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This Position Statement provides guidelines for health professionals who work with individuals and families seeking predictive genetic testing and laboratory staff conducting the tests. It presents the major practical, psychosocial and ethical considerations associated with presymptomatic and predictive genetic testing in adults who have the capacity to make a decision, children and young people who lack capacity, and adults living with reduced or fluctuating cognitive capacity. Predictive Testing Recommendations: (1) Predictive testing in adults, young people and children should only be offered with pretest genetic counseling, and the option of post-test genetic counseling. (2) An individual considering whether to have a predictive test should be supported to make an autonomous and informed decision. Regarding Children and Young People: (1) Predictive testing should only be offered to children and young people for conditions where there is likely to be a direct medical benefit to them through surveillance, use of prevention strategies, or other medical interventions in the immediate future. (2) Where symptoms are likely to develop in childhood, in the absence of direct medical benefit from this knowledge, genetic health professionals and parents/guardians should discuss whether undertaking predictive testing is the best course of action for the child and the family as a whole. (3) Where symptoms are likely to develop in adulthood, the default position should be to postpone predictive testing until the young person achieves the capacity to make an autonomous and informed decision. This is applicable regardless of whether there is some action that can be taken in adulthood. [ABSTRACT FROM AUTHOR]

This Position Statement provides guidelines to assist all health professionals who receive requests for carrier testing and laboratory staff conducting the tests. In this Statement, the term 'carrier testing' refers to genetic testing in an individual to determine whether they have inherited a pathogenic variant associated with an autosomal or X-linked recessive condition previously identified in a blood relative. Carrier testing recommendations: (1) Carrier testing should only be performed with the individual's knowledge and consent; (2) An individual considering (for themselves, or on behalf of another) whether to have a carrier test should be supported to make an informed decision; (3) The mode of inheritance, the individual's personal experience with the condition, and the healthcare setting in which the test is being performed should be considered when determining whether carrier testing should be offered by a genetic health professional. Regarding children and young people: Unless there is direct medical benefit in the immediate future, the default position should be to postpone carrier testing until the child or young person can be supported to make an informed decision. There may be some specific situations where it is appropriate to facilitate carrier testing in children and young people (see section in this article). In such cases, testing should only be offered with pre- and post-test genetic counseling in which genetic health professionals and parents/guardians should explore the rationale for testing and the interests of the child and the family. [ABSTRACT FROM AUTHOR]

Allowing competent children to exercise their right to consent relies largely on healthcare practitioners' own understanding and attitudes regarding the maturity and decision-making capacity of minor patients, particularly in circumstances when professional guidelines for practice do not exist. The aim of this study was to explore Serbian primary care physicians' a) views and experiences regarding decision-making capacity of adolescents, b) experiences with adolescents' parents regarding their children's right to give autonomous consent and c) views on their own role in adolescents' healthcare. Qualitative semi-structured interviews were conducted in person with twelve pediatricians and gynecologists at eight primary health care institutions at Belgrade (Serbia) from March to May 2016. Qualitative content analysis was used to identify categories in the data. Participants agreed that decision-making capacity is reached at an individual pace, making it difficult to set age boundaries for consent. However, they noted that adolescents' decision-making capacity can be enhanced by providing appropriate support, by both physicians and parents. Participants described witnessing overprotective behavior in parents, yet highlighted that physicians are well placed to help parents understand the importance of letting their adolescent children participate in decision-making. Since participation in decision-making is considered to be in the best interest of minors, primary care physicians can be important agents in strengthening adolescents' positions as decision-makers in healthcare. In addition, healthcare workers would benefit from additional training in skills to enhance communication with both adolescents and parents. Highlights: Adolescents need to be encouraged and assisted in the development of their decisional capacity and autonomy. Parents need to be educated on the importance of adolescents' right to participation in health care decision-making. Cultural values and inter-familial relations need to be taken into account when deciding on the level of children's autonomy. Primary care physicians would benefit from additional training in adolescent medicine and skills for communication with both adolescents and parents. [ABSTRACT FROM AUTHOR]

Objective: To examine i) how ethical frameworks can be used in concrete cases of parent–doctors’ disagreements for extremely preterm infants born in the grey zone to guide such difficult decision-making; and ii) what challenges stakeholders may encounter in using these frameworks. Design: We did a case analysis of a concrete case of parent–doctor disagreement in the grey zone using two ethical frameworks: the best interest standard and the zone of parental discretion. Results: Both ethical frameworks entailed similar advantages and challenges. They have the potential 1) to facilitate decision-making because they follow a structured method; 2) to clarify the situation because all relevant ethical issues are explored; and 3) to facilitate reaching an agreement because all parties can explain their views. We identified three main challenges. First, how to objectively evaluate the risk of severe disability. Second, parents’ interests should be considered but it is not clear to what extent. Third, this is a value-laden situation and different people have different values, meaning that the frameworks are at least partially subjective. Conclusions: These challenges do not mean that the ethical frameworks are faulty; rather, they reflect the complexity and the sensitivity of cases in the grey zone. [ABSTRACT FROM AUTHOR]

Despite the plethora of empirical studies conducted to date, debate continues about whether and to what extent results should be returned to participants of genomic research. We aimed to systematically review the empirical literature exploring stakeholders' perspectives on return of individual research results (IRR) from genomic research. We examined preferences for receiving or willingness to return IRR, and experiences with either receiving or returning them. The systematic searches were conducted across five major databases in August 2018 and repeated in April 2020, and included studies reporting findings from primary research regardless of method (quantitative, qualitative, mixed). Articles that related to the clinical setting were excluded. Our search identified 221 articles that met our search criteria. This included 118 quantitative, 69 qualitative and 34 mixed methods studies. These articles included a total number of 118,874 stakeholders with research participants (85,270/72%) and members of the general public (40,967/35%) being the largest groups represented. The articles spanned at least 22 different countries with most (144/65%) being from the USA. Most (76%) discussed clinical research projects, rather than biobanks. More than half (58%) gauged views that were hypothetical. We found overwhelming evidence of high interest in return of IRR from potential and actual genomic research participants. There is also a general willingness to provide such results by researchers and health professionals, although they tend to adopt a more cautious stance. While all results are desired to some degree, those that have the potential to change clinical management are generally prioritized by all stakeholders. Professional stakeholders appear more willing to return results that are reliable and clinically relevant than those that are less reliable and lack clinical relevance. The lack of evidence for significant enduring psychological harm and the clear benefits to some research participants suggest that researchers should be returning actionable IRRs to participants. [ABSTRACT FROM AUTHOR]

While integrating genomic sequencing into clinical care carries clear medical benefits, it also raises difficult ethical questions. Compared to traditional sequencing technologies, genomic sequencing and analysis is more likely to identify unsolicited findings (UF) and variants that cannot be classified as benign or disease-causing (variants of uncertain significance; VUS). UF and VUS pose new challenges for genetic health professionals (GHPs) who are obtaining informed consent for genomic sequencing from patients. We conducted semi-structured interviews with 31 GHPs across Europe, Australia and Canada to identify some of these challenges. Our results show that GHPs find it difficult to prepare patients to receive results because a vast amount of information is required to fully inform patients about VUS and UF. GHPs also struggle to engage patients – many of whom may be focused on ending their 'diagnostic odyssey' – in the informed consent process in a meaningful way. Thus, some questioned how 'informed' patients actually are when they agree to undergo clinical genomic sequencing. These findings suggest a tension remains between sufficient information provision at the risk of overwhelming the patient and imparting less information at the risk of uninformed decision-making. We suggest that a shift away from 'fully informed consent' toward an approach aimed at realizing, as far as possible, the underlying goals that informed consent is meant to promote. [ABSTRACT FROM AUTHOR]

In 2020, the Human Genetics Society of Australasia released its Position Statement on Predictive and Presymptomatic Genetic Testing in Adults and Children. This Position Statement synthesizes the major practical, psychosocial and ethical considerations associated with presymptomatic and predictive genetic testing in adults who have the capacity to make a decision, children and young people who lack capacity and adults living with reduced or fluctuating capacity. Recommendations include that predictive testing in adults, young people and children should only be offered with pretest genetic counseling and the option of posttest genetic counseling. An individual considering (for themselves or on behalf of another) whether to have a predictive test should also be supported to allow them to make an autonomous and informed decision. Predictive testing should only be offered to children and young people for conditions where there is likely to be a direct medical benefit to them through surveillance, use of prevention strategies or other medical interventions in the immediate future. Where symptoms are likely to develop in childhood, in the absence of options to implement surveillance or risk reduction measures, genetic health professionals and parents/guardians should discuss whether undertaking predictive testing is the best course of action for the child and the family as a whole. Where symptoms are likely to develop in adulthood, the default position should be to postpone predictive testing until the young person achieves the capacity to make their own autonomous and informed decision. [ABSTRACT FROM AUTHOR]

Medical imaging is predominantly a visual field. In this context, prenatal ultrasound images assume intense social, ethical, and psychological significance by virtue of the subject they represent: the fetus. This feature, along with the sophistication introduced by three-dimensional (3D) ultrasound imaging that allows improved visualization of the fetus, has contributed to the common impression that prenatal ultrasound scans are like photographs of the fetus. In this article we discuss the consistency of such a comparison. First, we investigate the epistemic role of both analogic and digital photographic images as visual information-providing representations holding a high degree of objectivity. Second, we examine the structure and process of production of ultrasound scans and argue that a comparison between two-dimensional (2D) ultrasound and photography is justified. This is in contrast to 3D ultrasound images that, due to the intensive mathematical processing involved in their production, present some structural issues that obfuscate their ontological and epistemic status. [ABSTRACT FROM AUTHOR]

Predictive genetic testing for susceptibility to psychiatric conditions is likely to become part of standard practice. Because the onset of most psychiatric diseases is in late adolescence or early adulthood, testing minors could lead to early identification that may prevent or delay the development of these disorders. However, due to their complex aetiology, psychiatric genetic testing does not provide the immediate medical benefits that current guidelines require for testing minors. While several authors have argued non-medical benefits may play a crucial role in favour of predictive testing for other conditions, little research has explored such a role in psychiatric disorders. This paper outlines the potential non-medical benefits and harms of psychiatric genetic testing in minors in order to consider whether the non-medical benefits could ever make such testing appropriate. Five non-medical themes arise in the literature: psychological impacts, autonomy/self-determination, implications of the biomedical approach, use of financial and intellectual resources, and discrimination. Non-medical benefits were prominent in all of them, suggesting that psychiatric genetic testing in minors may be appropriate in some circumstances. Further research needs to empirically assess these potential non-medical benefits, incorporate minors in the debate, and include normative reflection to evaluate the very purposes and motivations of psychiatric genetic testing in minors. [ABSTRACT FROM AUTHOR]

The nature of next generation sequencing technologies (NGS) results in the generation of large amounts of data and the identification of numerous variants, for some of which the clinical significance may be difficult to ascertain based on our current knowledge. These Variants of Uncertain Significance (VUS) may be identified in genes in which the function is known or unknown and which may or may not be related to the original rationale for sequencing the patient. Little is known about whether laboratories report VUS to clinicians and current guidelines issued by some of the most notable professional bodies do not provide specific recommendations on this point. To address this, 26 interviews were conducted with 27 laboratory personnel, representing 24 laboratories in Europe (12), Canada (5) and Australasia (7) in order to explore their reporting practices. Participants highlighted that the classification of variants is a real challenge despite the presence of classification guidelines. We identified variation in the reporting practices of VUS across the laboratories within the study. While some laboratories limit their reporting to variants that are pathogenic and thought to be causative of the phenotype, more commonly laboratories report VUS when they are identified in genes related to the clinical question. Some laboratories will also report VUS in candidate genes. VUS that are secondary findings are generally not reported. While it is unclear whether uniformity in reporting is desirable, exploring the perspectives of laboratory personnel undertaking these analyses are critical to ensure the feasibility of any future reporting recommendations. [ABSTRACT FROM AUTHOR]

Many international guidelines recommend that carrier testing in minors should be postponed either until the age of majority or until the child can be actively involved in the decision making process. Although a number of high school programs exist which provide carrier screening to adolescents in at-risk populations, recent guidelines published by the American Society of Human Genetics do not advocate this testing. Despite this, there are some circumstances in which carrier testing does occur in minors. This testing might be intentional, in which identification of carrier status is the goal of the test, or unintentional, where carrier status is identified as a by-product of testing. In this review we outline the situations in which carriers may be identified in childhood and the positions of professional guidelines that address carrier testing in children. We then review the arguments for and against carrier testing presented in the literature and compare this to the empirical evidence in this field. [ABSTRACT FROM AUTHOR]

Patients are increasingly being encouraged and supported to access and control their own medical and genomic data. We argue that well-established and transparent raw genomic data retention and returning policies are imperative to enable patients to practice their rights to access and control raw data. [ABSTRACT FROM AUTHOR]

Summary Recognition of the role of genetics in the epilepsies has increased dramatically, impacting on clinical practice across many epilepsy syndromes. There is limited research investigating the impact of gene identification on individuals and families with epilepsy. While research has focused on the impact of delivering genetic information to families at the time of diagnosis in genetic diseases more broadly, little is known about how genetic results in epileptic diseases influences people's lives many years after it has been conveyed. This study used qualitative methods to explore the experience of receiving a genetic result in people with familial epilepsy. Interviews were conducted with individuals with familial epilepsies in whom the underlying genetic mutation had been identified. Recorded interviews underwent thematic analysis. 20 individuals from three families with different epilepsy syndromes and causative genes were interviewed. Multiple generations within families were studied. The mean time from receiving the genetic result prior to interview was 10.9 years (range 5–14 years). Three major themes were identified: 1) living with epilepsy: an individual's experience of the severity of epilepsy in their family influenced their view. 2) Clinical utility of the test: participants expressed varying reactions to receiving a genetic result. While for some it provided helpful information and relief, others were not surprised by the finding given the familial context. Some valued the use of genetic information for reproductive decision-making, particularly in the setting of severely affected family members. While altruistic reasons for participating in genetic research were discussed, participants emphasised the benefit of participation to them and their families. 3) ‘Talking about the family genes’: individuals reported poor communication between family members about their epilepsy and its genetic implications. The results provide important insights into the family experience of genetic epilepsies and communication within families. This information can be used to inform the development of guidelines for genetic result disclosure and genetic counselling for individuals and families with epilepsies. [ABSTRACT FROM AUTHOR]

Universal newborn hearing screening (UNHS) facilitates early detection of permanent congenital hearing loss in newborns. In recognition of specific needs among parents, support services have been established within some UNHS programs, including the Victorian Infant Hearing Screening Program (VIHSP). Despite this, there is limited research about how to best support parents in the context of well-established UNHS programs. This project aims to retrospectively explore parental support needs between the newborn hearing screen and enrolment into early intervention services. We used semi-structured interviews with parents three- to- six-months post confirmation of their newborn's diagnosis of bilateral moderate-profound sensorineural hearing loss. Data were analysed using inductive content analysis. Thirteen parents of ten children were interviewed. Parents described high satisfaction with the support they received. Some parents felt unprepared for a diagnosis of hearing loss, having been reassured that transient causes such as middle ear fluid caused the hearing screen result. Parents reported mixed responses regarding the value of parent-mentor support along the pathway and some parents described needing additional psychological input to adjust to their child's diagnosis. These findings provide insights into how a well-established UNHS program, VIHSP, supports parents along the hearing diagnosis pathway and how support can be further enriched. [ABSTRACT FROM AUTHOR]

Purpose To characterize the frequency and nature of the family history of seizures in probands with epilepsy falling within the epilepsy-aphasia spectrum ( EAS) in order to understand the genetic architecture of this group of disorders. Methods Patients with epileptic encephalopathy with continuous spike-and-wave during sleep ( ECSWS), Landau- Kleffner syndrome ( LKS), atypical benign partial epilepsy ( ABPE), and intermediate epilepsy-aphasia disorders ( IEAD) were recruited. All affected and available unaffected relatives up to three degrees of relatedness underwent phenotyping using a validated seizure questionnaire. Pedigrees were constructed for all families. The proportion of affected relatives according to each degree of relatedness was calculated. The epilepsy phenotypes in close relatives were analyzed. The data were compared to the families of probands with benign childhood epilepsy with centrotemporal spikes ( BECTS) using the same methodology. Key Findings Thirty-one probands, including five ECSWS, three LKS, one ABPE, and 22 IEAD were recruited. The mean age of seizure onset was 3.9 (range 0.5-7) years. A male predominance was seen (68%, 21/31) . Sixteen (51.6%) of 31 had a positive family history of seizures. Among 1,254 relatives, 30 (2.4%) had a history of seizures: 13 (10.2%) of 128 first-degree relatives, 5 (1.7%) of 291 second-degree relatives, and 12 (1.4%) of 835 third-degree relatives. Thirteen had febrile seizures, including two who had both febrile seizures and epilepsy. Of the 19 relatives with epilepsy, 4 had BECTS, 4 epilepsies with focal seizures of unknown cause, 3 IEAD, and 7 unclassified. One had genetic generalized epilepsy. In the families of the BECTS probands, 9.8% of first-degree, 3% of second-degree, and 1.5% of third-degree relatives had seizures, which was not significantly different from the EAS cohort families. Significance The frequencies of seizures in relatives of probands with EAS suggest that the underlying genetic influence of EAS is consistent with complex inheritance and similar to BECTS. The phenotypic pattern observed in the affected relatives comprised predominantly febrile seizures and focal seizures. These findings suggest that a shared genetic predisposition to focal epilepsies underpins the epilepsy-aphasia spectrum. [ABSTRACT FROM AUTHOR]

Purpose: Eyelid myoclonia with absences (EM) is an uncommon type of absence seizure associated with a variety of epilepsy syndromes. The syndrome of epilepsy with EM (EMA) has been proposed to denote the onset of frequent EM induced by eye closure and photic stimulation beginning in childhood. The clinical genetics of EMA has not been well characterized, although a family history of seizures is not infrequent. Methods: Individuals with EMA were ascertained by referral and through the investigators' clinical practices. All available family members were assessed for seizures using a validated seizure questionnaire. Electroclinical data were obtained on each proband and all affected family members; pedigrees were constructed. Families were analyzed for phenotypic patterns. Key Findings: Eighteen individuals with EMA were recruited. A history of seizures was found in 34 relatives in 15 (83%) of 18 families. In terms of epilepsy syndromes, 9 relatives from 7 of 15 families had febrile seizures. Two relatives had EMA. Classical genetic generalized epilepsy (GGE) syndromes were seen in five relatives: two generalized tonic-clonic seizures alone, two childhood absence epilepsy (CAE), and one juvenile myoclonic epilepsy (JME). Genetic epilepsy with febrile seizures plus (GEFS+) phenotypes occurred in 16 relatives. On review of the epilepsy syndromes within each family, seven families had a pattern consistent with GEFS+, whereas three families had classical GGE. Significance: The clinical genetics of EMA is suggestive of complex inheritance with shared genetic determinants overlapping with both classical GGE and GEFS+. The epilepsy syndromes in relatives of probands with EMA differ from those found in families of probands with CAE, supporting the concept that patients with EMA have a syndrome that is distinct from CAE. This presumably reflects different genetic components contributing to their genetic architecture. [ABSTRACT FROM AUTHOR]

Aim: Despite a recent increase in the use of ventilators in the home setting for children with chronic respiratory failure, there is currently no unified approach for clinical decision‐making for children requiring long‐term mechanical ventilation. The purpose of this study is to understand the clinician's perspective on decision‐making around home ventilation for children, and how home‐based care contributes to successful outcomes in this population. Methods: We recruited physicians and home ventilation nurses with at least 2 years' experience working in an Australian paediatric tertiary home ventilation service using professional networks and snowball sampling. Semi‐structured interviews were conducted by two researchers between February 2019 and June 2020. Interviews were audio‐recorded, transcribed, and analysed using inductive content analysis. Results: Twenty‐five individuals participated (17 physicians and 8 home ventilation nurses). Participants viewed themselves as impartial medical advocates in the decision‐making process, believing the decision to initiate or cease ventilation belonged to the child's family. While participants held the child's quality of life as the cornerstone of decision‐making, quality of life was subjective and family specific. Conclusion: These findings provide insight into how clinicians working with children with chronic respiratory insufficiency approach the decision to introduce home‐based ventilation. By understanding their role, strategies can be developed to assist them, leading to better outcomes for patients and families. Further research is needed to compare the perspectives of clinicians with the experience of ventilator‐assisted children and families in Australia. [ABSTRACT FROM AUTHOR]

This study explores the different manifestations and navigations of uncertainty in the practice of diagnostic next‐generation sequencing (NGS) testing. Drawing upon multi‐sited fieldwork conducted at a large Centre for Human Genetics in Belgium, we analyse how uncertainty takes shape and is managed in the different steps of the diagnostic process: starting from the testing offer, to the analysis in the lab, the multidisciplinary team meetings (MDTs) and ending with the consultation with the patient. Building on interviews with genetic healthcare professionals and their patients and observations in consultations and MDTs, our empirical work underlines the duality of uncertainty as both burdensome and productive. Building on the existing literature on uncertainty in medicine and NGS, our analysis shows the ontological politics at play in the everyday uncertainty work in this CHG. We show how the, at times, contrasting ways of dealing with uncertainty lead to friction but also result in constructive negotiation and collaboration between actors, making use of multiple types of evidence and expertise. By not only minimising but also sustaining or inviting uncertainty, genetic healthcare professionals are able to advance the practices around NGS in a way that matches their multidisciplinary understandings, considerations and more normative stances. [ABSTRACT FROM AUTHOR]

Summary We report the efficacy of the ketogenic diet in refractory epilepsies focusing on outcomes with regard to epilepsy syndromes and etiology in children and adults with refractory epilepsy. Sixty-four consecutive children and four adults were prospectively enrolled from 2002 to 2009; seven were excluded from analysis. The classical ketogenic diet was initiated on an inpatient basis with dietary ratios ranging from 2:1 to 4:1 fat to carbohydrate and protein. Patients were classified according to syndrome and etiology using the 1989 and more recent 2010 International League Against Epilepsy (ILAE) classification systems. Responders were defined as >50% reduction in seizure frequency compared to baseline. Syndromes included symptomatic generalized (52), genetic (idiopathic) generalized (7), and focal epilepsies (2) and etiologies included structural (24), genetic (18), and unknown (19). Twenty-nine (48%) of 61 patients were responders at 3 months. Two children became seizure-free: one with focal epilepsy of unknown etiology and another with refractory childhood absence epilepsy. Responsive syndromes included migrating partial epilepsy of infancy, childhood absence epilepsy, focal epilepsy, epilepsy with myoclonic-atonic seizures, and Dravet syndrome. Children with lissencephaly and hypoxic ischemic encephalopathy had surprisingly good responses. The ketogenic diet is an effective treatment for children and adults with refractory epilepsy. The response is predicted by type of epilepsy syndrome. Accurate characterization of the electroclinical syndrome is an important factor in decisions about timing of initiation of the ketogenic diet. [ABSTRACT FROM AUTHOR]

Like any new technology, rapid integration of genomic sequencing (GS) into the clinical setting can pose challenges for genetic health professionals (GHPs) using it to diagnose patients. We conducted semi-structured interviews with 31 clinical geneticists and genetic counsellors across Europe, Australia and Canada to gain a better understanding of the issues they were experiencing when requesting GS and receiving reports from laboratories. There was a spectrum of interactions between genetic health professionals and laboratories. This ranged from those that almost exclusively request sequencing from the laboratory that is affiliated with their genetic service, to those who do not have access to exome sequencing 'in-house' and instead send patient samples to a selection of different external laboratories. In general, a closer interaction between the clinicians and the laboratory scientists increased the involvement of the clinicians in the analysis/interpretation process. This appeared to lead to fewer, but more clinically relevant variants being reported, and greater GHP satisfaction in what is reported. Our findings suggest that GHPs consider integration of clinical expertise into the analysis/interpretation process is critical to ensure that the variants reported are of high clinical significance to patients. They also highlight the importance of providing GHPs with training in report interpretation. [ABSTRACT FROM AUTHOR]

Although Next Generation Sequencing (NGS) has increased our ability to test and diagnose, its results are often not clear-cut and require a complex interpretation and negotiation process by both healthcare professionals and patients involved. In this paper, we explore how diagnoses identified through NGS are socially shaped under influence of the broader social context. Using an analytical framework stemming from the sociology of health and illness and science and technology studies, with a focus on the construction of diagnosis and the role of uncertainty in medicine, we analyze the existing corpus of literature on NGS diagnostic practices. We show how in this early implementation phase of NGS, in which standardization efforts are not yet solidified, the boundary struggles around diagnoses obtained through NGS are particularly visible. We discuss the different steps in the diagnosis shaping process and what it subsequently entails to give and a receive a diagnosis using NGS. [ABSTRACT FROM AUTHOR]

Recently, Australia became the second jurisdiction worldwide to legalize the use of mitochondrial donation technology. The Mitochondrial Donation Law Reform (Maeve's Law) Bill 2021 allows individuals with a family history of mitochondrial disease to access assisted reproductive techniques that prevent the inheritance of mitochondrial disease. Using inductive content analysis, we assessed submissions sent to the Senate Committee as part of a programme of scientific inquiry and public consultation that informed drafting of the Bill. These submissions discussed a range of bioethical and legal considerations of central importance to the political debate. Significantly, submissions from those with a first-hand experience of mitochondrial disease, including clinicians and those with a family history of mitochondrial disease, were in strong support of this legislation. Those in support of the Bill commended the two-staged approach and rigorous licencing requirements as part of the Bill's implementation strategy. Submissions which outlined arguments against the legislation either opposed the use of these techniques in general or opposed aspects of the implementation strategy in Australia. These findings offer a window into the ethical arguments and perspectives that matter most to those Australians who took part in the Senate inquiry into mitochondrial donation. The insights garnered from these submissions may be used to help refine policy and guidelines as the field progresses. [ABSTRACT FROM AUTHOR]

The article [Title], written by [AuthorNames], was originally published electronically on the publisher’s internet portal (currently SpringerLink) on [date of OnlineFirst publication] without open access. [ABSTRACT FROM AUTHOR]

There is ongoing debate regarding whether and under which circumstances secondary findings (SF) should be offered in the pediatric context. Although studies have examined patient perspectives on receiving SF, little research has been conducted examining the experiences of clinicians offering SF to parents of newborns receiving genomic sequencing for a recently diagnosed medical condition. To address this, we conducted qualitative interviews exploring the views and experiences of 12 clinicians who offered SF to parents of infants who had diagnostic exome sequencing (ES) to identify the cause of their hearing loss. Interviews explored clinicians' accounts of parents' choices and decision-making about receiving SF, their views on whether and when to offer SF, their experiences returning SF, and any ethical challenges they encountered. Interviews were audio-recorded, transcribed and analyzed using inductive content analysis. Clinicians reported parents who declined all SF often felt finding out about future conditions unrelated to their child's hearing loss may be unhelpful, or even harmful, or were overwhelmed by their child's diagnosis. Clinicians also reported that some parents chose SF because they felt obliged to, even if they did not want to receive them. They explained that while some parents experienced decision-making regarding SF as positive, for others, this process was challenging or distressing. While clinicians generally agreed SF should be offered, mainly to promote parental choice, most felt SF should be offered after disclosing diagnostic results, primarily to avoid overwhelming parents. Clinicians encountered several ethical challenges, including balancing parental autonomy with non-maleficence, wanting to report or not report certain SF, and questioning whether parents can make an autonomous choice regarding SF. Our findings, which are novel as they relate to parents of young infants with a recent diagnosis of hearing loss, add new insights into clinicians' and parents' decision-making regarding SF in pediatrics. [ABSTRACT FROM AUTHOR]

Intensified and extensive data production and data storage are characteristics of contemporary western societies. Health data sharing is increasing with the growth of Information and Communication Technology (ICT) platforms devoted to the collection of personal health and genomic data. However, the sensitive and personal nature of health data poses ethical challenges when data is disclosed and shared even if for scientific research purposes. With this in mind, the Science and Values Working Group of the COST Action CHIP ME 'Citizen's Health through public-private Initiatives: Public health, Market and Ethical perspectives' (IS 1303) identified six core values they considered to be essential for the ethical sharing of health data using ICT platforms. We believe that using this ethical framework will promote respectful scientific practices in order to maintain individuals' trust in research. We use these values to analyse five ICT platforms and explore how emerging data sharing platforms are reconfiguring the data sharing experience from a range of perspectives. We discuss which types of values, rights and responsibilities they entail and enshrine within their philosophy or outlook on what it means to share personal health information. Through this discussion we address issues of the design and the development process of personal health data and patient-oriented infrastructures, as well as new forms of technologically-mediated empowerment. [ABSTRACT FROM AUTHOR]

Summary Purpose: To accurately determine the frequency and nature of the family history of seizures in patients with benign childhood epilepsy with centrotemporal spikes (BECTS). Method: Participants with BECTS were recruited from the electroencephalography (EEG) laboratories of three pediatric centers and by referral. Pedigrees were constructed for up to three degrees of relatedness for each proband. All available affected and unaffected individuals underwent phenotyping using a validated seizure questionnaire. The proportion of affected relatives according to degree of relatedness was calculated and phenotypic patterns were analyzed. Key Findings: Fifty-three probands with BECTS had a mean age of seizure onset at 7.8 years (range 2-12 years). Thirty-four (64%) of 53 patients were male. For 51 participants, pedigrees were available for three degrees of relatedness. Fifty-seven (2.7%) of 2,085 relatives had a history of seizures: Twenty-one (9.8%) of 214 first-degree, 15 (3%) of 494 second-degree, and 21 (1.5%) of 1,377 third-degree relatives. Febrile seizures were the most frequent phenotype, occurring in 26 of 57 affected relatives. There were 34 relatives with epilepsy: 6.5% (14 of 214) first-degree, 1.8% (9 of 494) second-degree, and 0.8% (11 of 1,377) third-degree relatives. Of 21 affected first-degree relatives: 8 of 21 had febrile seizures (FS), 4 had BECTS, 2 had epilepsy-aphasia spectrum disorder, one had temporal lobe epilepsy with hippocampal sclerosis, 2 had focal epilepsy of unknown cause, 2 had genetic generalized epilepsies, and 3 had miscellaneous. Significance: The frequency of epilepsies in relatives and the heterogeneous syndromes observed suggest that BECTS has a genetic component consistent with complex inheritance. Focal epilepsies are the most common seizure disorder observed in relatives, especially BECTS and epilepsy-aphasia spectrum disorder. Additional acquired or environmental factors are likely to be necessary for expression of the seizure disorder. [ABSTRACT FROM AUTHOR]

Genomic sequencing technologies (GS) pose novel challenges not seen in older genetic technologies, making traditional standards for fully informed consent difficult or impossible to meet. This is due to factors including the complexity of the test and the broad range of results it may identify. Meaningful informed consent is even more challenging to secure in contexts involving significant time constraints and emotional distress, such as when rapid genomic testing (RGS) is performed in neonatal intensive care units. In this article, we propose that informed consent matters not for its own sake, but because obtaining it furthers a range of morally important goals, such as promoting autonomy, well‐being, and trust in medicine. These goals form the basis of a new framework [PROmoting Morally Important Consent Ends (PROMICE)] for assessing the ethical appropriateness of various informed consent models. We illustrate this framework with two examples: (a) a tiered and layered consent model for obtaining consent for GS, and (b) consent for RGS in critically ill newborns. We conclude that appropriately—rather than fully—informed consent provides the correct standard for genomic medicine and research. [ABSTRACT FROM AUTHOR]

Trust may be important in shaping public attitudes to genetics and intentions to participate in genomics research and big data initiatives. As such, we examined trust in data sharing among the general public. A cross-sectional online survey collected responses from representative publics in the USA, Canada, UK and Australia (n = 8967). Participants were most likely to trust their medical doctor and less likely to trust other entities named. Company researchers were least likely to be trusted. Low, Variable and High Trust classes were defined using latent class analysis. Members of the High Trust class were more likely to be under 50 years, male, with children, hold religious beliefs, have personal experience of genetics and be from the USA. They were most likely to be willing to donate their genomic and health data for clinical and research uses. The Low Trust class were less reassured than other respondents by laws preventing exploitation of donated information. Variation in trust, its relation to areas of concern about the use of genomic data and potential of legislation are considered. These findings have relevance for efforts to expand genomic medicine and data sharing beyond those with personal experience of genetics or research participants. [ABSTRACT FROM AUTHOR]

With the use of genetic technology, researchers have the potential to inform medical diagnoses and treatment in actionable ways. Accurate variant interpretation is a necessary condition for the utility of genetic technology to unfold. This relies on the ability to access large genomic datasets so that comparisons can be made between variants of interest. This can only be successful if DNA and medical data are donated by large numbers of people to 'research', including clinical, non-profit and for-profit research initiatives, in order to be accessed by scientists and clinicians worldwide. The objective of the 'Your DNA, Your Say' global survey is to explore public attitudes, values and opinions towards willingness to donate and concerns regarding the donation of one's personal data for use by others. Using a representative sample of 8967 English-speaking publics from the UK, the USA, Canada and Australia, we explore the characteristics of people who are unwilling (n = 1426) to donate their DNA and medical information, together with an exploration of their reasons. Understanding this perspective is important for making sense of the interaction between science and society. It also helps to focus engagement initiatives on the issues of concern to some publics. [ABSTRACT FROM AUTHOR]

Kufs disease is the major adult form of neuronal ceroid lipofuscinosis, but is rare and difficult to diagnose. Diagnosis was traditionally dependent on the demonstration of characteristic storage material, but distinction from normal age-related accumulation of lipofuscin can be challenging. Mutation of CLN6 has emerged as the most important cause of recessive Kufs disease but, remarkably, is also responsible for variant late infantile ceroid lipofuscinosis. Here we provide a detailed description of Kufs disease due to CLN6 pathogenic variants. We studied 20 cases of Kufs disease with CLN6 pathogenic variants from 13 unrelated families. Mean age of onset was 28 years (range 12-51) with bimodal peaks in teenage and early adult life. The typical presentation was of progressive myoclonus epilepsy with debilitating myoclonic seizures and relatively infrequent tonic-clonic seizures. Patients became wheelchair-bound with a mean 12 years post-onset. Ataxia was the most prominent motor feature. Dementia appeared to be an invariable accompaniment, although it could take a number of years to manifest and occasionally cognitive impairment preceded myoclonic seizures. Patients were usually highly photosensitive on EEG. MRI showed progressive cerebral and cerebellar atrophy. The median survival time was 26 years from disease onset. Ultrastructural examination of the pathology revealed fingerprint profiles as the characteristic inclusions, but they were not reliably seen in tissues other than brain. Curvilinear profiles, which are seen in the late infantile form, were not a feature. Of the 13 unrelated families we observed homozygous CLN6 pathogenic variants in four and compound heterozygous variants in nine. Compared to the variant late infantile form, there was a lower proportion of variants that predicted protein truncation. Certain heterozygous missense variants in the same amino acid position were found in both variant late infantile and Kufs disease. There was a predominance of cases from Italy and surrounding regions; this was partially explained by the discovery of three founder pathogenic variants. Clinical distinction of type A (progressive myoclonus epilepsy) and type B (dementia with motor disturbance) Kufs disease was supported by molecular diagnoses. Type A is usually caused by recessive pathogenic variants in CLN6 or dominant variants in DNAJC5. Type B Kufs is usually associated with recessive CTSF pathogenic variants. The diagnosis of Kufs remains challenging but, with the availability of genetic diagnosis, this will largely supersede the use of diagnostic biopsies, particularly as biopsies of peripheral tissues has unsatisfactory sensitivity and specificity. [ABSTRACT FROM AUTHOR]

Results from genomic sequencing often have implications not just for patients but also for their relatives. To date, there are no studies in Belgium exploring whether potential relatives would want to be informed of a genetic risk in the family and their preferences on different approaches to disclosure. We surveyed the attitudes of the Flemish general population (n = 407) towards receiving genetic information from their family members, including attitudes towards breaches in confidentiality, preferences for who communicates genetic risk and how the information is communicated, and policy approaches to nondisclosure. Most participants wanted to be informed of their genetic risk and receive genetic testing to confirm their diagnosis. Most preferred to be informed of genetic risk by a close family member, but that when given the choice between a distant family member and a clinician, most participants preferred to be contacted by a clinician. In Belgium there is currently no clear legal pathway for clinicians to directly initiate contact with at-risk relatives, but the responses from members of the Flemish population analyzed in this study indicate that this approach to disclosure of genetic risk deserves further consideration. Our findings indicate that the general population would support legislation allowing clinicians to inform relatives even in cases where the patient did not want to inform them. As this is not currently allowed in Belgium, policy alternatives should be considered. [ABSTRACT FROM AUTHOR]

Whole-exome sequencing (WES) has been instrumental in the discovery of novel genes and mechanisms causing Mendelian diseases. While this technology is now being successfully applied in a number of clinics, particularly to diagnose patients with rare diseases, it also raises a number of ethical, legal and social issues. In order to identify what challenges were directly foreseen by technology users, we performed a systematic review of the literature. In this paper, we focus on recent publications related to the use of WES in the pediatric context and analyze the most prominent challenges raised by technology users. This is particularly relevant considering that a) most patients currently undergoing testing using WES to identify the genetic basis for rare diseases are children and b) their lack of capacity to consent for themselves makes them a vulnerable population and generates the need for specific ethical, legal and regulatory procedures. We identified key challenges that related to four main categories: (1) intake; (2) sequence production and analysis; (3) reporting of results and counseling considerations and (4) collaborative data interpretation and data sharing. We then contextualize these challenges in light of the recent recommendations and guidelines, published by professional societies that have significant potential to impact the field. [ABSTRACT FROM AUTHOR]

Aims: To explore the views of the Belgian public on various topics surrounding genetics and genetic testing (GT). Materials and Methods: A written questionnaire was administered to visitors of the annual cartoon festival in Knokke-Heist, Belgium, during the summer of 2014. The main theme of the festival was challenges and progress in human genetics and it was attended by more than 100,000 visitors. Results: The survey was completed by 1182 respondents, resulting in a demographically diverse sample with a mean age of 48.5 years. Our respondents expressed moderate interest in predictive GT, with 39.1% willing to learn about their predisposition to diseases through GT and 49.5% indicating interest in getting tested exclusively for treatable/preventable diseases. We observed higher interest in GT for reproductive purposes, such as preconception screening for recessive disorders (53.8%) and prenatal GT (60.7%). A substantial minority (46.4%) of the respondents were worried that GT could further stigmatize people with disabilities, while 39.7% believed that carrier screening for recessive diseases would lead to an inferior image of people affected by them. Conclusion: Paying due attention to the attitudes, beliefs, and concerns of the general public is important to ensure ethically sound and socially acceptable implementation of new genetic technologies. [ABSTRACT FROM AUTHOR]

Background: The use of genome-wide (whole genome or exome) sequencing for population-based newborn screening presents an opportunity to detect and treat or prevent many more serious early-onset health conditions than is possible today. Methods: The Paediatric Task Team of the Global Alliance for Genomics and Health's Regulatory and Ethics Working Group reviewed current understanding and concerns regarding the use of genomic technologies for population-based newborn screening and developed, by consensus, eight recommendations for clinicians, clinical laboratory scientists, and policy makers. Results: Before genome-wide sequencing can be implemented in newborn screening programs, its clinical utility and cost-effectiveness must be demonstrated, and the ability to distinguish disease-causing and benign variants of all genes screened must be established. In addition, each jurisdiction needs to resolve ethical and policy issues regarding the disclosure of incidental or secondary findings to families and ownership, appropriate storage and sharing of genomic data. Conclusion: The best interests of children should be the basis for all decisions regarding the implementation of genomic newborn screening. [ABSTRACT FROM AUTHOR]

Diagnostic genomic sequencing generates unprecedented amounts of data. In addition to its primary use, this data could be used for a wide range of secondary purposes, including research and informing future healthcare for the data donor. These opportunities may require data to be shared with third parties. Although effective data sharing relies on public support, there are barriers which may prevent people from choosing to donate their genomic data and surprisingly few studies explore these barriers in depth. To address this need, this study aimed to qualitatively explore the Australian public's views and preferences for storing and sharing genomic data. Online focus groups were recorded, transcribed, and analysed using inductive content analysis. A total of 7 focus groups were conducted with 39 members of the Australian public ranging from 18 to 67 years of age. Participants were mostly supportive of genomic data being stored and shared for secondary purposes, recognising the potential benefits for individual health and wider medical research. However, some concerns were identified. Participants felt genomic data was particularly sensitive information, and raised the potential for discrimination, stigma, and other malicious uses of such data. Concerns for privacy and security of the data were also prevalent. Trustworthiness of data users was important when considering who genomic data should be shared with. Although participants were supportive of data being freely available to health professionals and researchers, they were opposed to insurance companies and employers accessing the data. There was greater controversy around sharing data with law enforcement and pharmaceutical companies. Participants recognised both benefits and harms to sharing with law enforcement. They were also cognizant of the dual purpose of pharmaceutical companies as both research and profit-driven organisations. Finally, participants expressed varying perspectives about sharing genomic data with family members, yet most agreed that explicit consent from the data donor should be required to share their information with relatives. This study highlighted several of the Australian public's perceived barriers and motivators for the storage and sharing of genomic data. Participants recognised both the benefits of collecting, storing and sharing such data widely but also the potential for harm from data misuse. While public acceptance of such endeavours is required to maximise the volume of data made available, the concerns around data access and security need to be addressed before this can occur. These findings also highlight the nuance and ethical complexity of decisions about who we should allow to access donated genomic data. These perspectives will be essential in helping to shape the way large-scale genomic data storage and sharing is developed and implemented in Australia, and internationally. [ABSTRACT FROM AUTHOR]

Participation in healthcare decision-making is considered to be an important right of minors, and is highlighted in both international legislation and public policies. However, despite the legal recognition of children's rights to participation, and also the benefits that children experience by their involvement, there is evidence that legislation is not always translated into healthcare practice. There are a number of factors that may impact on the ability of the child to be involved in decisions regarding their medical care. Some of these factors relate to the child, including their capacity to be actively involved in these decisions. Others relate to the family situation, sociocultural context, or the underlying beliefs and practices of the healthcare provider involved. In spite of these challenges to including children in decisions regarding their clinical care, we argue that it is an important factor in their treatment. The extent to which children should participate in this process should be determined on a case-by-case basis, taking all of the potential barriers into account. [ABSTRACT FROM AUTHOR]

Exome sequencing (ES) is an effective method for identifying the genetic cause of hearing loss in infants diagnosed through newborn hearing screening programs. ES has the potential to be integrated into routine clinical care, yet little is known about the experiences of clinicians offering this test to families. To address this gap, clinicians involved in a clinical study using ES to identify the cause of infants' hearing loss were interviewed to explore their experiences with offering and returning results to parents. Interview transcripts were analysed using inductive content analysis. Twelve clinicians participated: seven genetic counsellors, four clinical geneticists, and one paediatrician. Most clinicians were supportive of offering ES to infants with hearing loss, primarily because results may inform the child's clinical management. However, some expressed concerns, questioning the utility of this information, particularly for isolated hearing loss. Clinicians had differing views regarding the optimal time to offer ES to families; while some felt that families can manage everything at once, others recommended delaying testing until parents have come to terms with their child's diagnosis. These findings show the complexity involved in determining how ES should be offered to families following the diagnosis of a child with hearing loss, particularly with regards to when testing is suggested. [ABSTRACT FROM AUTHOR]

We previously identified a homozygous mutation in the Golgi SNAP receptor complex 2 gene (GOSR2) in six patients with progressive myoclonus epilepsy. To define the syndrome better we analysed the clinical and electrophysiological phenotype in 12 patients with GOSR2 mutations, including six new unrelated subjects. Clinical presentation was remarkably similar with early onset ataxia (average 2 years of age), followed by myoclonic seizures at the average age of 6.5 years. Patients developed multiple seizure types, including generalized tonic clonic seizures, absence seizures and drop attacks. All patients developed scoliosis by adolescence, making this an important diagnostic clue. Additional skeletal deformities were present, including pes cavus in four patients and syndactyly in two patients. All patients had elevated serum creatine kinase levels (median 734 IU) in the context of normal muscle biopsies. Electroencephalography revealed pronounced generalized spike and wave discharges with a posterior predominance and photosensitivity in all patients, with focal EEG features seen in seven patients. The disease course showed a relentless decline; patients uniformly became wheelchair bound (mean age 13 years) and four had died during their third or early fourth decade. All 12 cases had the same variant (c.430G>T, G144W) and haplotype analyses confirmed a founder effect. The cases all came from countries bounding the North Sea, extending to the coastal region of Northern Norway. ‘North Sea’ progressive myoclonus epilepsy has a homogeneous clinical presentation and relentless disease course allowing ready identification from the other progressive myoclonus epilepsies. [ABSTRACT FROM AUTHOR]

Summary Incomplete penetrance and variable phenotypic expression are characteristic of a number of syndromes of familial epilepsy. The purpose of the present investigation is to determine if the 15q13.3 copy number deletion functions as a locus modifying the epilepsy phenotype caused by other known or presumed pathogenic mutations segregating in families with epilepsies. No 15q13.3 microdeletions were detected in 756 affected or definite obligate carrier individuals across 151 families selected on the basis of having multiple members affected with epilepsy and showing a range of seizure types. Therefore, the 15q13.3 microdeletion does not act as a genetic modifier in this cohort of families and is not responsible for any of the genetic heterogeneity hypothesized to account for failure to detect linkage in previous genome-wide scans in five of the larger families included in this study. [ABSTRACT FROM AUTHOR]

The molecular basis of Kufs disease is unknown, whereas a series of genes accounting for most of the childhood-onset forms of neuronal ceroid lipofuscinosis (NCL) have been identified. Diagnosis of Kufs disease is difficult because the characteristic lipopigment is largely confined to neurons and can require a brain biopsy or autopsy for final diagnosis. We mapped four families with Kufs disease for whom there was good evidence of autosomal-recessive inheritance and found two peaks on chromosome 15. Three of the families were affected by Kufs type A disease and presented with progressive myoclonus epilepsy, and one was affected by type B (presenting with dementia and motor system dysfunction). Sequencing of a candidate gene in one peak shared by all four families identified no mutations, but sequencing of CLN6, found in the second peak and shared by only the three families affected by Kufs type A disease, revealed pathogenic mutations in all three families. We subsequently sequenced CLN6 in eight other families, three of which were affected by recessive Kufs type A disease. Mutations in both CLN6 alleles were found in the three type A cases and in one family affected by unclassified Kufs disease. Mutations in CLN6 are the major cause of recessive Kufs type A disease. The phenotypic differences between variant late-infantile NCL, previously found to be caused by CLN6, and Kufs type A disease are striking; there is a much later age at onset and lack of visual involvement in the latter. Sequencing of CLN6 will provide a simple diagnostic strategy in this disorder, in which definitive identification usually requires invasive biopsy. [ABSTRACT FROM AUTHOR]

The progressive myoclonus epilepsies (PMEs) are a group of predominantly recessive disorders that present with action myoclonus, tonic-clonic seizures, and progressive neurological decline. Many PMEs have similar clinical presentations yet are genetically heterogeneous, making accurate diagnosis difficult. A locus for PME was mapped in a consanguineous family with a single affected individual to chromosome 17q21. An identical-by-descent, homozygous mutation in GOSR2 (c.430G>T, p.Gly144Trp), a Golgi vesicle transport gene, was identified in this patient and in four apparently unrelated individuals. A comparison of the phenotypes in these patients defined a clinically distinct PME syndrome characterized by early-onset ataxia, action myoclonus by age 6, scoliosis, and mildly elevated serum creatine kinase. This p.Gly144Trp mutation is equivalent to a loss of function and results in failure of GOSR2 protein to localize to the cis-Golgi. [ABSTRACT FROM AUTHOR]

Temporal lobe epilepsy is the commonest partial epilepsy of adulthood. Although generally perceived as an acquired disorder, several forms of familial temporal lobe epilepsy, with mesial or lateral seizure semiology, have been described. Descriptions of familial mesial temporal lobe epilepsy have varied widely from a benign epilepsy syndrome with prominent déjà vu and without antecedent febrile seizures or magnetic resonance imaging abnormalities, to heterogeneous, but generally more refractory epilepsies, often with a history of febrile seizures and with frequent hippocampal atrophy and high T2 signal on magnetic resonance imaging. Compelling evidence of a genetic aetiology (rather than chance aggregation) in familial mesial temporal lobe epilepsy has come from twin studies. Dominant inheritance has been reported in two large families, though the usual mode of inheritance is not known. Here, we describe clinical and neurophysiological features of 20 new mesial temporal lobe epilepsy families including 51 affected individuals. The epilepsies in these families were generally benign, and febrile seizure history was infrequent (9.8%). No evidence of hippocampal sclerosis or dysplasia was present on brain imaging. A single individual underwent anterior temporal lobectomy, with subsequent seizure freedom and histopathological evidence of hippocampal sclerosis was not found. Inheritance patterns in probands’ relatives were analysed in these families, together with 19 other temporal lobe epilepsy families previously reported by us. Observed frequencies of epilepsies in relatives were lower than predicted by dominant Mendelian models, while only a minority (8/39) of families could be compatible with recessive inheritance. These findings strongly suggest that complex inheritance, similar to that widely accepted in the idiopathic generalized epilepsies, is the usual mode of inheritance in familial mesial temporal lobe epilepsy. This disorder, which appears to be relatively common, and not typically associated with hippocampal sclerosis, is an appropriate target for contemporary approaches to complex disorders such as genome-wide association studies for common genetic variants or deep sequencing for rare variants. [ABSTRACT FROM PUBLISHER]

Benign childhood epilepsy with centrotemporal spikes (BECTS) is the most common epilepsy syndrome of childhood and can be associated with language difficulties. The exact profile of these difficulties and their neurofunctional underpinnings, however, are not yet clear. To further understand the impact of the BECTS syndrome on language, we assessed language performance using standard neuropsychological measures, and patterns of language lateralization using functional magnetic resonance imaging (fMRI) in children with typical BECTS (n = 20) and healthy controls (n = 20). The fMRI analyses revealed that language-related activation was less lateralized to the left hemisphere in anterior brain regions in the patients relative to the control group. This finding was consistent with decreased performance in the BECTS group compared to the control group on the neuropsychological measure most dependent on the integrity of anterior aspects of the language axis, namely, sentence production. The converging lines of evidence from the neuropsychological and activation methodologies support the view that BECTS is associated with language difficulties that are regional, and anterior, in nature. [ABSTRACT FROM AUTHOR]

Action myoclonus-renal failure syndrome (AMRF) is an autosomal-recessive disorder with the remarkable combination of focal glomerulosclerosis, frequently with glomerular collapse, and progressive myoclonus epilepsy associated with storage material in the brain. Here, we employed a novel combination of molecular strategies to find the responsible gene and show its effects in an animal model. Utilizing only three unrelated affected individuals and their relatives, we used homozygosity mapping with single-nucleotide polymorphism chips to localize AMRF. We then used microarray-expression analysis to prioritize candidates prior to sequencing. The disorder was mapped to 4q 13-21, and microarray-expression analysis identified SCARB2/Limp2, which encodes a lysosomal-membrane protein, as the likely candidate. Mutations in SCARB2/Limp2 were found in all three families used for mapping and subsequently confirmed in two other unrelated AMRF families. The mutations were associated with lack of SCARB2 protein. Reanalysis of an existing Limp2 knockout mouse showed intracellular inclusions in cerebral and cerebellar cortex, and the kidneys showed subtle glomerular changes. This study highlights that recessive genes can be identified with a very small number of subjects. The ancestral lysosomal-membrane protein SCARB2/LIMP-2 is responsible for AMRF. The heterogeneous pathology in the kidney and brain suggests that SCARB2/Limp2 has pleiotropic effects that may be relevant to understanding the pathogenesis of other forms of glomerulosclerosis or collapse and myoclonic epilepsies. [ABSTRACT FROM AUTHOR]