Weaving the Strands of Life (Iiná Bitł’ool): History of Genetic Research Involving Navajo People

To date, some genetic studies offer medical benefits, but lack a clear pathway to benefit for people from underrepresented backgrounds. Historically Indigenous people, including the Diné (Navajo people), have raised concerns about the lack of benefits, misuse of DNA samples, lack of consultation, and ignoring cultural and traditional ways of knowing. Shortly after the Navajo Nation Human Research Review Board was established in 1996, the Navajo Nation recognized growing concerns about genetic research and established a moratorium on human genetic research studies in 2002. The moratorium effectively has protected their citizens from potential genetic research harms. Despite the placement of the moratorium, some genetic research studies have continued using blood and DNA samples from Navajo people. In order to understand the history of genetic research involving Navajo people, we conducted a literature review of 79 genetic or genetic-related research publications that involved Navajo people from the years 1925 to 2018. In this review, we divided the genetic research studies into the following general classifications: a) bacteria or virus genetics studies, b) blood and human leukocyte antigen, c) complex diseases, d) forensics, e) hereditary diseases, and f) population genetics and migration. We evaluated the methods for each study, described the number of Navajo individuals included in each study, recorded the academic or tribal approval statements, and noted whether the study considered Diné cultural values. Several studies focused on Severe Combined Immunodeficiency Disease, population history, neuropathy, albinism, eye and skin disorders that affect Navajo people. We found genetic research publications involving Navajo people spanning over the course of 93 years. To our knowledge, no known literature reviews have examined the history of genetic research in the Navajo community. In our Discussion, we contextualize Diné ways of knowing related to genetics and health with Western scientific concepts to acknowledge the complex philosophy and belief system that guides Diné people and recognizes Indigenous science. We encourage researchers consider cultural perspectives and traditional knowledge that has the potential to create stronger conclusions and better informed, ethical, and respectful science

Decreased levels of BAG3 in a family with a rare variant and in idiopathic dilated cardiomyopathy.

The most common cause of dilated cardiomyopathy and heart failure (HF) is ischemic heart disease; however, in a third of all patients the cause remains undefined and patients are diagnosed as having idiopathic dilated cardiomyopathy (IDC). Recent studies suggest that many patients with IDC have a family history of HF and rare genetic variants in over 35 genes have been shown to be causative of disease. We employed whole-exome sequencing to identify the causative variant in a large family with autosomal dominant transmission of dilated cardiomyopathy. Sequencing and subsequent informatics revealed a novel 10-nucleotide deletion in the BCL2-associated athanogene 3 (BAG3) gene (Ch10:del 121436332_12143641: del. 1266_1275 [NM 004281]) that segregated with all affected individuals. The deletion predicted a shift in the reading frame with the resultant deletion of 135 amino acids from the C-terminal end of the protein. Consistent with genetic variants in genes encoding other sarcomeric proteins there was a considerable amount of genetic heterogeneity in the affected family members. Interestingly, we also found that the levels of BAG3 protein were significantly reduced in the hearts from unrelated patients with end-stage HF undergoing cardiac transplantation when compared with non-failing controls. Diminished levels of BAG3 protein may be associated with both familial and non-familial forms of dilated cardiomyopathy

FLNC Gene Splice Mutations Cause Dilated\ua0Cardiomyopathy

OBJECTIVE: To identify novel dilated cardiomyopathy (DCM) causing genes, and to elucidate the pathological mechanism leading to DCM by utilizing zebrafish as a model organism. BACKGROUND: DCM, a major cause of heart failure, is frequently familial and caused by a genetic defect. However, only 50% of DCM cases can be attributed to a known DCM gene variant, motivating the ongoing search for novel disease genes. METHODS: We performed whole exome sequencing (WES) in two multigenerational Italian families and one US family with arrhythmogenic DCM without skeletal muscle defects, in whom prior genetic testing had been unrevealing. Pathogenic variants were sought by a combination of bioinformatic filtering and cosegregation testing among affected individuals within the families. We performed function assays and generated a zebrafish morpholino knockdown model. RESULTS: A novel filamin C gene splicing variant (FLNC c.7251+1 G>A) was identified by WES in all affected family members in the two Italian families. A separate novel splicing mutation (FLNC c.5669-1delG) was identified in the US family. Western blot analysis of cardiac heart tissue from an affected individual showed decreased FLNC protein, supporting a haploinsufficiency model of pathogenesis. To further analyze this model, a morpholino knockdown of the ortholog filamin Cb in zebrafish was created which resulted in abnormal cardiac function and ultrastructure. CONCLUSIONS: Using WES, we identified two novel FLNC splicing variants as the likely cause of DCM in three families. We provided protein expression and in vivo zebrafish data supporting haploinsufficiency as the pathogenic mechanism leading to DCM

Designing Inclusive HPV Cancer Vaccines and Increasing Uptake among Native Americans—A Cultural Perspective Review

Despite a global and nationwide decrease, Native Americans continue to experience high rates of cancer morbidity and mortality. Vaccination is one approach to decrease cancer incidence such as the case of cervical cancer. However, the availability of vaccines does not guarantee uptake, as evident in the Coronavirus 2019 pandemic. Therefore, as we consider current and future cancer vaccines, there are certain considerations to be mindful of to increase uptake among Native Americans such as the incidence of disease, social determinants of health, vaccine hesitancy, and historical exclusion in clinical trials. This paper primarily focuses on human papillomavirus (HPV) and potential vaccines for Native Americans. However, we also aim to inform researchers on factors that influence Native American choices surrounding vaccination and interventions including cancer therapies. We begin by providing an overview of the historical distrust and trauma Native Americans experience, both past and present. In addition, we offer guidance and considerations when engaging with sovereign Tribal Nations in vaccine development and clinical trials in order to increase trust and encourage vaccine uptake

Role of Titin Missense Variants in Dilated Cardiomyopathy

BACKGROUND-\u2014The titin gene (TTN) encodes the largest human protein, which plays a central role in sarcomere organization and passive myocyte stiffness. TTN truncating mutations cause dilated cardiomyopathy (DCM); however, the role of TTN missense variants in DCM has been difficult to elucidate because of the presence of background TTN variation. METHODS AND RESULTS-\u2014A cohort of 147 DCM index subjects underwent DNA sequencing for 313 TTN exons covering the N2B and N2BA cardiac isoforms of TTN. Of the 348 missense variants, we identified 44 \u201csevere\u201d rare variants by using a bioinformatic filtering process in 37 probands. Of these, 5 probands were double heterozygotes (additional variant in another DCM gene) and 7 were compound heterozygotes (2 TTN \u201csevere\u201d variants). Segregation analysis allowed the classification of the \u201csevere\u201d variants into 5 \u201clikely\u201d (cosegregating), 5 \u201cunlikely\u201d (noncosegregating), and 34 \u201cpossibly\u201d (where family structure precluded segregation analysis) disease-causing variants. Patients with DCM carrying \u201clikely\u201d or \u201cpossibly\u201d pathogenic TTN \u201csevere\u201d variants did not show a different outcome compared with \u201cunlikely\u201d and noncarriers of a \u201csevere\u201d TTN variant. However, the \u201clikely\u201d and \u201cpossibly\u201d disease-causing variants were overrepresented in the C-zone of the A-band region of the sarcomere. CONCLUSIONS-\u2014TTN missense variants are common and present a challenge for bioinformatic classification, especially when informative families are not available. Although DCM patients carrying bioinformatically \u201csevere\u201d TTN variants do not appear to have a worse clinical course than noncarriers, the nonrandom distribution of \u201clikely\u201d and \u201cpossibly\u201d disease-causing variants suggests a potential biological role for some TTN missense variants

Water back: A review centring rematriation and Indigenous Water research sovereignty

The recent Land Back movement has catalysed global solidarity towards addressing the oppression and dispossession of Indigenous Peoples’ Lands and territories. Largely absent from the discourse, however, is a discussion of the alienation of Indigenous Peoples from Water by settler-colonial states. Some Indigenous Water Protectors argue that there cannot be Land Back without Water Back. In response to this emergent movement of Water Back, this review of research by Indigenous and non-Indigenous writers traces the discursive patterns of Indigenous Water relationships and rematriation across themes of colonialism, climate change, justice, health, rights, responsibilities, governance and cosmology. It advances a holistic conceptualization of Water Back as a framework for future research sovereignty, focusing mainly on instances in Canada, Australia, Aotearoa New Zealand, and the United States. We present the findings on the current global Waterscape of Indigenous-led research on Indigenous Water issues. Water Back offers an important framework centring Indigenous ways of knowing, doing, and being as a foundation for advancing Indigenous Water research

FLNC Gene Splice Mutations Cause Dilated Cardiomyopathy

A genetic etiology has been identified in 30% to 40% of dilated cardiomyopathy (DCM) patients, yet only 50% of these cases are associated with a known causative gene variant. Thus, in order to understand the pathophysiology of DCM, it is necessary to identify and characterize additional genes. In this study, whole exome sequencing in combination with segregation analysis was used to identify mutations in a novel gene, filamin C (FLNC), resulting in a cardiac-restricted DCM pathology. Here we provide functional data via zebrafish studies and protein analysis to support a model implicating FLNC haploinsufficiency as a mechanism of DCM

Advancing genomics to improve health equity.

Health equity is the state in which everyone has fair and just opportunities to attain their highest level of health. The field of human genomics has fallen short in increasing health equity, largely because the diversity of the human population has been inadequately reflected among participants of genomics research. This lack of diversity leads to disparities that can have scientific and clinical consequences. Achieving health equity related to genomics will require greater effort in addressing inequities within the field. As part of the commitment of the National Human Genome Research Institute (NHGRI) to advancing health equity, it convened experts in genomics and health equity research to make recommendations and performed a review of current literature to identify the landscape of gaps and opportunities at the interface between human genomics and health equity research. This Perspective describes these findings and examines health equity within the context of human genomics and genomic medicine