Outcomes of patient self-referral for the diagnosis of several rare inherited kidney diseases

PurposeTo evaluate self-referral from the Internet for genetic diagnosis of several rare inherited kidney diseases.MethodsRetrospective study from 1996 to 2017 analyzing data from an academic referral center specializing in autosomal dominant tubulointerstitial kidney disease (ADTKD). Individuals were referred by academic health-care providers (HCPs) nonacademic HCPs, or directly by patients/families.ResultsOver 21 years, there were 665 referrals, with 176 (27%) directly from families, 269 (40%) from academic HCPs, and 220 (33%) from nonacademic HCPs. Forty-two (24%) direct family referrals had positive genetic testing versus 73 (27%) families from academic HCPs and 55 (25%) from nonacademic HCPs (P = 0.72). Ninety-nine percent of direct family contacts were white and resided in zip code locations with a mean median income of $77,316 ± 34,014 versus US median income $49,445.ConclusionUndiagnosed families with Internet access bypassed their physicians and established direct contact with an academic center specializing in inherited kidney disease to achieve a diagnosis. Twenty-five percent of all families diagnosed with ADTKD were the result of direct family referral and would otherwise have been undiagnosed. If patients suspect a rare disorder that is undiagnosed by their physicians, actively pursuing self-diagnosis using the Internet can be successful. Centers interested in rare disorders should consider improving direct access to families.     

Secondary findings from next generation sequencing: Psychological and ethical issues. Family and patient perspectives

Access to active search for actionable secondary findings (SF) in diagnostic practice is a major psychological and ethical issue for genomic medicine. In this study, we analyzed the preferences of patients and their families regarding SF and identified the reporting procedures necessary for informed consent. We interviewed parents of patients with undiagnosed rare diseases potentially eligible for exome sequencing and patients affected by the diseases listed in the ACMG recommendations. Four focus groups (FG) were formed: parents of patients with undiagnosed rare diseases (FG1, n = 5); patients with hereditary cancers (FG2, n = 10); patients with hereditary cardiac conditions (FG3, n = 3); and patients with metabolic diseases (FG4, n = 3). Psychologists presented three broad topics for discussion: 1. Favorable or not to SF access, 2. Reporting procedures, 3. Equity of access. Discussions were recorded and analyzed using simplified Grounded Theory. Overall, 8 participants declared being favorable to SF because of the medical benefit (mainly FG1); 11 were unfavorable because of the psychological consequences (mainly FG2, FG3, FG4); 2 were ambivalent. The possibility of looking for SF in minors was debated. The 4 key information-based issues for participants ranked as follows: explanation of SF issues, autonomy of choice, importance of a reflection period, and quality of interactions between patients and professionals. Examining equity of access to SF led to philosophical discussions on quality of life. In conclusion, individual experience and life context (circumstances) were decisive in participants’ expectations and fears regarding access to SF. Additional longitudinal studies based on actual SF disclosure announcements are needed to establish future guidelines.     

Genetic counseling for prion disease: Updates and best practices

Prion disease is a rare, fatal, and often rapidly progressive neurodegenerative disease. Ten to fifteen percent of cases are caused by autosomal dominant gain-of-function variants in the prion protein gene, PRNP. Rarity and phenotypic variability complicate diagnosis, often obscuring family history and leaving families unprepared for the genetic implications of an index case. Several recent developments inspire this update in best practices for prion disease genetic counseling. A new prion-detection assay has transformed symptomatic diagnosis. Meanwhile, penetrance, age of onset, and duration of illness have been systematically characterized across PRNP variants in a global cohort. Clinically, the traditional genotype–phenotype correlation has weakened over time, and the term genetic prion disease may now better serve providers than the historical subtypes Creutzfeldt-Jakob disease, fatal familial insomnia, and Gerstmann-Sträussler-Scheinker disease. Finally, in the age of genetically targeted therapies, clinical trials for prion disease are being envisaged, and healthy at-risk individuals may be best positioned to benefit. Such individuals need to be able to access clinical services for genetic counseling and testing. Thus, this update on the genetics of prion disease and best practices for genetic counseling for this disease aims to provide the information needed to expand genetic counseling services.     

Patient and family social media use surrounding a novel treatment for a rare genetic disease: a qualitative interview study

PurposeAdvances in gene therapy and precision medicine have led to a growing number of novel treatments for rare genetic diseases. Patients/families may lack access to up-to-date, accurate, and relevant information about these treatments. Social media offers one potentially important resource for these communities. Our goal was to understand how patients/families with spinal muscular atrophy (SMA)—a rare genetic condition—used social media to share, consume, and evaluate information about the novel treatment nusinersen (Spinraza) following the drug’s approval.MethodsWe conducted qualitative, semistructured interviews with 20 SMA patients or parents of patients, deriving themes and subthemes through content and thematic network analysis. Participants also completed a demographic survey.ResultsParticipants described leveraging social media to learn about nusinersen treatment, make informed treatment decisions, and advocate for/access treatment. They also described critically evaluating the trustworthiness of nusinersen-related information on social media and the privacy risks of social media use.ConclusionPatients/families used social media to navigate the new and dynamic landscape of nusinersen treatment for SMA, while attempting to mitigate misinformation and privacy risks. As new treatments become available, providers and patients/families may benefit from proactively discussing social media use, so as to maximize important benefits while minimizing risks.     

The value of diagnostic testing for parents of children with rare genetic diseases

PurposeExome sequencing (ES) can rapidly identify disease-causing variants responsible for rare, single-gene diseases, and potentially reduce the duration of the diagnostic odyssey. Our study examines how parents and families value ES.MethodsWe developed a discrete choice experiment (DCE) survey that was administered to parents of children with rare diseases. The DCE included 14 choice tasks with 6 attributes and 3 alternatives. A valuation-space model was used to estimate willingness to pay, willingness to wait for test results, and minimum acceptable chance of a diagnosis for changes in each attribute.ResultsThere were n = 319 respondents of whom 89% reported their child had genetic testing, and 66% reported their child had a diagnosis. Twenty-six percent reported that their child had been offered ES. Parents were willing to pay CAD$6590 (US$4943), wait 5.2 years to obtain diagnostic test results, and accept a reduction of 3.1% in the chance of a diagnosis for ES compared with operative procedures.ConclusionTimely access to ES could reduce the diagnostic odyssey and associated costs. Before ES is incorporated routinely into care for patients with rare diseases in Canada and more broadly, there must be a clear understanding of its value to patients and families.     

Identification of UBAP1 mutations in juvenile hereditary spastic paraplegia in the 100,000 Genomes Project

Hereditary spastic paraplegia (HSP) is a group of heterogeneous inherited degenerative disorders characterized by lower limb spasticity. Fifty percent of HSP patients remain yet genetically undiagnosed. The 100,000 Genomes Project (100KGP) is a large UK-wide initiative to provide genetic diagnosis to previously undiagnosed patients and families with rare conditions. Over 400 HSP families were recruited to the 100KGP. In order to obtain genetic diagnoses, gene-based burden testing was carried out for rare, predicted pathogenic variants using candidate variants from the Exomiser analysis of the genome sequencing data. A significant gene-disease association was identified for UBAP1 and HSP. Three protein truncating variants were identified in 13 patients from 7 families. All patients presented with juvenile form of pure HSP, with median age at onset 10 years, showing autosomal dominant inheritance or de novo occurrence. Additional clinical features included parkinsonism and learning difficulties, but their association with UBAP1 needs to be established.Subject terms: Genetics research, Neurological disorders     

The implementation of an enhanced clinical model to improve the diagnostic yield of exome sequencing for patients with a rare genetic disease: A Canadian experience

The introduction of clinical exome sequencing (ES) has provided a unique opportunity to decrease the diagnostic odyssey for patients living with a rare genetic disease (RGD). ES has been shown to provide a diagnosis in 29%–57% of patients with a suspected RGD, with as many as 70% remaining undiagnosed. There is a need to advance the clinical model of care by more formally integrating approaches that were previously considered research into an enhanced diagnostic workflow. We developed an Exome Clinic, which set out to evaluate a workflow for improving the diagnostic yield of ES for patients with an undiagnosed RGD. Here, we report the outcomes of 47 families who underwent clinical ES in the first year of the clinic. The diagnostic yield from clinical ES was 40% (19/47). Families who remained undiagnosed after ES had the opportunity for follow-up studies that included phenotyping and candidate variant segregation in relatives, genomic matchmaking, and ES reanalysis. This enhanced diagnostic workflow increased the diagnostic yield to 55% (26/47), predominantly through the resolution of variants and genes of uncertain significance. We advocate that this approach be integrated into mainstream clinical practice and highlight the importance of a coordinated translational approach for patients with RGD.     

Genetics of cerebrotendinous xanthomatosis (CTX): An autosomal recessive trait with high gene frequency in Sephardim of Moroccan origin

We describe 6 patients (from 3 families) affected with cerebrotendinous xanthomatosis (CTX). All are Sephardic Jews of Moroccan extraction. In view of the small number of CTX patients diagnosed in the world (a total of 50 including our 6 patients), we are probably dealing with an ethnic subgroup with a high CTX gene frequency, which we have estimated to be 1/108. Since there are differences in expression in this disease, we recommend cholestanol study in cases of undiagnosed cataract or tendinous xanthomas in childhood or early adolescence. The diagnosis in CTX is important not only for genetic counseling, but also in view of possible treatment.     

Waiting for a diagnosis in Rubinstein–Taybi: The journey from “ignorance is bliss” to the value of “a label”

The journey to receiving a diagnosis for rare genetic disease can be long and emotionally impactful. This study describes parental experiences of receiving their child's diagnosis of Rubinstein–Taybi syndrome (RTS), a rare genetic condition characterized by growth and developmental delay together with dysmorphic features. Parents from the RTS Australia support group participated in qualitative, semi‐structured phone interviews, which were transcribed verbatim and thematically analyzed. Questions focused on psychosocial challenges and benefits pre and post‐diagnosis. Ten mothers and three fathers participated, with the mean age of diagnosis being 8 months. Parents reported positive psychological effects from a slight delay in diagnosis, and negative effects from an extended diagnostic delay, suggesting the ideal time for a parent to receive a diagnosis lies in the post attachment stage, prior to the development of significant parental concerns. This stage would vary depending on condition severity. Parents desired a diagnosis to reduce uncertainty; however, uncertainty remained post diagnosis, and shifted its focus from broadly encompassing etiology and prognosis, to specifically focusing on concerns regarding severity within the spectrum. Perceived benefits of a diagnosis mainly centered on the provision of a label. Parents articulated that a label increased social acceptance, enhanced coping, promoted communication, and improved access to medical, financial, and support services. This study provides insights into the experience of families prior to and following receipt of a diagnosis. It also highlights the possibility of an optimal time window to receive a diagnosis; in which bonding is maximized and parental distress is minimized.     

Support among persons infected with HIV for routine health department contact for HIV partner notification

Public health partner notification (PN) services are provided inconsistently to persons diagnosed with HIV/AIDS in the United States, and some community groups representing persons with HIV/AIDS have opposed widespread application of PN. We surveyed persons with HIV recently reported to our health department and a random sample of HIV-infected persons attending an HIV/AIDS clinic. A total of 95 persons, of whom 76 (80%) were men who have sex with men, completed an anonymous self-administered questionnaire. Eighty-four percent of participants believed the health department should routinely offer everyone diagnosed with HIV help in notifying their partners; 79% indicated they would be somewhat or very likely to provide information to a doctor, case worker, or health department employee for purposes of PN; and 20% indicated they wanted help in notifying a recent sex partner. Seventy-eight percent of participants believed the health department should contact all HIV-infected persons after diagnosis to help them access medical care and social services, and 68% wanted the health department to contact them about the availability of medical or social services. In contrast to common public perceptions, these results suggest that most persons with HIV support health departments routinely contacting people after HIV diagnosis and that many want assistance with PN.     

Evaluation of a screening questionnaire for genetic studies of Parkinson's disease.

A screening questionnaire with high sensitivity for detection of Parkinson's disease would make it easier to identify undiagnosed, yet affected, family members for genetic research. We assessed the validity of a screening questionnaire developed by Duarte et al. [1995: Mov Disord 10:643-649] with reported high specificity and sensitivity for Parkinson's disease (PD). We applied the questionnaire to 78 asymptomatic members of families that had at least two people diagnosed with PD. These families were participating in a linkage study of Parkinson's disease. Examination of these 78 revealed that 53 were normal (normal controls) and 25 were classified ("undiagnosed" PD defined) as possible, probable, or clinically definite PD based on standardized criteria. We compared these results with 123 patients with clinically definite PD ("diagnosed" PD). There were significant differences among the mean scores on the questionnaire for normal controls (4.4), subjects with undiagnosed PD (9.8), and patients with diagnosed PD (42.1; p<0.000001) and a significant difference between undiagnosed PD and normals (p<0.01). The questionnaire had only 4% sensitivity for detection of parkinsonism in undiagnosed PD using the original criteria [Duarte et al., 1995]. Revising the criteria increased the sensitivity from 4 to 48% in the undiagnosed group. The positive predictive value was 39% and the negative predictive value was 72%. Prospective application of these revised criteria is necessary to confirm the improved sensitivity. However, we conclude that this screening questionnaire has inadequate sensitivity for detection of mild parkinsonism and direct examination is still critical for accurate classification for genetic studies.     

Genetic diagnosis of Down syndrome in an underserved community

It is a matter of course that in high‐income countries, infants born with features suggestive of Down syndrome (DS) are offered genetic testing for confirmation of a clinical diagnosis. Benefits of a definitive diagnosis include an end to the diagnostic odyssey, informed prognosis, opportunities for caregiver support, inclusion to social support networks, and more meaningful genetic counseling. The healthcare experience for families of children born with DS in low‐ and middle‐income nations is in stark contrast with such a level of care. Barriers to obtaining genetic diagnosis might include economic disparities, geographical isolation, and lack of access to health care professionals trained in genetic medicine. As part of a combined research and community outreach effort, we provided genetic testing for several patients with DS. These individuals and their families live on several resource‐limited Caribbean islands and have either limited or virtually no access to medical genetics services. Within this group were three families with recurrent DS. Karyotype established that translocation events were not involved in the DS in any of these families. This information enabled genetic counseling to help family members understand their recurrent DS. A definitive diagnosis of DS is beneficial to families in resource‐limited communities and may help to provide such families with genetic counseling, reassurance, and peace of mind.

     

Using deep learning and electronic health records to detect Noonan syndrome in pediatric patients

PurposeThe variable expressivity and multisystem features of Noonan syndrome (NS) make it difficult for patients to obtain a timely diagnosis. Genetic testing can confirm a diagnosis, but underdiagnosis is prevalent owing to a lack of recognition and referral for testing. Our study investigated the utility of using electronic health records (EHRs) to identify patients at high risk of NS.MethodsUsing diagnosis texts extracted from Cincinnati Children’s Hospital’s EHR database, we constructed deep learning models from 162 NS cases and 16,200 putative controls. Performance was evaluated on 2 independent test sets, one containing patients with NS who were previously diagnosed and the other containing patients with undiagnosed NS.ResultsOur novel method performed significantly better than the previous method, with the convolutional neural network model achieving the highest area under the precision-recall curve in both test sets (diagnosed: 0.43, undiagnosed: 0.16).ConclusionThe results suggested the validity of using text-based deep learning methods to analyze EHR and showed the value of this approach as a potential tool to identify patients with features of rare diseases. Given the paucity of medical geneticists, this has the potential to reduce disease underdiagnosis by prioritizing patients who will benefit most from a genetics referral.     

“Matching” consent to purpose: The example of the Matchmaker Exchange

The Matchmaker Exchange (MME) connects rare disease clinicians and researchers to facilitate the sharing of data from undiagnosed patients for the purpose of novel gene discovery. Such sharing raises the odds that two or more similar patients with candidate genes in common may be found, thereby allowing their condition to be more readily studied and understood. Consent considerations for data sharing in MME included both the ethical and legal differences between clinical and research settings and the level of privacy risk involved in sharing varying amounts of rare disease patient data to enable patient matches. In this commentary, we discuss these consent considerations and the resulting MME Consent Policy as they may be relevant to other international data sharing initiatives.     

Use and non-use of genetic counseling after diagnosis of a birth defect

We examined factors and experiences associated with parents' use or non-use of genetic counseling services within 5 years of the diagnosis of a birth defect in their child. Eligible parents were identified using birth defects data for births in 2004 in Victoria, Australia, and invited to complete a written questionnaire and optional telephone interview. Participants were asked about sources of genetic information, experiences and satisfaction with obtaining this information, and impressions of genetic services. Reasons given for not attending genetic counseling services included not knowing the service was available, or not feeling a need to attend. Non-users commonly stated they would not consider termination of pregnancy for the type of birth defect experienced or that they obtained information from other sources, such as pediatricians. This study indicates that parents, whose child has been diagnosed with a birth defect, could benefit from being informed about available genetic counseling services. The results show that some non-users of genetics services may have misconceptions about the purpose of genetic counseling and correcting these may increase utilization. This is important in order to ensure all parents receive sufficient information and support after diagnosis of a birth defect in their child.     

Parents’ perceptions of genetics services for congenital heart disease: the role of demographic,clinical, and psychological factors in determining service attendance

PurposeWe sought to identify the demographic, clinical, and psychological factors associated with parents’ attendance at clinical genetics services for congenital heart disease.MethodsA survey assessing access to cardiac genetics services and a range of other variables was sent to the families of 213 children diagnosed with congenital heart disease between the years 2000 and 2009 at the Sydney Children’s Hospital, Australia.ResultsOf the 114 respondents, 22% had accessed cardiac genetics services. Variables strongly associated with service attendance included presence of a syndrome associated with congenital heart disease (odds ratio = 17.93; P < 0.001) and antenatal diagnosis of congenital heart disease (odds ratio = 4.13; P = 0.02). Most participants (87%) perceived genetic factors as “quite” or “extremely important” in the development of congenital heart disease, and many (73%) believed that receiving information about congenital heart disease and genetics was “quite” or “extremely important”; however, only 36% of participants could recall receiving information of this nature. Forty-two percent of parents reported current concerns about their child’s health, and a substantial subset reported levels of depression (26%), anxiety (27%), and stress (32%) warranting clinical attention.ConclusionThere is a strong desire among parents of children with congenital heart disease for greater information about the role of genetic factors; however, most families do not access cardiac genetics services and report limited recall of information gathered from other sources.Genet Med16 6, 460–468.     

Seguro popular: achievements and perspectives

Healthcare systems are organized following one of two basic models: social security systems, which link access to health services to labor status, and national health systems, which grant access to health as a citizen's right. Mexico adopted, since the institutionalization of social security and healthcare services in 1943, a mixed system. Social security institutions covered the salaried workers and public assistance was granted to the remaining of the population. At the beginning of the XXI century the Mexican health system entered a crisis as the conditions to expand health coverage through social security were not met and public assistance services were insufficient. In order to address these developments, the Healthcare Social Protection System was founded (2004) as a mechanism to effectively guarantee every person's right to health as established after the constitutional amendment of article fourth in 1983. Seguro Popular is the mechanism that through federal and states' contributions seeks to financially protect the population without access to social security's health services, and thus prevent impoverishment due to out of pocket and catastrophic health expenditures.     

A mixed methods exploration of families' experiences of the diagnosis of childhood spinal muscular atrophy

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease with a carrier frequency of 1 in 41 in Australia. Childhood SMA is classified into three types based on the age at which children present with symptoms and the clinical severity. Families'' experiences leading up to the diagnosis have not been described, but are important when considering the potential for a diagnostic odyssey. Using a mixed methods approach, data were collected from interviews and a national survey of families of children with SMA to explore their experiences of this journey. The combined findings (n=28) revealed that the journey to receiving a diagnosis was protracted. The time from first noticing symptoms to finally receiving a diagnosis was emotional and frustrating. Once parents or other family members became aware of symptoms, almost all had consulted with multiple different health professionals before the diagnosis was ultimately made. Not surprisingly, receiving the diagnosis was devastating to the families. The nature of the information and the way it was given to them was not always optimal, particularly because of the difficulties predicting clinical severity. Most felt that their child could have been diagnosed earlier and, although there were mixed views around the benefit of this for their child, they felt it may have reduced the emotional impact on families. Overall, families were more in favour of population carrier screening for SMA when compared with newborn screening of the population. Despite an increasing awareness of SMA, the diagnostic delay continues to have negative impacts on families.     

Child-Directed Interaction Training for Young Children With Autism Spectrum Disorders: Parent and Child Outcomes

This study examined the efficacy of the Child-Directed Interaction Training (CDIT) phase of Parent–Child Interaction Therapy for children with an Autism Spectrum Disorder (ASD). Thirty mother–child dyads with children ages 3–7 years with a diagnosis of ASD participated in this randomized controlled study. Following manualized CDIT, statistically significant and meaningful improvements in child disruptive behavior and social awareness as well as maternal distress associated with child disruptive behavior occurred. Across 8 sessions, mothers learned to provide positive attention to their children's appropriate social and play behaviors. Both child and parent changes were maintained at 6-week follow-up. A relatively brief, time-limited, and accessible intervention may be efficacious for improving child and parent behaviors in families of young children with ASD. By decreasing child disruptive behaviors, CDIT may also help to prepare children to benefit further from future interventions.