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Up to 40% of referrals from primary care to 'breast cancer family clinics' prove to be of women whose assessed risk falls below the guidelines' threshold for management in secondary or tertiary care, despite recommendations that they should be screened out at primary care level. A randomised trial, involving 87 such women referred to the Tayside Familial Breast Cancer Service compared two ways of communicating risk information, letter or personal interview. Both were found to be acceptable to referred women and to their family doctors, although the former expressed a slight preference for interview. Only four women returned to their family doctors with continuing concerns about breast cancer. Nevertheless, understanding of information provided by either route was unsatisfactory, with apparent confusion about both absolute and relative risks of breast cancer. Substantial minorities appear to believe that they are at no increased risk at all, or even below the population level of risk, while others remain convinced that their personal risk has been underestimated. Family history record forms, completed by the referred women, preferably with the assistance of relatives, are crucial to full assessment of familial risk but one quarter of women referred to the Tayside Familial Breast Cancer Service currently do not complete and return these forms ahead of their clinic appointment. Further collaboration between primary care and the Breast Cancer Family Service is required to improve provision for concerned women whose risks fall below the threshold for special surveillance and to maximise effective use of the family history record form. [ABSTRACT FROM AUTHOR]

Nager syndrome (MIM #154400) is the best-known preaxial acrofacial dysostosis, mainly characterized by craniofacial and preaxial limb anomalies. The craniofacial abnormalities mainly consist of downslanting palpebral fissures, malar hypoplasia, micrognathia, external ear anomalies, and cleft palate. The preaxial limb defects are characterized by radial and thumb hypoplasia or aplasia, duplication of thumbs and proximal radioulnar synostosis. Haploinsufficiency of SF3B4 (MIM *605593), which encodes SAP49, a component of the pre-mRNA spliceosomal complex, has recently been identified as the underlying cause of Nager syndrome. In our study, we performed exome sequencing in two and Sanger sequencing of SF3B4 in further ten previously unreported patients with the clinical diagnosis of Nager syndrome, including one familial case. We identified heterozygous SF3B4 mutations in seven out of twelve patients. Four of the seven mutations were shown to be de novo; in three individuals, DNA of both parents was not available. No familial mutations were discovered. Three mutations were nonsense, three were frameshift mutations and one T > C transition destroyed the translation start signal. In three of four SF3B4 negative families, EFTUD2 was analyzed, but no pathogenic variants were identified. Our results indicate that the SF3B4 gene is mutated in about half of the patients with the clinical diagnosis of Nager syndrome and further support genetic heterogeneity for this condition. [ABSTRACT FROM AUTHOR]

To evaluate current guidelines criteria for inclusion of women in special 'breast cancer family history' surveillance programmes, records were reviewed of women referred to Scottish breast cancer family clinics between January 1994 and December 2003 but discharged as at 'less than 'moderate' familial risk'. The Scottish Cancer Registry was then interrogated to determine subsequent age-specific incidence of breast cancer in this cohort and corresponding Scottish population figures. Among 2074 women, with an average follow-up of 4.0 years, 28 invasive breast cancers were recorded up to December 2003, where 14.4 were expected, a relative risk (RR) of 1.94. Eleven further breast cancers were recorded between January 2004 and February 2006 (ascertainment incomplete for this period). The overall RR for women in the study cohort exceeded the accepted 'cutoff' level (RR=1.7) for provision of special counselling and surveillance. The highest RR was found for the age group 45-59 years and this group also generated the majority of breast cancers. The National Institute for Clinical Excellence ('NICE') guidelines appear to be more accurate than those of the Scottish Intercollegiate Guidelines Network ('SIGN') in defining 'moderate' familial risk, and longer follow-up of this cohort could generate an evidence base for further modification of familial breast cancer services. [ABSTRACT FROM AUTHOR]

The MSSE gene predisposes to multiple invasive but self-healing skin tumours (multiple self-healing epitheliomata). MSSE was previously mapped to chromosome 9q22–q31 and a shared haplotype in affected families suggested a founder mutation. We have refined the MSSE critical region (<1 cM, <1 Mb) between the zinc-finger gene ZNF169 and the Fanconi anaemia gene FANCC. By genetic mapping we have excluded ZNF169 and FANCC as well as PTCH (PATCHED) and TGFBR1 (transforming growth factor beta receptor type-1) genes. The CDC14B cell cycle phosphatase gene also lies in the region but screening of the complete coding region revealed no mutation in MSSE patients. Somatic cell hybrids created by haploid conversion of an MSSE patient's cells enabled screening of the MSSE chromosome 9 and showed no CDC14B deletion or mutation that abrogates CDC14B mRNA expression. Thus, CDC14B is unlikely to be the MSSE gene. We also report the first molecular analysis of MSSE tumours showing loss of heterozygosity of the MSSE region, with loss of the normal allele, providing the first evidence that MSSE is a tumour suppressor gene.Oncogene (2006) 25, 806–812. doi:10.1038/sj.onc.1209092; published online 19 September 2005 [ABSTRACT FROM AUTHOR]

The OMICs cascade describes the hierarchical flow of information through biological systems. The epigenome sits at the apex of the cascade, thereby regulating the RNA and protein expression of the human genome and governs cellular identity and function. Genes that regulate the epigenome, termed epigenes, orchestrate complex biological signaling programs that drive human development. The broad expression patterns of epigenes during human development mean that pathogenic germline mutations in epigenes can lead to clinically significant multi-system malformations, developmental delay, intellectual disabilities, and stem cell dysfunction. In this review, we refer to germline developmental disorders caused by epigene mutation as "chromatinopathies". We curated the largest number of human chromatinopathies to date and our expanded approach more than doubled the number of established chromatinopathies to 179 disorders caused by 148 epigenes. Our study revealed that 20.6% (148/720) of epigenes cause at least one chromatinopathy. In this review, we highlight key examples in which OMICs approaches have been applied to chromatinopathy patient biospecimens to identify underlying disease pathogenesis. The rapidly evolving OMICs technologies that couple molecular biology with high-throughput sequencing or proteomics allow us to dissect out the causal mechanisms driving temporal-, cellular-, and tissue-specific expression. Using the full repertoire of data generated by the OMICs cascade to study chromatinopathies will provide invaluable insight into the developmental impact of these epigenes and point toward future precision targets for these rare disorders. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary fibrosis (IPF) is a fatal and devastating lung disease of unknown etiology, described as the result of multiple cycles of epithelial cell injury and fibroblast activation. Despite this impressive increase in understanding, a therapy that reverses this form of fibrosis remains elusive. In our previous study, we found that miR-29b has a therapeutic effect on pulmonary fibrosis. However, its anti-fibrotic mechanism is not yet clear. Recently, our study identified that F-Actin Binding Protein (TRIOBP) is one of the target genes of miR-29b and found that deficiency of TRIOBP increases resistance to lung fibrosis in vivo. TRIOBP knockdown inhibited the proliferation of epithelial cells and attenuated the activation of fibroblasts. In addition, deficiency of Trio Rho Guanine Nucleotide Exchange Factor (TRIO) in epithelial cells and fibroblasts decreases susceptibility to lung fibrosis. TRIOBP interacting with TRIO promoted abnormal epithelial–mesenchymal crosstalk and modulated the nucleocytoplasmic translocation of β-catenin. We concluded that the miR-29b‒TRIOBP–TRIO–β-catenin axis might be a key anti-fibrotic axis in IPF to regulate lung regeneration and fibrosis, which may provide a promising treatment strategy for lung fibrosis. [ABSTRACT FROM AUTHOR]

Arboleda-Tham Syndrome (ARTHS) is a rare genetic disorder caused by heterozygous, de novo mutations in Lysine(K) acetyltransferase 6A (KAT6A). ARTHS is clinically heterogeneous and characterized by several common features, including intellectual disability, developmental and speech delay, and hypotonia, and affects multiple organ systems. KAT6A is the enzymatic core of a histone–acetylation protein complex; however, the direct histone targets and gene regulatory effects remain unknown. In this study, we use ARTHS patient (n = 8) and control (n = 14) dermal fibroblasts and perform comprehensive profiling of the epigenome and transcriptome caused by KAT6A mutations. We identified differential chromatin accessibility within the promoter or gene body of 23% (14/60) of genes that were differentially expressed between ARTHS and controls. Within fibroblasts, we show a distinct set of genes from the posterior HOXC gene cluster (HOXC10, HOXC11, HOXC-AS3, HOXC-AS2, and HOTAIR) that are overexpressed in ARTHS and are transcription factors critical for early development body segment patterning. The genomic loci harboring HOXC genes are epigenetically regulated with increased chromatin accessibility, high levels of H3K23ac, and increased gene–body DNA methylation compared to controls, all of which are consistent with transcriptomic overexpression. Finally, we used unbiased proteomic mass spectrometry and identified two new histone post-translational modifications (PTMs) that are disrupted in ARTHS: H2A and H3K56 acetylation. Our multi-omics assays have identified novel histone and gene regulatory roles of KAT6A in a large group of ARTHS patients harboring diverse pathogenic mutations. This work provides insight into the role of KAT6A on the epigenomic regulation in somatic cell types. [ABSTRACT FROM AUTHOR]

Hand pose estimation is a challenging task in hand-object interaction scenarios due to the uncertainty caused by object occlusions. Inspired by human reasoning from a hand-object interaction video sequence, we propose a hand pose estimation model. It uses three cascaded modules to imitate human's estimation and observation process. The first module predicts an initial pose based on the visible information and the prior hand knowledge. The second module updates the hand shape memory based on the new information coming from the subsequent frames. The bone's length updating is initiated by the predicted joint's reliability. The third module refines the coarse pose according to the hand-object contact state represented by the object's Signed Distance Function field. Our model gets the mean joints estimation error of 21.3 mm, the Procrustes error of 9.9 mm, and the Trans &Scale error of 22.3 mm on HO3Dv2, and Root-Relative error of 12.3 mm on DexYCB which are superior to other state-of-the-art models. [ABSTRACT FROM AUTHOR]

Epigenetics, one mechanism by which gene expression can change without any changes to the DNA sequence, was described nearly a century ago. However, the importance of epigenetic processes to neurodevelopment and higher order neurological functions like cognition and behavior is only now being realized. A group of disorders known as the Mendelian disorders of the epigenetic machinery are caused by the altered function of epigenetic machinery proteins, which consequently affects downstream expression of many genes. These disorders almost universally have cognitive dysfunction and behavioral issues as core features. Here, we review what is known about the neurodevelopmental phenotypes of some key examples of these disorders divided into categories based on the underlying function of the affected protein. Understanding these Mendelian disorders of the epigenetic machinery can illuminate the role of epigenetic regulation in typical brain function and can lead to future therapies and better management for a host of neurodevelopmental and neuropsychological disorders. [ABSTRACT FROM AUTHOR]

The vast majority of skin cancers can be classified into two main types: melanoma and keratinocyte carcinomas. The most common keratinocyte carcinomas include basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Multiple familial syndromes have been identified that can increase the risk of developing SCC, BCC, and/or melanoma. The major syndromes include oculocutaneous albinism for SCC, basal cell nevus syndrome for BCC, familial atypical multiple mole-melanoma syndrome, and hereditary breast and ovarian cancer syndrome for melanoma. In addition, familial syndromes that can predispose individuals to all three major skin cancers include xeroderma pigmentosum and Li–Fraumeni syndrome. This review highlights the epidemiology, risk factors, pathogenesis, and etiology of the major and minor syndromes to better identify and manage these conditions. Current investigational trials in genomic medicine are making their way in revolutionizing the clinical diagnosis of these familial syndromes for earlier preventative measures and improvement of long-term prognosis in these patients. [ABSTRACT FROM AUTHOR]

Objective: To explore the effect and mechanism of the miR-339-3p/KAT6A/TRIM24 axis in nasopharyngeal carcinoma (NPC) cell growth and epithelial–mesenchymal transition (EMT) progression. Methods: CNE2 and 5-8F NPC cell lines were transfected with miR-339-3p-mimic or sh-KAT6A alone or co-transfected with miR-339-3p-mimic and oe-KAT6A. The expression levels of miR-339-3p, KAT6A, TRIM24, and EMT-related proteins were assessed, in addition to cell biological behaviors. Then, the relationship between miR-339-3p and KAT6A was predicted and validated. The correlations between miR-339-3p and KAT6A or between KAT6A and TRIM24 were analyzed by Pearson coefficient and the enrichment of H3K23ac in TRIM24 promoter region was measured by chromatin immunoprecipitation. Results: miR-339-3p was downregulated, but KAT6A and TRIM24 were highly expressed in NPC cells and tissues. Upregulated miR-339-3p or downregulated KAT6A could inhibit the growth and EMT of NPC cells. Further experiments showed that miR-339-3p regulated NPC cell growth and EMT by mediating KAT6A in a targeted fashion. KAT6A was positively correlated with TRIM24, and the enrichment of H3K23ac was much higher in NPC tissues. miR-339-3p suppressed the growth and EMT of NPC cells by the KAT6A/TRIM24 axis. In a xenograft study, miR-339-3p overexpression inhibited NPC tumor growth in vivo. Conclusion: Conclusively, miR-339-3p inhibited the growth and EMT of NPC cells via the KAT6A/TRIM24 axis. [ABSTRACT FROM AUTHOR]

Neuronal stimulation induced by the brain‐derived neurotrophic factor (BDNF) triggers gene expression, which is crucial for neuronal survival, differentiation, synaptic plasticity, memory formation, and neurocognitive health. However, its role in chromatin regulation is unclear. Here, using temporal profiling of chromatin accessibility and transcription in mouse primary cortical neurons upon either BDNF stimulation or depolarization (KCl), we identify features that define BDNF‐specific chromatin‐to‐gene expression programs. Enhancer activation is an early event in the regulatory control of BDNF‐treated neurons, where the bZIP motif‐binding Fos protein pioneered chromatin opening and cooperated with co‐regulatory transcription factors (Homeobox, EGRs, and CTCF) to induce transcription. Deleting cis‐regulatory sequences affect BDNF‐mediated Arc expression, a regulator of synaptic plasticity. BDNF‐induced accessible regions are linked to preferential exon usage by neurodevelopmental disorder‐related genes and the heritability of neuronal complex traits, which were validated in human iPSC‐derived neurons. Thus, we provide a comprehensive view of BDNF‐mediated genome regulatory features using comparative genomic approaches to dissect mammalian neuronal stimulation. Synopsis: Dynamic multi‐omic profiling and comparative genomics are used to dissect the role of BDNF on neuronal chromatin. A comprehensive description of BDNF‐specific regulatory features is provided, from transcription factor interactions to complex traits.Comparative profiling of mouse neuron stimulation with BDNF or KCl using ATAC‐, RNA‐seq, and proteomics reveals BDNF‐specific gene expression regulatory features.Early enhancer activation is a signature feature of BDNF stimulation that coordinates the transcriptional response, whereas KCl stimulation directly affects promoters with a delayed effect on transcription.BDNF‐responsive chromatin regions conserved between mouse and human display shared neuropsychiatric complex trait associations. [ABSTRACT FROM AUTHOR]

Hand pose estimation is important for many applications, but the performance is not satisfying when the hand is interacting with objects. To alleviate the influence of unknown objects, we propose a novel network which makes full use of the multimodal information of the RGB-D images. The network can use the color features and/or the depth features selectively according to the prediction result of whether the hand is severely occluded or slightly occluded. We also use a new principal feature enhancement structure with an irrelevant feature weakening strategy to make the pose estimation more accurate. The FHAD dataset is used in the experiments for the performance evaluation. For 'action-split' data group and 'subject-split' data group, the obtained mean joint error is 10.63 mm and 10.61mm, respectively. These results are better than those of the state-of-the-art methods. For 'object-split' data group, the obtained mean joint error is 17.42mm, which is on par with the best results so far. The experimental results show the effectiveness of the proposed architecture. [ABSTRACT FROM AUTHOR]

Benign hereditary chorea (BHC) is a rare genetically heterogeneous movement disorder, in which conventional neuroimaging has been reported as normal in most cases. Cystic pituitary abnormalities and features of empty sella have been described in only 7 patients with BHC to date. We present 4 patients from 2 families with a BHC phenotype, 3 of whom underwent targeted pituitary MR imaging and genetic testing. All four patients in the two families displayed a classic BHC phenotype. The targeted pituitary MR imaging demonstrated abnormal pituitary sella morphology. Genetic testing was performed in three patients, and showed mutations causing BHC in three of the patients, as well as identifying a novel nonsense mutation of the TITF1/NKX2-1 gene in one of the patients. The presence of the abnormal pituitary sella in two affected members of the same family supports the hypothesis that this sign is a distinct feature of the BHC phenotype spectrum due to mutations in the TITF1 gene. Interestingly, these abnormalities seem to develop in adult life and are progressive. They occur in at least 26% of patients affected with Brain-lung-thyroid syndrome. As a part of the management of these patients we recommend to perform follow-up MRI brain with dedicated pituitary imaging also in adult life as the abnormality can occur years after the onset of chorea. [ABSTRACT FROM AUTHOR]

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A nonverbal 3-year-old male with a complex past medical history was referred to pediatric neurosurgery for evaluation of Chiari I malformation. A full clinical evaluation suggested that the "Chiari" was a secondary change caused by craniocerebral disproportion that was the result of delayed pan-sutural craniosynostosis. Given his unknown cause of craniosynostosis, whole-exome sequencing (WES) was performed. WES revealed a de novo, somatic mosaic variant in the KAT6A gene. This report discusses importance of keeping a broad differential in the setting of referral for Chiari I malformation and presents a unique case of craniosynostosis. Additionally, it emphasizes the value of utilizing genetic testing for complex craniofacial cases with unknown causes to provide clinical answers and guide clinical management. [ABSTRACT FROM AUTHOR]

Type 1 Chiari malformation (C1M) is characterized by cerebellar tonsillar herniation of 3–5 mm or more, the frequency of which is presumably much higher than one in 1000 births, as previously believed. Its etiology remains undefined, although a genetic basis is strongly supported by C1M presence in numerous genetic syndromes associated with different genes. Whole-exome sequencing (WES) in 51 between isolated and syndromic pediatric cases and their relatives was performed after confirmation of the defect by brain magnetic resonance image (MRI). Moreover, in all the cases showing an inherited candidate variant, brain MRI was performed in both parents and not only in the carrier one to investigate whether the defect segregated with the variant. More than half of the variants were Missense and belonged to the same chromatin-remodeling genes whose protein truncation variants are associated with severe neurodevelopmental syndromes. In the remaining cases, variants have been detected in genes with a role in cranial bone sutures, microcephaly, neural tube defects, and RASopathy. This study shows that the frequency of C1M is widely underestimated, in fact many of the variants, in particular those in the chromatin-remodeling genes, were inherited from a parent with C1M, either asymptomatic or with mild symptoms. In addition, C1M is a Mendelian trait, in most cases inherited as dominant. Finally, we demonstrate that modifications of the genes that regulate chromatin architecture can cause localized anatomical alterations, with symptoms of varying degrees. [ABSTRACT FROM AUTHOR]

Purpose of Review: Since the advent of next-generation sequencing, the number of genes associated with dystonia has been growing exponentially. We provide here a comprehensive review of the latest genetic discoveries in the field of dystonia and discuss how the growing knowledge of biology underlying monogenic dystonias may influence and challenge current classification systems. Recent Findings: Pathogenic variants in genes without previously confirmed roles in human disease have been identified in subjects affected by isolated or combined dystonia (KMT2B, VPS16, HPCA, KCTD17, DNAJC12, SLC18A2) and complex dystonia (SQSTM1, IRF2BPL, YY1, VPS41). Importantly, the classical distinction between isolated and combined dystonias has become harder to sustain since many genes have been shown to determine multiple dystonic presentations (e.g., ANO3, GNAL, ADCY5, and ATP1A3). In addition, a growing number of genes initially linked to other neurological phenotypes, such as developmental delay, epilepsy, or ataxia, are now recognized to cause prominent dystonia, occasionally in an isolated fashion (e.g., GNAO1, GNB1, SCN8A, RHOBTB2, and COQ8A). Finally, emerging analyses suggest biological convergence of genes linked to different dystonic phenotypes. Summary: While our knowledge on the genetic basis of monogenic dystonias has tremendously grown, their clinical boundaries are becoming increasingly blurry. The current phenotype-based classification may not reflect the molecular structure of the disease, urging the need for new systems based on shared biological pathways among dystonia-linked genes. [ABSTRACT FROM AUTHOR]

Purpose Of Review: In this review, we summarize studies investigating genetics of gestational diabetes mellitus (GDM) and glucose metabolism in pregnancy. We describe these studies in the context of the larger body of literature on type 2 diabetes (T2D) and glycemic trait genomics.Recent Findings: We reviewed 23 genetic association studies for GDM and performed a meta-analysis, which revealed variants at eight T2D loci significantly associated with GDM after the Bonferroni correction. These studies suggest that GDM and T2D share a number of genetic risk loci. Only two unbiased genome-wide association studies (GWASs) have successfully revealed genetic associations for GDM and related glycemic traits in pregnancy. A GWAS for GDM in Korean women identified two loci (near CDKAL1 and MTNR1B) known to be associated with T2D, though the association of the MTNR1B locus with GDM appears to be stronger than that for T2D. A multi-ethnic GWAS for glycemic traits in pregnancy identified two novel loci (near HKDC1 and BACE2) which appear to be associated with post-load glucose and fasting c-peptide specifically in pregnant women. There are ongoing efforts to use this genetic information, in the form of polygenic scores, to predict risk of GDM and postpartum T2D. The body of literature examining genetic associations with GDM is limited, especially when compared to the available literature on T2D and glycemic trait genomics. Additional genetic discovery for glucose metabolism in pregnant women will require larger pregnancy cohorts and international collaborative efforts. Studies on the clinical implications of these findings are also warranted. [ABSTRACT FROM AUTHOR]

Chorea is defined by the presence of abnormal, involuntary, continuous, random movements that results from a number of autoimmune, hereditary, vascular, metabolic, drug-induced and functional (psychogenic) causes. Chorea may present at all stages of life, from newborns to elderly individuals. While Huntington disease is the main suspicion in adults presenting with chorea, once a drug-induced or parkinsonian dyskinesia have been ruled out; Huntington disease exceptionally presents with chorea in children. Sydenham chorea is considered the most common cause of acute childhood-onset chorea, but its prevalence has decreased in Western countries. However, in younger children other etiologies such as dyskinetic cerebral palsy, anti-NMDAR receptor encephalitis, other autoimmune conditions, or mutations in NKX2-1, ADCY-5, FOXG1, GNAO1, GPR88, SLC2A1, SQSTM1, ATP8A2, or SYT-1 should be considered. In this manuscript, we review the main causes, diagnosis and management of chorea in children. [ABSTRACT FROM AUTHOR]

This paper investigates use of inventories, or checklists of activities, as an emergency management tool to motivate preparedness action in individuals. It develops the inventory concept to provide the foundation for a more targeted approach to storm preparation communication and community engagement. It also examines the potential efficacy of alternatives to paper-based checklists, such as web or smartphone applications. Academic and grey literature was reviewed to collect activities for a storm inventory for emergency agencies to measure individual preparedness and for individuals to measure their preparation progress. The resulting master list was refined for application and tested for useability in a pilot study of semi-structured interviews in a storm-susceptible community in Queensland, Australia. Also, clustering items by type of preparedness activity reveal where strengths and weaknesses exist in individual preparedness. For instance, preparation for leaving and safety planning were shown to be the areas of weakest activity in the pilot sample, while preparation of the house for a storm was the strongest area. In addition, behaviour change literature shows potential for effective use of an inventory-based smartphone application in motivating preparation activity. Data collected by a storm preparedness smartphone application could show where a communication or engagement program for targeted communities should be focused. It is supported by health literature that identifies preferences of individuals to make progress on complex tasks in stages, the value of lists to achievement of goals and demonstrated increase in uptake of activities prompted by smartphone applications over web or paper-based diaries. [ABSTRACT FROM AUTHOR]

Genetic brain channelopathies result from inherited or de novo mutations of genes encoding ion channel subunits within the central nervous system. Most neurological channelopathies arise in childhood with paroxysmal or episodic symptoms, likely because of a transient impairment of homeostatic mechanisms regulating membrane excitability, and the prototypical expression of this impairment is epilepsy. Migraine, episodic ataxia and alternating hemiplegia can also occur, as well as chronic phenotypes, such as spinocerebellar ataxias, intellectual disability and autism spectrum disorder. Voltage-gated and ligand-gated channels may be involved. In most cases, a single gene may be associated with a phenotypical spectrum that shows variable expressivity. Different clinical features may arise at different ages and the adult phenotype may be remarkably modified from the syndrome onset in childhood or adolescence. Recognizing the prominent phenotypical traits of brain channelopathies is essential to perform appropriate diagnostic investigations and to provide the better care not only in the paediatric setting but also for adult patients and their caregivers. Herein, we provide an overview of genetic brain channelopathies associated with epilepsy, highlight the different molecular mechanisms and describe the different clinical characteristics which may prompt the clinician to suspect specific syndromes and to possibly establish tailored treatments. [ABSTRACT FROM AUTHOR]

In 2011, the Spanish Society of Medical Oncology (SEOM) first published a clinical guideline of venous thromboembolism (VTE) and cancer. This guideline was updated in 2014, and since then, multiple studies and clinical trials have changed the landscape of the treatment and prophylaxis of VTE in cancer patients. To incorporate the most recent evidence, including data from direct oral anticoagulants (DOACs) randomized clinical trials, SEOM presents a new update of the guideline. [ABSTRACT FROM AUTHOR]

Purpose of Review: To summarize the molecular and clinical findings of KMT2B-related dystonia (DYT-KMT2B), a newly identified genetic dystonia syndrome. Recent Findings: Since first described in 2016, 66 different KMT2B-affecting variants, encompassing a set of frameshift, nonsense, splice-site, missense, and deletion mutations, have been reported in 76 patients. Most mutations are de novo and expected to mediate epigenetic dysregulation by inducing KMT2B haploinsufficiency. DYT-KMT2B is characterized phenotypically by limb-onset childhood dystonia that tends to spread progressively, resulting in generalized dystonia with cranio-cervical involvement. Co-occuring signs such as intellectual disability are frequently observed. Sustained response to deep brain stimulation (DBS), including restoration of independent ambulation, is seen in 93% (27/29) of patients. Summary: DYT-KMT2B is emerging as a prevalent monogenic dystonia. Childhood-onset dystonia presentations should prompt a search for KMT2B mutations, preferentially via next-generation-sequencing and genomic-array technologies, to enable specific counseling and treatment. Prospective multicenter studies are desirable to establish KMT2B mutational status as a DBS outcome predictor. [ABSTRACT FROM AUTHOR]

Succinate dehydrogenase (SDH) is an enzyme complex, composed of four protein subunits, that plays a role in both the citric acid cycle and the electron transport chain. The genes for SDHA, SDHB, SDHC, and SDHD are located in the nuclear DNA, and mutations in these genes have initially been described in paragangliomas (PGL) and pheochromocytomas (PCC), which are relatively rare tumors derived from the autonomic nervous system and the adrenal medulla, respectively. Patients with SDH mutations, that are almost exclusively in the germline, are frequently affected by multiple PGL and/or PCC. In addition, other tumors have been associated with SDH mutations as well, including gastrointestinal stromal tumors, SDH-deficient renal cell carcinoma, and pituitary adenomas. Immunohistochemistry for SDHB and SDHA has been shown to be a valuable additional tool in the histopathological analysis of these tumors, and can be considered as a surrogate marker for molecular analysis. In addition, SDHB immunohistochemistry is relevant in the decision-making whether a genetic sequence variant represents a pathogenic mutation or not. In this review, we highlight the current knowledge of the physiologic and pathologic role of the SDH enzyme complex and its involvement in endocrine and non-endocrine tumors, with an emphasis on the applicability of immunohistochemistry. [ABSTRACT FROM AUTHOR]

Purpose: To provide the reader with a comprehensive but concise understanding of congenital scoliosisMethods: We have undertaken to summarize available literature on the pathophysiology, epidemiology, and management of congenital scoliosis.Results: Congenital scoliosis represents 10% of pediatric spine deformity and is a developmental error in segmentation, formation, or a combination of both leading to curvature of the spine. Treatment options are complicated by balancing growth potential with curve severity. Often associated abnormalities of cardiac, genitourinary, or intraspinal systems are concurrent and should be evaluated as part of the diagnostic work-up. Management balances the risk of progression, growth potential, lung development/function, and associated risks. Surgical treatment options involve growth-permitting systems or fusions.Conclusion: Congenital scoliosis is a complex spinal problem associated with many other anomalous findings. Treatment options are diverse but enable optimization of management and care of these children. [ABSTRACT FROM AUTHOR]

Numerous reports have demonstrated that activities of nicotinamide N-methyltransferase (NNMT) are significantly associated with type 2 diabetes (T2D), and more than 200 single nucleotide polymorphisms (SNPs) have been identified across NNMT gene to date. Although two SNPs (rs694539 and rs1941404) have been found significantly associated with a variety of noninfectious chronic diseases, the association between NNMT gene polymorphisms and T2D has not been reported yet. In this paper, 558 T2D patients and 442 healthy controls were recruited from Chinese Han population. After a case-control study on the association between the two SNPs (rs694539 and rs1941404) and T2D, we found that the rs1941404 is significantly associated with T2D and the CC carriers at this locus are T2D susceptible population. The following metabolomics study showed that the rs1941404 variation is able to affect the metabolic pathways of tryptophan, tyrosine, and arginine, which may partly explain why the rs1941404 variation is significantly associated with T2D. [ABSTRACT FROM AUTHOR]

Context: Pseudoacromegaly describes conditions with an acromegaly related physical appearance without abnormalities in the growth hormone (GH) axis. Acromegaloid facies, together with hypertrichosis, are typical manifestations of Cantú syndrome.Case description: We present a three-generation family with 5 affected members, with marked acromegaloid facies and prominent hypertrichosis, due to a novel missense variant in the ABCC9 gene. The proband, a 2-year-old girl, was referred due to marked hypertrichosis, noticed soon after birth, associated with coarsening of her facial appearance. Her endocrine assessment, including of the GH axis, was normal. The proband's father, paternal aunt, and half-sibling were referred to the Endocrine department for exclusion of acromegaly. Although the GH axis was normal in all, two subjects had clinically non-functioning pituitary macroadenomas, a feature which has not previously been associated with Cantú syndrome.Conclusions: Activating mutations in the ABCC9 and, less commonly, KCNJ8 genes—representing the two subunits of the ATP-sensitive potassium channel—have been linked with Cantú syndrome. Interestingly, minoxidil, a well-known ATP-sensitive potassium channel agonist, can cause a similar phenotype. There is no clear explanation why activating this channel would lead to acromegaloid features or hypertrichosis. This report raises awareness for this complex condition, especially for adult or pediatric endocrinologists who might see these patients referred for evaluation of acromegaloid features or hirsutism. The link between Cantú syndrome and pituitary adenomas is currently unclear. [ABSTRACT FROM AUTHOR]

Anticoagulant treatment of acute pulmonary embolism (PE) has traditionally been hospital-based. The lesser need for monitoring with the increasingly used direct acting oral anticoagulants (DOAC) in comparison to warfarin potentially facilitates outpatient treatment of PE with these drugs. This study aimed to evaluate efficacy and safety of outpatient treatment of PE with DOAC. We extracted data from the Swedish quality registry for patients on oral anticoagulation (AuriculA) for all 245 patients in the southernmost hospital region in Sweden (1.3 million inhabitants) selected for outpatient treatment with of PE with DOAC during 2013–2015. Comorbidites, risk factors, and simplified pulmonary embolism severity index were evaluated at baseline, and death, recurrent venous thromboembolism (VTE), and bleeding was recorded during 6 months of follow-up. Outpatient treatment was defined as discharge from the emergency department within 24 h. During 6 months of follow-up, one patient died during DOAC therapy, the cause of death was unrelated to VTE. No VTE recurrences occured, whereas, one patient experienced major bleeding, and five patients experienced minor bleedings. Outpatient treatment of PE with DOAC is efficient and safe in selected patients. [ABSTRACT FROM AUTHOR]

Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are the most common adult form of muscular dystrophy, characterized by autosomal dominant progressive myopathy, myotonia, and multiorgan involvement. The onset and symptoms of the myotonic dystrophies are diverse, complicating their diagnoses and limiting a comprehensive approach to their clinical care. Diagnostic delay in DM2 is due not only to the heterogeneous phenotype and the aspecific onset but also to the unfamiliarity with the disorder by most clinicians. Moreover, the DM2 diagnostic odyssey is complicated by the difficulties to develop an accurate, robust, and cost-effective method for a routine molecular assay. The aim of this review is to underline by challenging approach the diagnostic limits and pitfalls that could results in failure to recognize the presence of DM2 disease. Understanding and preventing delays in DM2 diagnosis may facilitate family planning, improve symptom management in the short term, and facilitate more specific treatment in the long term. [ABSTRACT FROM AUTHOR]

This research compares two location-based methods of evaluating public transport accessibility and applies them in Helsinki. After discussing a series of methodological aspects, the authors calculate the Structural Accessibility Layer (SAL) public transport indicator and the Public Transport and Walking Accessibility Index (PTWAI) for a grid with 8,325 zones, comparable in size to the smallest census unit. Both methods are operational for urban planners and policy makers interested in a relatively straightforward way of quantifying the accessibility of sustainable transport modes such as public transport. The results display similar accessibility patterns when moving from larger to smaller isochrones (60 to 38 min). However, the findings are inconclusive between SAL and PTWAI: SAL (38 min) displays good accessibility by public transport (more than 94 % of the population living within two-thirds of the metropolitan area has very high and high access to public transport), but PTWAI indicates that 35 % of the population, primarily households with children (43 %), experience low and very low access. The contrasting results are mainly due to the derivation of the two indicators and have considerable implications for policy making. The findings of this research imply that PTWAI is preferable to planning assessments regarding public transport, given its relatively richer content. However, for multi-mode-based accessibility categorization, SAL appears more appropriate. It is the analyst's role to understand the objective and contents of each index and choose the tool fit for their purpose. Then, a judgement should be made on the trade-off between the detail of the measures and results and the computational burden. Given the sensitivity of the models to various input parameters and assumptions, cross-validation and replication are key for ascertaining the credibility and usefulness of the models. [ABSTRACT FROM AUTHOR]

Central venous catheters (CVC), used for the management of children with hemato-oncological disorders, are burdened by a significant incidence of mechanical, infective, or thrombotic complications. These complications favor an increasing risk in prolongation of hospitalization, extra costs of care, and sometimes severe life-threatening events. No guidelines for the management of CVC-related occlusion and CVC-related thrombosis are available for children. To this aim, members of the coagulation defects working group and the supportive therapy working group of the Italian Association of Pediatric Hematology and Oncology (AIEOP) reviewed the pediatric and adult literature to propose the first recommendations for the management of CVC-related occlusion and CVC-related thrombosis in children with hemato-oncological disorders. [ABSTRACT FROM AUTHOR]

In mammals, iodothyronine deiodinase and iodotyrosine deiodinase (IYD) are known to catalyze the reductive dehalogenation. IYD is a critical enzyme in maintaining iodine homeostasis. Advances in the study of iodothyronine deiodinase have been published steadily; research on IYD has been slow on its function and regulation. We studied the expression of IYD in thyroid, liver, and kidney in conditions such as iodine deficiency and excess to determine its regulation and role in iodine recycling. Sixty 4-week-old female Wistar rats were randomly divided into two groups, with each group containing three subgroups. The rats were fed with different iodine intake for 3 months. After 3 months, all the rats were sacrificed, and the expression of IYD in thyroid, liver, and kidney of the rats were determined. We found that the expression of thyroidal IYD in 0.3-fold-iodine intake group was significantly higher as compared with the low-iodine feed control group ( p < 0.01), whereas the expression in 6-fold-iodine intake group was significantly decreased as compared with normal-iodine feed control group ( p < 0.01). However, the variation of IYD expression in thyroid was not similar to liver and kidney. In conclusion, iodine deficiency results in an increased expression of IYD in thyroid, whereas excess iodine decreases the expression of thyroidal IYD. In humans, daily iodine intake of <75 or >500 μg can affect the expression of thyroidal IYD. The safety range of iodine intake is narrow. In addition, further investigations are required to study the expression and regulation of IYD in various organs. [ABSTRACT FROM AUTHOR]

Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant neurodegenerative disorder manifested by ataxia with a variable presentation of epileptic seizures, which is caused by a large expansion of an intronic ATTCT pentanucleotide repeat in ATXN10 on 22q13.3. Herein, we report the first description of SCA10 in a Peruvian family, supporting the Amerindian origin of SCA10 and the Panamerican geographical distribution of the disease in North, Central and South America. Moreover, the presence of an interruption motif in the SCA10 expansion along with epileptic seizures in this family supports the correlation between the two, as seen in other families. Finally, this is the first SCA10 patient ever observed outside of America, specifically in Italy. Since this patient is a Peruvian immigrant of Amerindian ancestry, our case report highlights the growing need for awareness amongst clinicians of seemingly geographically restricted rare diseases. [ABSTRACT FROM AUTHOR]

Women with a genetic predisposition to breast cancer tend to develop the disease at a younger age with denser breasts making mammography screening less effective. The introduction of magnetic resonance imaging (MRI) for familial breast cancer screening programs in recent years was intended to improve outcomes in these women. We aimed to assess whether introduction of MRI surveillance improves 5- and 10-year survival of high-risk women and determine the accuracy of MRI breast cancer detection compared with mammography-only or no enhanced surveillance and compare size and pathology of cancers detected in women screened with MRI + mammography and mammography only. We used data from two prospective studies where asymptomatic women with a very high breast cancer risk were screened by either mammography alone or with MRI also compared with BRCA1/2 carriers with no intensive surveillance. 63 cancers were detected in women receiving MRI + mammography and 76 in women receiving mammography only. Sensitivity of MRI + mammography was 93 % with 63 % specificity. Fewer cancers detected on MRI were lymph node positive compared to mammography/no additional screening. There were no differences in 10-year survival between the MRI + mammography and mammography-only groups, but survival was significantly higher in the MRI-screened group (95.3 %) compared to no intensive screening (73.7 %; p = 0.002). There were no deaths among the 21 BRCA2 carriers receiving MRI. There appears to be benefit from screening with MRI, particularly in BRCA2 carriers. Extended follow-up of larger numbers of high-risk women is required to assess long-term survival. [ABSTRACT FROM AUTHOR]

Hippocampal sclerosis of aging (HS-Aging) is a high-morbidity brain disease in the elderly but risk factors are largely unknown. We report the first genome-wide association study (GWAS) with HS-Aging pathology as an endophenotype. In collaboration with the Alzheimer's Disease Genetics Consortium, data were analyzed from large autopsy cohorts: (#1) National Alzheimer's Coordinating Center (NACC); (#2) Rush University Religious Orders Study and Memory and Aging Project; (#3) Group Health Research Institute Adult Changes in Thought study; (#4) University of California at Irvine 90+ Study; and (#5) University of Kentucky Alzheimer's Disease Center. Altogether, 363 HS-Aging cases and 2,303 controls, all pathologically confirmed, provided statistical power to test for risk alleles with large effect size. A two-tier study design included GWAS from cohorts #1-3 (Stage I) to identify promising SNP candidates, followed by focused evaluation of particular SNPs in cohorts #4-5 (Stage II). Polymorphism in the ATP-binding cassette, sub-family C member 9 ( ABCC9) gene, also known as sulfonylurea receptor 2, was associated with HS-Aging pathology. In the meta-analyzed Stage I GWAS, ABCC9 polymorphisms yielded the lowest p values, and factoring in the Stage II results, the meta-analyzed risk SNP (rs704178:G) attained genome-wide statistical significance ( p = 1.4 × 10), with odds ratio (OR) of 2.13 (recessive mode of inheritance). For SNPs previously linked to hippocampal sclerosis, meta-analyses of Stage I results show OR = 1.16 for rs5848 ( GRN) and OR = 1.22 rs1990622 ( TMEM106B), with the risk alleles as previously described. Sulfonylureas, a widely prescribed drug class used to treat diabetes, also modify human ABCC9 protein function. A subsample of patients from the NACC database ( n = 624) were identified who were older than age 85 at death with known drug history. Controlling for important confounders such as diabetes itself, exposure to a sulfonylurea drug was associated with risk for HS-Aging pathology ( p = 0.03). Thus, we describe a novel and targetable dementia risk factor. [ABSTRACT FROM AUTHOR]

Epilepsy is one of the most common neurological disorders characterized by abnormal electrical activity in the central nervous system. The clinical features of this disorder are recurrent seizures, difference in age onset, type, and frequency, leading to motor, sensory, cognitive, psychic, or autonomic disturbances. Since the discovery of the first monogenic gene mutation in 1995, it is proposed that genetic factor plays an important role in the mechanism of epilepsy. Genes discovered in idiopathic epilepsies encode for ion channel or neurotransmitter receptor proteins, whereas syndromes with epilepsy as a main feature are caused by genes that are involved in functions such as cortical development, mitochondrial function, and cell metabolism. The identification of these monogenic epilepsy-causing genes provides new insight into the pathogenesis of epilepsies. Although most of the identified gene mutations present a monogenic inheritance, most of idiopathic epilepsies are complex genetic diseases exhibiting a polygenic or oligogenic inheritance. This article reviews recent genetic and molecular progresses in exploring the pathogenesis of epilepsy, with special emphasis on monogenic epilepsy-causing genes, including voltage-gated channels (Na, K, Ca, Cl, and HCN), ligand-gated channels (nicotinic acetylcholine and GABA receptors), non-ion channel genes as well as the mitochondrial DNA genes. These progresses have improved our understanding of the complex neurological disorder. [ABSTRACT FROM AUTHOR]

Genes in which germline mutations confer highly or moderately increased risks of cancer are called cancer predisposition genes. More than 100 of these genes have been identified, providing important scientific insights in many areas, particularly the mechanisms of cancer causation. Moreover, clinical utilization of cancer predisposition genes has had a substantial impact on diagnosis, optimized management and prevention of cancer. The recent transformative advances in DNA sequencing hold the promise of many more cancer predisposition gene discoveries, and greater and broader clinical applications. However, there is also considerable potential for incorrect inferences and inappropriate clinical applications. Realizing the promise of cancer predisposition genes for science and medicine will thus require careful navigation. [ABSTRACT FROM AUTHOR]

Purpose: Recently, a clinical prediction rule for recurrent venous thromboembolism (VTE) in cancer patients, named Ottawa score, was derived to individualize treatments with different intensities. It is composed of four variables including sex, primary tumor site, tumor stage, and prior history of VTE. The objective of this study was to validate the Ottawa score in an independent patient population in a tertiary hospital in Korea. Methods: Medical records of consecutive adult patients (>18 years) with active malignancy and newly diagnosed VTE from January 1, 2006 to December 31, 2010 were analyzed. Using the same definition of predictor variables in the original derivation study, patients were divided into low (score ≤0) and high (score ≥1) risk groups for recurrent VTE, and their actual recurrence rate were analyzed. Results: Of the 546 patients with newly diagnosed VTE, 99 (18.1 %) had recurrent VTE during the follow-up period. In the low-risk group, 34 (13.2 %) had recurrence, compared to 65 (22.4 %) in the high-risk group. Ottawa score's performance showed 66 % sensitivity, 50 % specificity, 22 % positive predictive value, and 87 % negative predictive value in our validation cohort. Conclusion: We were not able to accurately ascertain the relevance of the Ottawa score in our validation cohort. Future validation studies, including a more diverse patient population with different cancer predominance, are warranted. [ABSTRACT FROM AUTHOR]

Congenital hypothyroidism (CH) due to thyroglobulin (TG) deficit is an autosomal recessive disease (OMIM #274700) characterized by hypothyroidism, goiter, low serum TG, and a negative perchlorate discharge test. The aim of this study was to perform the genetic analysis of the TG gene in two sisters born from consanguineus parents and affected by CH and low serum TG levels. The index patient and her sister were identified at neonatal screening for CH and treated with L-thyroxine (L-T4). After discontinuation of L-T4 therapy, hypothyroidism was confirmed, serum TG was undetectable, and no organification defect after I scintigraphy and perchlorate test was shown; thyroid ultrasound showed a eutopic gland of normal size. DNA was extracted from peripheral white blood cells of the two sisters and the father. All 48 exons of TG gene were amplified by polymerase chain reaction and subjected to direct sequencing. A novel homozygous point mutation in exon 10 of TG gene was identified in the patient and her sister. The mutation determined a stop codon at position 768 (R768X) resulting in an early truncated protein or in the complete absence of the protein. The father (euthyroid) was heterozygous carrier of the mutation. Conclusion: Genetic analysis of TG gene was performed in two sisters affected by CH. A novel point mutation of the TG gene determining a stop codon at position 768 of the protein was identified. The early truncated nonfunctioning protein or the absence of the protein due to the premature degradation of abnormal mRNA may be responsible of the observed phenotype. [ABSTRACT FROM AUTHOR]