Prevalence and architecture of de novo mutations in developmental disorders.

The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year

Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy.

We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

The role of BMP4 in the Ex vivo expansion of cord blood haemopoietic stem cells.

Establishment of conditions supporting haemopoietic stem cell (HSC) maintenance and expansion ex vivo is critical for wider clinical application of cord blood (CB) transplantation. AFT024 is a murine fetal liver cell line that expands primitive haemopoietic cells via a process that is not understood. Here we shoe that bone morphogenetic protein (BMP) 4, which is a member of the transforming growth factor-beta super family of pleitropic regulators, is produced by AFT024 and contributes significantly to the maintenance of co-cultured CB-derived primitive cells ... BMP4 can contribute to HSC maintenance both in an established long-term co-culture model and in a clinical ex vivo expansion setting.Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 200

Development of CD4+CD25+FoxP3+ regulatory T cells from cord blood hematopoietic progenitor cells

Adult stem cells are capable of generating all of the cells of the hematopoietic system, and this process is orchestrated in part by the interactions between these cells and the stroma. T cell progenitors emerge from the stem cell compartment and migrat

Pudendal nerve injury impairs anorectal function and health related quality of life measures ≥2 years after 3D conformal radiotherapy for prostate cancer

<p><b>Purpose:</b> To compare GI symptoms, measures of generic and disease specific health related quality of life (HRQoL), anorectal and pudendal nerve function and anal sphincter morphology between (i) patients ≥2 years after 3D conformal radiotherapy (3D-CRT)±high dose rate (HDR) brachytherapy for carcinoma of the prostate and aged matched patients before radiotherapy and (ii) symptomatic and asymptomatic patients ≥2 years after 3D-CRT ± HDR brachytherapy.</p> <p><b>Material and methods:</b> Methodology included: (i) modified LENT-SOMA scales for GI symptoms, (ii) EORTC QLQ-C30 and EORTC QLQ-PR25 questionnaires for generic and disease specific HRQoL, (iii) anorectal manometry and terminal motor latency for anorectal and pudendal nerve function and (iv) endorectal ultrasound for anal sphincter morphology. GI symptoms, parameters of HRQoL, anorectal and pudendal nerve function and anal sphincter morphology were compared using Mann–Whitney’s <i>U</i>, unpaired <i>t</i> and <i>χ</i>² tests.</p> <p><b>Results:</b> Impairment of HRQoL bowel symptoms in the patients ≥2 years after 3D-CRT ± HDR brachytherapy was associated with worse anorectal motor and sensory function, internal and external anal sphincter morphology and 5× greater prevalence of pudendal nerve dysfunction compared with age matched patients before radiotherapy. Symptomatic patients had worse (i) HRQoL measures including global quality of life and bowel and urinary symptom scores, (ii) rectal bleeding, fecal urgency and incontinence scores and (iii) a 2× higher prevalence of pudendal nerve dysfunction compared with asymptomatic patients.</p> <p>Rectal and anal (i) <i>V</i> 40 Gy >65%, (ii) Dmax >60 Gy, (iii) pudendal nerve Dmax >60 Gy and (iv) Anal <i>V</i> 60 Gy >40% were associated with a greater prevalence of pudendal nerve dysfunction.</p> <p><b>Conclusions:</b> 3D-CRT ± HDR brachytherapy for prostate carcinoma, impairs late functional measures including HRQoL, anorectal and pudendal nerve function. Rectal, anal and pudendal nerve radiation dose constraints are proposed for reducing the prevalence of pudendal nerve dysfunction.</p

Radiation Therapy and Indigenous Peoples in Canada and Australia: Building Paths Toward Reconciliation in Cancer Care Delivery

Indigenous peoples represent approximately 5% of the world's population and reside in over 90 countries worldwide. They embody a rich diversity of cultures, traditions, languages and relationships with the land that are shared through many generations and that are distinct from those of the settler societies within which they now live. Many Indigenous peoples have a shared experience of discrimination, trauma, and violation of rights, rooted in complex sociopolitical relationships with settler societies that are still ongoing. This results in continuing social injustices and pronounced disparities in health for many Indigenous peoples around the globe. Indigenous peoples exhibit a significantly higher cancer incidence, mortality, and poorer survival compared to non-Indigenous peoples. Cancer services, including radiotherapy, have not been designed to support the specific values and needs of Indigenous populations, resulting in poorer access to cancer services for Indigenous peoples globally across the entire cancer care spectrum. Specific to radiotherapy, available evidence demonstrates disparities in radiotherapy uptake between Indigenous and non-Indigenous patients. Radiotherapy centres are also located disparately further away from Indigenous communities. Studies are limited by a lack of Indigenous-specific data to help inform effective radiotherapy delivery. Recent Indigenous-led partnerships and initiatives have helped to address existing gaps in cancer care, and radiation oncologists play an important role in supporting such efforts. In this article, we present an overview of access to radiotherapy for Indigenous peoples in Canada and Australia, with a focus on strengthening cancer care delivery through education, partnerships, and research