Genetic and phenotypic spectrum in the NONO-associated syndromic disorder.

The non-POU domain-containing octamer-binding (NONO) protein is involved in multiple steps of gene regulation such as RNA metabolism and DNA repair. Hemizygous pathogenic variants in the NONO gene were confirmed to cause a rare X-linked syndromic disorder. Through our in-house diagnostics and subsequent matchmaking, we identified six unrelated male individuals with pathogenic or likely pathogenic NONO variants. For a detailed comparison, we reviewed all published characterizations of the NONO-associated disorder. The combined cohort consists of 16 live-born males showing developmental delay, corpus callosum anomalies, non-compaction cardiomyopathy and relative macrocephaly as leading symptoms. Seven prenatal literature cases were characterized by cardiac malformations. In this study, we extend the phenotypic spectrum through two more cases with epilepsy as well as two more cases with hematologic anomalies. By RNA expression analysis and structural modeling of a new in-frame splice deletion, we reinforce loss-of-function as the pathomechanism for the NONO-associated syndromic disorder.

LoVE in a time of CoVID: Clinician and patient experience using telemedicine for chronic epilepsy management.

As part of our ongoing interest in patient- and family-centered care in epilepsy, we began, before the onset of the CoVID-19 pandemic, to evaluate the concerns and preferences of those delivering and receiving care via telemedicine. CoVID-19 arrived and acted as an unexpected experiment in nature, catalyzing telemedicine's widespread implementation across many disciplines of medicine. The arrival of CoVID-19 in Ireland gave us the opportunity to record these perceptions pre- and post-CoVID. Data were extracted from the National Epilepsy Electronic Patient Record (EEPR). Power BI Analytics collated data from two epilepsy centers in Dublin. Analysis of data on reasons for using the telephone support line was conducted. A subset of patients and clinicians who attended virtual encounters over both periods were asked for their perception of telemedicine care through a mixed methods survey. Between 23rd December 2019 and 23rd March 2020 (pre-CoVID era), a total of 1180 patients were seen in 1653 clinical encounters. As part of a telemedicine pilot study, 50 of these encounters were scheduled virtual telephone appointments. Twenty eight surveys were completed by clinicians and 18 by patients during that period. From 24th March 2020 to 24th June 2020, 1164 patients were seen in 1693 encounters of which 729 (63%) patients were seen in 748 scheduled virtual encounters. 118 clinician impressions were captured through an online survey and 75 patients or carers completed a telephone survey during the post-CoVID era. There was no backlog of appointments or loss of care continuity forced by the pandemic. Clinicians expressed strong levels of satisfaction, but some doubted the suitability of new patients to the service or candidates for surgery receiving care via telemedicine. Patients reported positive experiences surrounding telephone appointments comparing them favorably to face-to-face encounters. The availability of a shared EEPR demonstrated no loss of care contact for patients with epilepsy. The survey showed that telemedicine is seen as an effective and satisfactory method of delivering chronic outpatient care.

Democratizing epilepsy care: Utility and usability of an electronic patient portal.

OBJECTIVES: Electronic patient portals (ePortals) can facilitate greater healthcare democratization by providing patients and/or their authorized care partners with secure access to their medical records when and where needed. Such democratization can promote effective healthcare provider-patient partnerships, shared decision-making, and greater patient engagement in managing their health condition. This study examined the usefulness of providing individualized services and care in epilepsy (PiSCES), an epilepsy ePortal, as an enabler of more democratized epilepsy care. METHODS: Seventy-two individuals with epilepsy and 18 care partners were invited to report on their experience of interacting via PiSCES with clinical documents (epilepsy care summary record; epilepsy clinic letters) authored about them by healthcare providers. The OpenNotes reporting tool was adapted to capture participant experience. RESULTS: Twenty-five percent of invited patients and 44% of invited care partners reported on interacting with their epilepsy care summary; 14% of patients and 67% of care partners invited reported on their epilepsy clinic letters. Participant testimonials illustrate the value of PiSCES in: promoting autonomy, aiding memory, developing the knowledgeable patient, and enhancing healthcare partnerships. Ninety-six percent and 100% of respondents, respectively, reported understanding their epilepsy care summary and epilepsy clinic letter; 77% said the summary described their epilepsy history to date; 96% indicated that the letter provided an accurate description of their clinical encounter; 92% and 96%, respectively, valued access to their summary record and clinic letters; 77% of summary record and 73% clinic letter respondents reported learning something about their epilepsy or the healthcare service via PiSCES. Illustrating their potential patient and care partner safety role, 42% respondents identified inaccuracies in their clinical documents which were subsequently resolved by a clinician. SIGNIFICANCE: In the post-digital world highly customized on-demand products and services have come to be expected. Similarly, in epilepsy care, technologies such as PiSCES can enable more personalized, transparent, and engaging services.

Coproducing health and well-being in partnership with patients, families, and healthcare providers: A qualitative study exploring the role of an epilepsy patient portal.

BACKGROUND: Coproduced epilepsy care sees people with epilepsy (PwE), their care-proxies, and healthcare providers (HCPs), working together as partners to build strong relationships, improve communication, trust, and share decision-making. Coproduction underpins good quality patient- and family-centered care (PFCC) that is responsive to individual patient needs, preferences, and values. By facilitating information sharing and exchange between partners, electronic patient portals (ePortal) can enable coproduction. This paper explores what HCPs, PwE, and their care-proxies value from their user experience of PiSCES, the Irish epilepsy ePortal. METHODS: A purposeful sample of actors involved in the receipt and delivery of epilepsy care and services were recruited via adult epilepsy centers at St James's and Beaumont Hospitals in Dublin. Interactive codesign sessions, surveys, and focus groups were used to elicit perspectives from PwE, care-proxies, and HCPs to understand their perception of how PiSCES could enhance or inhibit the epilepsy care process. RESULTS: Results illustrate that participants welcome the role PiSCES can play in: empowering PwE/care-proxies, strengthening confidence in the healthcare system; aiding memory; advancing health literacy, motivating PwE to understand their condition better; acting as a passport of care between different clinical settings; and creating a foundation for stronger coproduction partnerships. PiSCES was generally embraced; however, some HCPs expressed plausible concerns about how clinical implementation might impact their work practices. CONCLUSION: "Nothing about me without me" is a core value of the PiSCES initiative, recognizing that people need to be included in the planning of their own treatment and care. Our data show that PwE, their care-proxies, and HCPs value PiSCES potential, particularly in bolstering healthcare partnerships that foster inclusion, confidence, and trust.

The development of an epilepsy electronic patient portal: Facilitating both patient empowerment and remote clinician-patient interaction in a post-COVID-19 world.

OBJECTIVES: The current coronavirus disease 2019 (COVID-19) pandemic stresses an urgency to accelerate much-needed health service reform. Rapid and courageous changes being made to address the immediate impact of the pandemic are demonstrating that the means and technology to enable new models of health care exist. For example, innovations such as electronic patient portals (ePortal) can facilitate (a) radical reform of outpatient care; (b) cost containment in the economically constrained aftermath of the pandemic; (c) environmental sustainability by reduction of unnecessary journeys/transport. Herein, the development of Providing Individualised Services and Care in Epilepsy (PiSCES), an ePortal to the Irish National Epilepsy Electronic Patient Record, is demonstrated. This project, which pre-dates the COVID-19 crisis, aims to facilitate better patient- and family-centered epilepsy care. METHODS: A combination of ethnographic research, document analysis, and joint application design sessions was used to elicit PiSCES requirements. From these, a specification of desired modules of functionality was established and guided the software development. RESULTS: PiSCES functional features include "My Epilepsy Care Summary," "My Epilepsy Care Goals," "My Epilepsy Clinic Letters," "Help Us Measure Your Progress," "Prepare For Your Clinic Visit," "Information for Your Healthcare Provider." The system provides people with epilepsy access to, and engages them as co-authors of, their own medical record. It can promote improved patient-clinician partnerships and facilitate patient self-management. SIGNIFICANCE: In the aftermath of COVID-19, it is highly unlikely that the healthcare sector will return to a "business as usual" way of delivering services. The pandemic is expected to accelerate adoption of innovations like PiSCES. It is therefore a catalyst for change that will deliver care that is more responsive to individual patient needs and preferences.

Development of a genomics module within an epilepsy-specific electronic health record: Toward genomic medicine in epilepsy care.

OBJECTIVES: Both clinical genomics and e-Health technology are changing the way medicine is being practiced. Although the basic clinical methodology of good medical care will remain unchanged, the combined power of genomics and electronic health records has the capability of enhancing, and in some cases transforming, the practice of medicine. This is particularly true in the care of patients with complex long-term medical conditions such as chronic refractory epilepsy, especially in those with related complex comorbidities including intellectual disability and psychiatric disease. METHODS: Herein we outline the development and integration of an epilepsy genomics module into a preexisting epilepsy electronic patient record (EPR) system. RESULTS: We describe how this EPR infrastructure is used to facilitate discussion at multidisciplinary clinical meetings around molecular diagnosis and resulting changes in management. SIGNIFICANCE: This work illustrates the role of eHealth technology in embedding genomics into the clinical pathway.

Similarity of Phenotype in Three Male Patients With the c.320A>G Variant in ALG13: Possible Genotype-Phenotype Correlation.

BACKGROUND: Congenital disorders of glycosylation (CDG) are a group of neurometabolic diseases that result from genetic defects in the glycosylation of proteins and/or lipids. Multiple pathogenic genes contribute to the varying reported phenotypes of individuals with CDG-1 syndromes, most of which are inherited as autosomal recessive traits, although X-linked inheritance has also been reported. Pathogenic variants in the asparagine-linked glycosylation 13 homolog (ALG13) gene have been implicated in the aetiology of developmental and epileptic encephalopathy (DEE) 36 (OMIM:*300776, DEE36). The NM_001099922.3:c.320A>G; p.(Asn107Ser) variant is the most frequently described pathogenic variant in ALG13, with 59 females and 2 males with this variant reported to date. METHODS: We report on a male with a de novo, hemizygous variant in ALG13: c.320A>G; p.(Asn107Ser), whose phenotype resembles that of two previously reported males with the same variant. RESULTS: All three males have a de novo mutation, infantile spasms, DEE, drug-resistant epilepsy, intellectual disability, dysmorphic findings, recurrent infections, skeletal anomalies, brain abnormalities and a movement disorder: a phenotype not consistently reported in males with other pathogenic variants in ALG13. CONCLUSION: The similarity of phenotype in the three males with the c.320A>G variant in ALG13, suggests a possible genotype-phenotype correlation.

Germline mosaicism in a family with MBD5 haploinsufficiency.

Haploinsufficiency of the methyl-CpG-binding domain protein 5 (MBD5) gene causes a neurodevelopmental disorder that includes intellectual disability, developmental delay, speech impairment, seizures, sleep disturbances, and behavioral difficulties. Microdeletion of 2q23.1 is the most common cause of haploinsufficiency, although MBD5 haploinsufficiency may also cause this genetic disorder. We report a family harboring a heterozygous loss-of-function variant in MBD5 (NM_018328.5:c.728delC; p.Pro243Hisfs*26), which includes three affected siblings with varying phenotypic features. Both parents were phenotypically normal but deep coverage sequencing of the parents showed germline mosaicism in the mother.

A comparison of genomic diagnostics in adults and children with epilepsy and comorbid intellectual disability.

Next generation sequencing provides an important opportunity for improved diagnosis in epilepsy. To date, the majority of diagnostic genetic testing is conducted in the paediatric arena, while the utility of such testing is less well understood in adults with epilepsy. We conducted whole exome sequencing (WES) and copy number variant analyses in an Irish cohort of 101 people with epilepsy and co-morbid intellectual disability to compare the diagnostic yield of genomic testing between adult and paediatric patients. Variant interpretation followed American College of Medical Genetics and Genomics (ACMG) guidelines. We demonstrate that WES, in combination with array-comparative genomic hybridisation, provides a diagnostic rate of 27% in unrelated adult epilepsy patients and 42% in unrelated paediatric patients. We observe a 2.7% rate of ACMG-defined incidental findings. Our findings indicate that WES has similar utility in both adult and paediatric cohorts and is appropriate for diagnostic testing in both epilepsy patient groups.