Primary brain calcification: an international study reporting novel variants and associated phenotypes.

Primary familial brain calcification (PFBC) is a rare cerebral microvascular calcifying disorder with a wide spectrum of motor, cognitive, and neuropsychiatric symptoms. It is typically inherited as an autosomal-dominant trait with four causative genes identified so far: SLC20A2, PDGFRB, PDGFB, and XPR1. Our study aimed at screening the coding regions of these genes in a series of 177 unrelated probands that fulfilled the diagnostic criteria for primary brain calcification regardless of their family history. Sequence variants were classified as pathogenic, likely pathogenic, or of uncertain significance (VUS), based on the ACMG-AMP recommendations. We identified 45 probands (25.4%) carrying either pathogenic or likely pathogenic variants (n = 34, 19.2%) or VUS (n = 11, 6.2%). SLC20A2 provided the highest contribution (16.9%), followed by XPR1 and PDGFB (3.4% each), and PDGFRB (1.7%). A total of 81.5% of carriers were symptomatic and the most recurrent symptoms were parkinsonism, cognitive impairment, and psychiatric disturbances (52.3%, 40.9%, and 38.6% of symptomatic individuals, respectively), with a wide range of age at onset (from childhood to 81 years). While the pathogenic and likely pathogenic variants identified in this study can be used for genetic counseling, the VUS will require additional evidence, such as recurrence in unrelated patients, in order to be classified as pathogenic

Genoombreed onderzoek in de spreekkamer : Ethische dilemma's door nevenbevindingen van DNA-sequencing

Whole genome sequencing (WGS) is increasingly being used in clinical practice. As a result, various healthcare professionals now encounter ethical dilemmas that were formerly confined within the genetics clinic. In addition to autonomy and well-being of both patients and their family members, which need to be balanced carefully, a societal perspective is also vital to ensure the ethically sound introduction of whole genome sequencing into daily practice. Important choices to be made are: who is eligible for whole genome sequencing; how can informed consent be sensibly obtained, when dealing with such vast quantities of genomic information; which type of information should be offered to patients; should professionals actively search for pathogenic mutations. The rise of WGS has an impact on the moral responsibilities incumbent on healthcare professionals and necessitates a comprehensive societal debate on the advent of personalized medicine

Genoombreed onderzoek in de spreekkamer : Ethische dilemma's door nevenbevindingen van DNA-sequencing

Whole genome sequencing (WGS) is increasingly being used in clinical practice. As a result, various healthcare professionals now encounter ethical dilemmas that were formerly confined within the genetics clinic. In addition to autonomy and well-being of both patients and their family members, which need to be balanced carefully, a societal perspective is also vital to ensure the ethically sound introduction of whole genome sequencing into daily practice. Important choices to be made are: who is eligible for whole genome sequencing; how can informed consent be sensibly obtained, when dealing with such vast quantities of genomic information; which type of information should be offered to patients; should professionals actively search for pathogenic mutations. The rise of WGS has an impact on the moral responsibilities incumbent on healthcare professionals and necessitates a comprehensive societal debate on the advent of personalized medicine

Scanning the body, sequencing the genome : Dealing with unsolicited findings

The introduction of novel diagnostic techniques in clinical domains such as genomics and radiology has led to a rich ethical debate on how to handle unsolicited findings that result from these innovations. Yet while unsolicited findings arise in both genomics and radiology, most of the relevant literature to date has tended to focus on only one of these domains. In this article, we synthesize and critically assess similarities and differences between “scanning the body” and “sequencing the genome” from an ethical perspective. After briefly describing the novel diagnostic contexts leading to unsolicited findings, we synthesize and reflect on six core ethical issues that relate to both specialties: Terminology; benefits and risks; autonomy; disclosure of unsolicited findings to children; uncertainty; and filters and routine screening. We identify ethical rationales that pertain to both fields and may contribute to more ethically sound policies. Considerations of preserving public trust and ensuring that people perceive healthcare policies as fair also support the need for a combined debate

Is It Our Duty To Hunt for Pathogenic Mutations?

Should professionals systematically screen whole-genome sequencing (WGS) data to check for life-threatening mutations? Alternatively, should genome analysis focus on the primary reason for testing – that is, aiming to achieve precision medicine? We present an ethical review of the arguments and compare the act of searching for mutations with disclosing mutations that are discovered incidentally

Towards a responsible transition to learning healthcare systems in precision medicine

Learning healthcare systems have recently emerged as a strategy to continuously use experiences and outcomes of clinica