Multiple Recurrent De Novo CNVs, Including Duplications of the 7q11.23 Williams Syndrome Region, Are Strongly Associated with Autism

SummaryWe have undertaken a genome-wide analysis of rare copy-number variation (CNV) in 1124 autism spectrum disorder (ASD) families, each comprised of a single proband, unaffected parents, and, in most kindreds, an unaffected sibling. We find significant association of ASD with de novo duplications of 7q11.23, where the reciprocal deletion causes Williams-Beuren syndrome, characterized by a highly social personality. We identify rare recurrent de novo CNVs at five additional regions, including 16p13.2 (encompassing genes USP7 and C16orf72) and Cadherin 13, and implement a rigorous approach to evaluating the statistical significance of these observations. Overall, large de novo CNVs, particularly those encompassing multiple genes, confer substantial risks (OR = 5.6; CI = 2.6–12.0, p = 2.4 × 10-7). We estimate there are 130–234 ASD-related CNV regions in the human genome and present compelling evidence, based on cumulative data, for association of rare de novo events at 7q11.23, 15q11.2-13.1, 16p11.2, and Neurexin 1

To Return or Not to Return? IRB Perspectives on Obligations to Return Genetic Incidental Findings to Research Participants

Purpose: Whether researchers have an obligation to disclose genetic incidental findings (GIFs) to research participants has been widely debated but has lacked empirical data. This is the first extensive national examination of IRB professionals’ understanding, experience, and beliefs surrounding GIFs in the context of genomic sequencing. Methods: We conducted a cross-sectional online survey of 796 individuals sampled from Public Responsibility in Medicine and Research (PRIM&R) about background and experience with GIFs and ethical reasoning supporting or diminishing an obligation to disclose. Results: Most participants have had experience dealing with GIFs (74%), but less than half (47%) felt well prepared to evaluate a plan for managing them. Respondents generally agreed (78%) that researchers have some obligation to disclose GIFs. The top-cited ethical principles were a duty to warn (84%), respect for autonomy (80%), and beneficence (79%). While a majority believed that the obligation could be undermined by inadequate clinical or analytical validity (72%) or inadequate clinical utility (66%), respondents disagreed that researchers’ additional time and effort (87%) and participants’ imperfect understanding of genetics (70%) were valid reasons for non-disclosure. Almost all (96%) indicated it is definitely or probably acceptable for a participant to elect not to receive any GIFs. This view, however, became less pronounced (63%) when applied to specific case studies. Conclusion: Most IRBs are actively dealing with GIFs but feel only moderately prepared to do so. A majority believes there is sometimes or always an obligation to disclose and that duty to warn, autonomy, and beneficence are guiding forces in this obligation. Respondents generally rejected instrumental and paternalistic concerns as valid reasons for non-disclosure

Book Review: \u3ci\u3eWhy people get lost: the psychology and neuroscience of spatial cognition\u3c/i\u3e by Paul A. Dudchenko

Why People Get Lost demands no specialized knowledge of neuroscience, as its inside flap advertises. This is true to an extent; the book is an academic behemoth of research and data, but Dudchenko guides the reader through it with engaging anecdotes that inject a personal flair into the hard science. He writes with a refreshing directness, beginning each new subject with an introduction that tells the reader: this is what you are going to learn, this is how I am going to show you, and this is why you should care. If wayfinding intrigues you without preamble, it may not be long before you become lost in the read

IRB perspectives on obligations to disclose genetic incidental findings to research participants

Purpose Researchers’ obligations to disclose genetic incidental findings (GIFs) have been widely debated, but there has been little empirical study of IRBs’ engagement with this issue. Methods: This article presents data from the first extensive (n=796) national survey of IRB professionals’ understanding of, experience with, and beliefs surrounding GIFs. Results: Most respondents had dealt with questions about GIFs (74%), but only a minority (47%) felt prepared to address them. Although a majority believed that there is an obligation to disclose GIFs (78%) there is still not consensus about the supporting ethical principles. Respondents generally did not endorse the idea that researchers’ additional time and effort (7%) and lack of resources (29%) were valid reasons for diminishing a putative obligation. Most (96%) supported a right not to know, but this view became less pronounced (63%) when framed in terms of specific case studies. Conclusions: IRBs are actively engaged with GIFs, but have not yet reached consensus. Respondents were uncomfortable with arguments that could be used to limit an obligation to return GIFs. This could indicate that IRBs are providing some of the impetus for the trend towards returning GIFs, although questions remain about the relative contribution of other stakeholders

Cancer Survivorship at Stanford Cancer Institute

The Stanford Cancer Survivorship Program is a key initiative of Stanford Cancer Institute. The program's mission is to improve the experience and outcomes of patients and family caregivers throughout all phases of the cancer trajectory by advancing survivorship research, clinical care, and education. The four pillars of the program include clinical care delivery with a focus on primary care-survivorship collaboration and expanding specialty services, education and training of healthcare professionals, transdisciplinary patient-oriented research, and community engagement. Cross-cutting areas of expertise include the following: (a) adolescents and young adults (AYAs), (b) mental health and patient self-management, (c) integration of primary care, and (d) postgraduate medical education. The clinical care model includes embedded survivorship clinics within disease groups in outpatient clinics, novel clinics designed to address unmet needs such as sexual health for women, and primary care-based faculty-led survivorship clinics for patients undergoing active cancer care requiring co-management, those who have completed active therapy and those at high risk for cancer due to genetic risk. Educational initiatives developed to date include an online course and medical textbook for primary care clinicians, a lecture series, monthly research team meetings, and rotations for medical trainees. Patient-facing activities include webinars and a podcast series designed to promote awareness, thus expanding the provision of expert-vetted information. Ongoing research focuses on oncofertility and family building after cancer, improving communication for AYAs, changing mindsets to improve quality of life through targeted digital interventions, increasing capacity to care for cancer survivors, and strengthening collaboration with community partners. IMPLICATIONS FOR CANCER SURVIVORS: Stanford's Cancer Survivorship Program includes a robust transdisciplinary and interdisciplinary research, training and clinical platform that is committed to advancing access and improving care for people living with and beyond cancer, through innovation in design and care delivery.</p

Concordance of peripheral blood and bone marrow measurable residual disease in adult acute lymphoblastic leukemia

Monitoring of measurable residual disease (MRD) is essential to the management of acute lymphoblastic leukemia (ALL) and is typically performed through repeated bone marrow (BM) assessments. Using a next-generation sequencing (NGS) MRD platform, we performed a prospective observational study evaluating the correlation between peripheral blood (PB) and BM MRD in adults with ALL receiving cellular therapies (hematopoietic cell transplantation [HCT] and chimeric antigen receptor T-cell [CAR-T] therapies). Among the study cohort (N = 69 patients; 126 paired PB/BM samples), we found strong correlation between PB and BM MRD (r = 0.87; P < .001), with a sensitivity and specificity of MRD detection in the PB of 87% and 90%, respectively, relative to MRD in the BM. MRD became detectable in the PB in 100% of patients who subsequently relapsed following HCT, with median time from MRD+ to clinical relapse of 90 days, and in 85% of patients who relapsed following CAR T, with median time from MRD+ to clinical relapse of 60 days. In adult patients with ALL undergoing cellular therapies, we demonstrate strong concordance between NGS-based MRD detected in the PB and BM. Monitoring of ALL MRD in the PB appears to be an adequate alternative to frequent invasive BM evaluations in this clinical setting

Therapy-related acute lymphoblastic leukemia is a distinct entity with adverse genetic features and clinical outcomes

Therapy-related ALL is a distinct entity associated with poor-risk cytogenetics and inferior survival compared with de novo ALL. Hematopoietic stem cell transplantation may improve outcomes and should be considered for all eligible patients with therapy-related ALL. Patients with therapy-related acute lymphoblastic leukemia (t-ALL) represent a small subset of acute lymphoblastic leukemia (ALL) patients who received genotoxic therapy (ie, chemotherapy or radiation) for a prior malignancy. These patients should be distinguished from patients with de novo ALL (dn-ALL) and ALL patients who have a history of prior malignancy but have not received cytotoxic therapies in the past (acute lymphoblastic leukemia with prior malignancy [pm-ALL]). We report a retrospective multi-institutional study of patients with t-ALL (n = 116), dn-ALL (n = 100), and pm-ALL (n = 20) to investigate the impact of prior cytotoxic therapies on clinical outcomes. Compared with patients with pm-ALL, t-ALL patients had a significantly shorter interval between the first malignancy and ALL diagnosis and a higher frequency of poor-risk cytogenetic features, including KMT2A rearrangements and myelodysplastic syndrome-like abnormalities (eg, monosomal karyotype). We observed a variety of mutations among t-ALL patients, with the majority of patients exhibiting mutations that were more common with myeloid malignancies (eg, DNMT3A , RUNX1 , ASXL1 ), whereas others had ALL-type mutations (eg, CDKN2A , IKZF1 ). Median overall survival was significantly shorter in the t-ALL cohort compared with patients with dn-ALL or pm-ALL. Patients who were eligible for hematopoietic cell transplantation had improved long-term survival. Collectively, our results support t-ALL as a distinct entity based on its biologic and clinical features

Rare Copy Number Variants in Tourette Syndrome Disrupt Genes in Histaminergic Pathways and Overlap with Autism

Background: Studies of copy number variation (CNV) have characterized loci and molecular pathways in a range of neuropsychiatric conditions. We analyzed rare CNVs in Tourette syndrome (TS) to identify novel risk regions and relevant pathways, to evaluate burden of structural variation in cases versus controls, and to assess overlap of identified variations with those in other neuropsychiatric syndromes. Methods: We conducted a case-control study of 460 individuals with TS, including 148 parent-child trios and 1131 controls. CNV analysis was undertaken using 370 K to 1 M probe arrays, and genotyping data were used to match cases and controls for ancestry. CNVs present in <1% of the population were evaluated. Results: While there was no significant increase in the number of de novo or transmitted rare CNVs in cases versus controls, pathway analysis using multiple algorithms showed enrichment of genes within histamine receptor (subtypes 1 and 2) signaling pathways (p = 5.8 x 10(-4) - 1.6 x 10(-2)), as well as axon guidance, cell adhesion, nervous system development, and synaptic structure and function processes. Genes mapping within rare CNVs in TS showed significant overlap with those previously identified in autism spectrum disorders but not intellectual disability or schizophrenia. Three large, likely pathogenic, de novo events were identified, including one disrupting multiple gamma-aminobutyric acid receptor genes. Conclusions: We identify further evidence supporting recent findings regarding the involvement of histaminergic and gamma-aminobutyric acidergic mechanisms in the etiology of TS and show an overlap of rare CNVs in TS and autism spectrum disorders