them A598T co-incided with the <it>LEMD3 </it>mutation. Co-incidence of <it>LEMD3 </it>and <it>EXT1 </it>gene mutations was not associated with a more severe skeletal phenotype in those patients.</p

NuRD suppresses pluripotency gene expression to promote transcriptional heterogeneity and lineage commitment

Transcriptional heterogeneity within embryonic stem cell (ESC) populations has been suggested as a mechanism by which a seemingly homogeneous cell population can initiate differentiation into an array of different cell types. Chromatin remodeling proteins have been shown to control transcriptional variability in yeast and to be important for mammalian ESC lineage commitment. Here we show that the Nucleosome Remodeling and Deacetylation (NuRD) complex, which is required for ESC lineage commitment, modulates both transcriptional heterogeneity and the dynamic range of a set of pluripotency genes in ESCs. In self-renewing conditions, the influence of NuRD at these genes is balanced by the opposing action of self-renewal factors. Upon loss of self-renewal factors, the action of NuRD is sufficient to silence transcription of these pluripotency genes, allowing cells to exit self-renewal. We propose that modulation of transcription levels by NuRD is key to maintaining the differentiation responsiveness of pluripotent cells

COVID-19 and children with congenital anomalies:a European survey of parents' experiences of healthcare services

Objective: To survey parents and carers of children with a congenital anomaly across Europe about their experiences of healthcare services and support during the COVID-19 pandemic. Design: Cross-sectional study. Setting: Online survey in 10 European countries, open from 8 March 2021 to 14 July 2021. Population: 1070 parents and carers of children aged 0-10 years with a cleft lip, spina bifida, congenital heart defect (CHD) requiring surgery and/or Down syndrome. Main outcome measures: Parental views about: the provision of care for their child (cancellation/postponement of appointments, virtual appointments, access to medication), the impact of disruptions to healthcare on their child's health and well-being, and satisfaction with support from medical sources, organisations and close relationships. Results: Disruptions to healthcare appointments were significantly higher (p<0.001) in the UK and Poland, with approximately two-thirds of participants reporting â € cancelled or postponed' tests (67/101; 256/389) and procedures compared with approximately 20% in Germany (13/74) and Belgium/Netherlands (11/55). A third of participants in the UK and Poland reported â € cancelled or postponed' surgeries (22/72; 98/266) compared with only 8% in Germany (5/64). In Poland, 43% (136/314) of parents reported that changes to their child's ongoing treatment had moderately to severely affected their child's health, significantly higher than all other countries (p<0.001). Satisfaction ratings for support from general practitioners were lowest in the UK and Poland, and lowest in Poland and Italy for specialist doctors and nurses. Conclusion: A large proportion of participants reported disruptions to healthcare during the pandemic, which for some had a significant impact on their child's health. Regional differences in disruptions raise questions about the competence of certain healthcare systems to meet the needs of this vulnerable group of patients and indicate improvements should be strived for in some regions

Isolated brachydactyly type E caused by a HOXD13 nonsense mutation: a case report

<p>Abstract</p> <p>Background</p> <p>Brachydactyly type E (BDE; MIM#113300) is characterized by shortening of the metacarpal, metatarsal, and often phalangeal bones, and predominantly affects postaxial ray(s) of the limb. BDE may occur as an isolated trait or as part of a syndrome. Isolated BDE is rare and in the majority of cases the molecular pathogenesis has so far not been resolved. Originally, the molecular cause of isolated BDE has been unravelled in 2 families and shown to result from heterozygous missense mutations in the homeodomain of the <it>HOXD13 </it>gene. Since the initial manuscript, one further <it>HOXD13 </it>mutation has been reported only in a single family manifesting isolated BDE.</p> <p>Case Presentation</p> <p>In this paper, we report on a Polish family exhibiting isolated BDE caused by a novel nonsense heterozygous <it>HOXD13 </it>mutation. We investigated a Polish female proband and her father, both affected by isolated BDE, in whom we identified a nonsense heterozygous mutation c.820C > T(p.R274X) in the <it>HOXD13 </it>gene. So far, only two missense <it>HOXD13 </it>substitutions (p.S308C and p.I314L), localized within the homeodomain of the HOXD13 transcription factor, as well as a single nonsense mutation (p.E181X) were associated with BDE. Both missense changes were supposed to alter DNA binding affinity of the protein.</p> <p>Conclusion</p> <p>The variant p.R274X identified in our proband is the fourth <it>HOXD13 </it>mutation, and the second truncating (nonsense) mutation, reported to result in typical isolated BDE. We refer our clinical and molecular findings to the previously described <it>HOXD13 </it>associated phenotypes and mutations.</p

Accuracy of congenital anomaly coding in live birth children recorded in European health care databases, a EUROlinkCAT study

Electronic health care databases are increasingly being used to investigate the epidemiology of congenital anomalies (CAs) although there are concerns about their accuracy. The EUROlinkCAT project linked data from eleven EUROCAT registries to electronic hospital databases. The coding of CAs in electronic hospital databases was compared to the (gold standard) codes in the EUROCAT registries. For birth years 2010–2014 all linked live birth CA cases and all children identified in the hospital databases with a CA code were analysed. Registries calculated sensitivity and Positive Predictive Value (PPV) for 17 selected CAs. Pooled estimates for sensitivity and PPV were then calculated for each anomaly using random effects meta-analyses. Most registries linked more than 85% of their cases to hospital data. Gastroschisis, cleft lip with or without cleft palate and Down syndrome were recorded in hospital databases with high accuracy (sensitivity and PPV ≥ 85%). Hypoplastic left heart syndrome, spina bifida, Hirschsprung’s disease, omphalocele and cleft palate showed high sensitivity (≥ 85%), but low or heterogeneous PPV, indicating that hospital data was complete but may contain false positives. The remaining anomaly subgroups in our study, showed low or heterogeneous sensitivity and PPV, indicating that the information in the hospital database was incomplete and of variable validity. Electronic health care databases cannot replace CA registries, although they can be used as an additional ascertainment source for CA registries. CA registries are still the most appropriate data source to study the epidemiology of CAs

Modulation of gene-specific epigenetic states and transcription by non-coding RNAs

Emerging evidence points to a role for long non-coding RNAs in the modulation of epigenetic states and transcription in human cells. New insights, using various forms of small non-coding RNAs, suggest that a mechanism of action is operative in human cells, which utilizes non-coding RNAs to direct epigenetic marks to homology containing loci resulting ultimately in the epigenetic-based modulation of gene transcription. Importantly, insights into this mechanism of action have allowed for certain target sequences, which are either actively involved in RNA mediated epigenetic regulation or targets for non-coding RNA based epigenetic regulation, to be selected. As such, it is now feasible to utilize small antisense RNAs to either epigenetically silence a gene expression or remove epigenetic silencing of endogenous non-coding RNAs and essentially turn on a gene expression. Knowledge of this emerging RNA-based epigenetic regulatory network and our ability to cognitively control gene expression has deep implications in the development of an entirely new area of pharmacopeia

The role of tropical waves in the genesis of Tropical Cyclone Seroja in the Maritime Continent

Tropical cyclone Seroja was one of the first tropical cyclones to significantly impact Indonesian land, and the strongest one in such close proximity to Timor Island. In April 2021 Seroja brought historic flooding to near-equatorial regions of Indonesia and East Timor, as well as impacting Western Australia. Here we show that the unusual near-equatorial cyclogenesis in close proximity to a land mass was due to “perfect storm” conditions associated with multiple wave interactions. Specifically, this was associated with enhanced equatorial convection on the leading edge of a Madden–Julian Oscillation (MJO) event. Within the MJO, the interaction between a convectively coupled equatorial Rossby wave and two convectively coupled Kelvin waves span up the initial vortex and accelerated cyclogenesis. On average, such favorable atmospheric conditions can occur once per year. These results indicate the potential for increased predictability of tropical cyclones over the Maritime Continent

Integration of Hi-C with short and long-read genome sequencing reveals the structure of germline rearranged genomes

Here the authors characterize structural variations (SVs) in a cohort of individuals with complex genomic rearrangements, identifying breakpoints by employing short- and long-read genome sequencing and investigate their impact on gene expression and the three-dimensional chromatin architecture. They find breakpoints are enriched in inactive regions and can result in chromatin domain fusions.Structural variants are a common cause of disease and contribute to a large extent to inter-individual variability, but their detection and interpretation remain a challenge. Here, we investigate 11 individuals with complex genomic rearrangements including germline chromothripsis by combining short- and long-read genome sequencing (GS) with Hi-C. Large-scale genomic rearrangements are identified in Hi-C interaction maps, allowing for an independent assessment of breakpoint calls derived from the GS methods, resulting in &gt;300 genomic junctions. Based on a comprehensive breakpoint detection and Hi-C, we achieve a reconstruction of whole rearranged chromosomes. Integrating information on the three-dimensional organization of chromatin, we observe that breakpoints occur more frequently than expected in lamina-associated domains (LADs) and that a majority reshuffle topologically associating domains (TADs). By applying phased RNA-seq, we observe an enrichment of genes showing allelic imbalanced expression (AIG) within 100 kb around the breakpoints. Interestingly, the AIGs hit by a breakpoint (19/22) display both up- and downregulation, thereby suggesting different mechanisms at play, such as gene disruption and rearrangements of regulatory information. However, the majority of interpretable genes located 200 kb around a breakpoint do not show significant expression changes. Thus, there is an overall robustness in the genome towards large-scale chromosome rearrangements

Mutations in DSTYK and dominant urinary tract malformations.

ABSTRACT Introduction Congenital abnormalities of the kidney of the urinary tract are the most common cause of pediatric kidney failure. These disorders are highly heterogeneous, and their etiology is poorly understood. Methods We performed genome-wide linkage analysis and whole-exome sequencing in a family with autosomal dominant congenital abnormalities of the kidney of the urinary tract (7 affected family members). We also performed sequence analysis in 311 unrelated patients, as well as histologic and functional studies. Results Linkage analysis identified five regions of the genome that were shared among all affected family members. Exome sequencing identified a single rare deleterious variant within these linkage intervals, a heterozygous splice-site mutation in dual serine/threonine and tyrosine protein kinase (DSTYK). This variant, which resulted in aberrant gene product splicing, was present in all affected family members. Additional independent DSTYK mutations, including nonsense and splice-site mutations, were detected among 7/311 unrelated patients. DSTYK is highly expressed in the maturing epithelia of all major organs, localizing to cell membranes. Knockdown in zebrafish resulted in multi-organ developmental defects, resembling loss of fibroblast growth factor (FGF) signaling. Consistent with this finding, DSTYK colocalizes with FGF receptors in the ureteric bud and metanephric mesenchyme. Finally, DSTYK knockdown in human embryonic kidney cells inhibited FGF-stimulated ERK-phosphorylation, the principal signal downstream of receptor tyrosine kinases. Conclusions We detected DSTYK mutations in 2.2% of patients with congenital abnormalities of the kidney and urinary tract whom we studied, suggesting that DSTYK is a major determinant of human urinary tract development, downstream of FGF signaling

Major Congenital Anomalies in Babies Born With Down Syndrome: A EUROCAT Population-Based Registry Study

Previous studies have shown that over 40% of babies with Down syndrome have a major cardiac anomaly and are more likely to have other major congenital anomalies. Since 2000, many countries in Europe have introduced national antenatal screening programs for Down syndrome. This study aimed to determine if the introduction of these screening programs and the subsequent termination of prenatally detected pregnancies were associated with any decline in the prevalence of additional anomalies in babies born with Down syndrome. The study sample consisted of 7,044 live births and fetal deaths with Down syndrome registered in 28 European population-based congenital anomaly registries covering seven million births during 2000-2010. Overall, 43.6% (95% CI: 42.4-44.7%) of births with Down syndrome had a cardiac anomaly and 15.0% (14.2-15.8%) had a non-cardiac anomaly. Female babies with Down syndrome were significantly more likely to have a cardiac anomaly compared to male babies (47.6% compared with 40.4%, P&#8201;<&#8201;0.001) and significantly less likely to have a non-cardiac anomaly (12.9% compared with 16.7%, P&#8201;<&#8201;0.001). The prevalence of cardiac and non-cardiac congenital anomalies in babies with Down syndrome has remained constant, suggesting that population screening for Down syndrome and subsequent terminations has not influenced the prevalence of specific congenital anomalies in these babies.