Reproductive outcomes in individuals with chromosomal reciprocal translocations.

PURPOSE: Patients with reciprocal balanced translocations (RBT) have a risk for recurrent pregnancy losses (RPL), affected child, and infertility. Currently, genetic counseling is based on karyotypes found among the products of conception (POC), although factors influencing the success of assisted reproductive technologies (ART) in RBT couples are not established. METHODS: Cytogenetic results from 261 POC and offspring of the parents (113 women and 90 men) with RBT were evaluated. Chromosome segregation modes and number of euploid embryos were assessed in couples undergoing in vitro fertilization. RESULTS: Patients with translocations involving an acrocentric chromosome have a higher risk of unbalanced gametes caused by a 3:1 segregation. Female RBT patients have a statistically higher risk of aneuploidy due to an interchromosomal effect. The rate of euploid embryos is low due to meiosis I malsegregation of RBT, meiosis II nondisjunction, additional whole chromosome or segmental aneusomies. RBT patients with RPL have a higher rate of miscarriage of euploid fetuses with RBT. CONCLUSION: Chromosome-specific factors, female gender, age, and history of RPL are the risk elements influencing pregnancy and in vitro fertilization success in RBT patients. Chromosomal microarray analysis of POC is necessary to provide an accurate and timely diagnosis for patients with adverse reproductive outcomes.

Four children with postnatally diagnosed mosaic trisomy 12: Clinical features, literature review, and current diagnostic capabilities of genetic testing.

Children or adults with mosaic trisomy 12 diagnosed postnatally are extremely rare. Only a small number of patients with this mosaicism have been reported in the literature. The clinical manifestation of mosaic trisomy 12 is variable, ranging from mild developmental delay to severe congenital anomaly and neonatal death. The trisomy 12 cells are not usually able to be detected by phytohemagglutinin stimulated peripheral blood chromosome analysis. The variability of phenotypes and the limited number of patients with this anomaly pose a challenge to predict the clinical outcomes. In this study, we present the phenotypes and laboratory findings in four patients and review the 11 previously reported patients with mosaic trisomy 12 diagnosed postnatally, as well as 11 patients with mosaic trisomy 12 diagnosed prenatally. The findings of this study provide useful information for laboratory diagnosis and clinical management of these patients.

Seventy-one important questions for the conservation of marine biodiversity.

The ocean provides food, economic activity, and cultural value for a large proportion of humanity. Our knowledge of marine ecosystems lags behind that of terrestrial ecosystems, limiting effective protection of marine resources. We describe the outcome of 2 workshops in 2011 and 2012 to establish a list of important questions, which, if answered, would substantially improve our ability to conserve and manage the world's marine resources. Participants included individuals from academia, government, and nongovernment organizations with broad experience across disciplines, marine ecosystems, and countries that vary in levels of development. Contributors from the fields of science, conservation, industry, and government submitted questions to our workshops, which we distilled into a list of priority research questions. Through this process, we identified 71 key questions. We grouped these into 8 subject categories, each pertaining to a broad component of marine conservation: fisheries, climate change, other anthropogenic threats, ecosystems, marine citizenship, policy, societal and cultural considerations, and scientific enterprise. Our questions address many issues that are specific to marine conservation, and will serve as a road map to funders and researchers to develop programs that can greatly benefit marine conservation.

Identification of Two Homozygous Variants in MYBPC3 and SMYD1 Genes Associated with Severe Infantile Cardiomyopathy.

Mutations in cardiac genes are one of the primary causes of infantile cardiomyopathy. In this study, we report the genetic findings of two siblings carrying variations in the MYBPC3 and SMYD1 genes. The first patient is a female proband exhibiting hypertrophic cardiomyopathy (HCM) and biventricular heart failure carrying a truncating homozygous MYBPC3 variant c.1224-52G>A (IVS13-52G>A) and a novel homozygous variant (c.302A>G; p.Asn101Ser) in the SMYD1 gene. The second patient, the proband's sibling, is a male infant diagnosed with hypertrophic cardiomyopathy and carries the same homozygous MYBPC3 variant. While this specific MYBPC3 variant (c.1224-52G>A, IVS13-52G>A) has been previously reported to be associated with adult-onset hypertrophic cardiomyopathy, this is the first report linking it to infantile cardiomyopathy. In addition, this work describes, for the first time, a novel SMYD1 variant (c.302A>G; p.Asn101Ser) that has never been reported. We performed a histopathological evaluation of tissues collected from both probands and show that these variants lead to myofibrillar disarray, reduced and irregular mitochondrial cristae and cardiac fibrosis. Together, these results provide critical insight into the molecular functionality of these genes in human cardiac physiology.

Comparison of pharmacological inhibitors of lysine-specific demethylase 1 in glioblastoma stem cells reveals inhibitor-specific efficacy profiles.

Introduction: Improved therapies for glioblastoma (GBM) are desperately needed and require preclinical evaluation in models that capture tumor heterogeneity and intrinsic resistance seen in patients. Epigenetic alterations have been well documented in GBM and lysine-specific demethylase 1 (LSD1/KDM1A) is amongst the chromatin modifiers implicated in stem cell maintenance, growth and differentiation. Pharmacological inhibition of LSD1 is clinically relevant, with numerous compounds in various phases of preclinical and clinical development, but an evaluation and comparison of LSD1 inhibitors in patient-derived GBM models is lacking. Methods: To assess concordance between knockdown of LSD1 and inhibition of LSD1 using a prototype inhibitor in GBM, we performed RNA-seq to identify genes and biological processes associated with inhibition. Efficacy of various LSD1 inhibitors was assessed in nine patient-derived glioblastoma stem cell (GSC) lines and an orthotopic xenograft mouse model. Results: LSD1 inhibitors had cytotoxic and selective effects regardless of GSC radiosensitivity or molecular subtype. In vivo, LSD1 inhibition via GSK-LSD1 led to a delayed reduction in tumor burden; however, tumor regrowth occurred. Comparison of GBM lines by RNA-seq was used to identify genes that may predict resistance to LSD1 inhibitors. We identified five genes that correlate with resistance to LSD1 inhibition in treatment resistant GSCs, in GSK-LSD1 treated mice, and in GBM patients with low LSD1 expression. Conclusion: Collectively, the growth inhibitory effects of LSD1 inhibition across a panel of GSC models and identification of genes that may predict resistance has potential to guide future combination therapies.

Compound heterozygous loss of function variants in MYL9 in a child with megacystis-microcolon-intestinal hypoperistalsis syndrome.

Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS), or "visceral myopathy," is a severe early onset disorder characterized by impaired muscle contractility in the bladder and intestines. Five genes are linked to MMIHS: primarily ACTG2, but also LMOD1, MYH11, MYLK, and MYL9. Here we describe a three-year-old girl with bilateral hydronephrosis diagnosed at 20 weeks gestation and congenital mydriasis (both of which have been previously observed among individuals with MMIHS). A clinical diagnosis of MMIHS was made based upon the presence of megacystis, lack of urinary bladder peristalsis, and intestinal pseudo-obstruction. After initial testing of ACTG2 was negative, further sequencing and deletion/duplication testing was performed on the LMOD1, MYH11,MYLK, and MYL9 genes. We identified two heterozygous loss of function variants in MYL9: an exon 4 deletion and a nine base pair deletion that removes the canonical splicing donor site at exon 2 (NM_006097.5:c.184+2_184+10del). Parental testing confirmed these variants to be in trans in our proband. To our knowledge, only one other individual with MMIHS has biallelic mutations in MYL9 (a homozygous deletion encompassing exon 4). We suggest MYL9 be targeted on genetic testing panels for MMIHS, smooth muscle myopathies, and cardiovascular phenotypes.

Adverse Events in Genetic Testing: The Fourth Case Series.

PURPOSE: In this ongoing national case series, we document 25 new genetic testing cases in which tests were recommended, ordered, interpreted, or used incorrectly. METHODS: An invitation to submit cases of adverse events in genetic testing was issued to the general National Society of Genetic Counselors Listserv, the National Society of Genetic Counselors Cancer Special Interest Group members, private genetic counselor laboratory groups, and via social media platforms (i.e., Facebook, Twitter, LinkedIn). Examples highlighted in the invitation included errors in ordering, counseling, and/or interpretation of genetic testing and did not limit submissions to cases involving genetic testing for hereditary cancer predisposition. Clinical documentation, including pedigree, was requested. Twenty-six cases were accepted, and a thematic analysis was performed. Submitters were asked to approve the representation of their cases before manuscript submission. RESULTS: All submitted cases took place in the United States and were from cancer, pediatric, preconception, and general adult settings and involved both medical-grade and direct-to-consumer genetic testing with raw data analysis. In 8 cases, providers ordered the wrong genetic test. In 2 cases, multiple errors were made when genetic testing was ordered. In 3 cases, patients received incorrect information from providers because genetic test results were misinterpreted or because of limitations in the provider's knowledge of genetics. In 3 cases, pathogenic genetic variants identified were incorrectly assumed to completely explain the suspicious family histories of cancer. In 2 cases, patients received inadequate or no information with respect to genetic test results. In 2 cases, result interpretation/documentation by the testing laboratories was erroneous. In 2 cases, genetic counselors reinterpreted the results of people who had undergone direct-to-consumer genetic testing and/or clarifying medical-grade testing was ordered. DISCUSSION: As genetic testing continues to become more common and complex, it is clear that we must ensure that appropriate testing is ordered and that results are interpreted and used correctly. Access to certified genetic counselors continues to be an issue for some because of workforce limitations. Potential solutions involve action on multiple fronts: new genetic counseling delivery models, expanding the genetic counseling workforce, improving genetics and genomics education of nongenetics health care professionals, addressing health care policy barriers, and more. Genetic counselors have also positioned themselves in new roles to help patients and consumers as well as health care providers, systems, and payers adapt to new genetic testing technologies and models. The work to be done is significant, but so are the consequences of errors in genetic testing.