Childhood rare diseases and the UN convention on the rights of the child

This letter discusses an initiative that considered the rights of a child living with a rare disease in the context of the United Nations Convention on the Rights of the Child (UNCRC). The aim was to inform laypeople on the intersection between the UNCRC and rare and undiagnosed diseases. The Project was initiated in Western Australia for a national audience, with a view that it might also provide a framework that is translatable to other jurisdictions internationally. This letter discusses some of the key themes raised by the Project and the potential for further work.

Lessons learnt from multifaceted diagnostic approaches to the first 150 families in Victoria’s Undiagnosed Diseases Program

BackgroundClinical exome sequencing typically achieves diagnostic yields of 30%–57.5% in individuals with monogenic rare diseases. Undiagnosed diseases programmes implement strategies to improve diagnostic outcomes for these individuals.AimWe share the lessons learnt from the first 3 years of the Undiagnosed Diseases Program-Victoria, an Australian programme embedded within a clinical genetics service in the state of Victoria with a focus on paediatric rare diseases.MethodsWe enrolled families who remained without a diagnosis after clinical genomic (panel, exome or genome) sequencing between 2016 and 2018. We used family-based exome sequencing (family ES), family-based genome sequencing (family GS), RNA sequencing (RNA-seq) and high-resolution chromosomal microarray (CMA) with research-based analysis.ResultsIn 150 families, we achieved a diagnosis or strong candidate in 64 (42.7%) (37 in known genes with a consistent phenotype, 3 in known genes with a novel phenotype and 24 in novel disease genes). Fifty-four diagnoses or strong candidates were made by family ES, six by family GS with RNA-seq, two by high-resolution CMA and two by data reanalysis.ConclusionWe share our lessons learnt from the programme. Flexible implementation of multiple strategies allowed for scalability and response to the availability of new technologies. Broad implementation of family ES with research-based analysis showed promising yields post a negative clinical singleton ES. RNA-seq offered multiple benefits in family ES-negative populations. International data sharing strategies were critical in facilitating collaborations to establish novel disease–gene associations. Finally, the integrated approach of a multiskilled, multidisciplinary team was fundamental to having diverse perspectives and strategic decision-making.

Ending diagnostic odyssey using clinical whole-exome sequencing (CWES)

Objectives Most rare diseases are genetic diseases. Due to the diversity of rare diseases and the high likelihood of patients with rare diseases to be undiagnosed or misdiagnosed, it is not unusual that these patients undergo a long diagnostic odyssey before they receive a definitive diagnosis. This situation presents a clear need to set up a dedicated clinical service to end the diagnostic odyssey of patients with rare diseases. Methods Therefore, in 2014, we started an Undiagnosed Diseases Program in Hong Kong with the aim of ending the diagnostic odyssey of patients and families with rare diseases by clinical whole-exome sequencing (CWES), who have not received a definitive diagnosis after extensive investigation. Results In this program, we have shown that genetic diseases diagnosed by CWES were different from that using traditional approaches indicating that CWES is an essential tool to diagnose rare diseases and ending diagnostic odysseys. In addition, we identified several novel genes responsible for monogenic diseases. These include the TOP2B gene for autism spectrum disorder, the DTYMK gene for severe cerebral atrophy, the KIF13A gene for a new mosaic ectodermal syndrome associated with hypomelanosis of Ito, and the CDC25B gene for a new syndrome of cardiomyopathy and endocrinopathy. Conclusions With the incorporation of CWES in an Undiagnosed Diseases Program, we have ended diagnostic odysseys of patients with rare diseases in Hong Kong in the past 7 years. In this program, we have shown that CWES is an essential tool to end diagnostic odysseys. With the declining cost of next-generation sequencers and reagents, CWES set-ups are now affordable for clinical laboratories. Indeed, owing to the increasing availability of CWES and treatment modalities for rare diseases, precedence can be given to both common and rare medical conditions.

ModelMatcher: A scientist-centric online platform to facilitate collaborations between stakeholders of rare and undiagnosed disease research

Next-generation sequencing is a prevalent diagnostic tool for undiagnosed diseases, and has played a significant role in rare disease gene discovery. While this technology resolves some cases, others are given a list of possibly damaging genetic variants necessitating functional studies. Productive collaborations between scientists, clinicians, and patients can help resolve such medical mysteries, and provide insights into in vivo function of human genes. Furthermore, facilitating interactions between scientists and research funders, including non-profit organizations or commercial entities, can dramatically reduce the time to translate discoveries from bench to bedside. Several systems designed to connect clinicians and researchers with a shared gene of interest have been successful. However, these platforms exclude some stakeholders based on their role or geography. Here we describe ModelMatcher, a global online matchmaking tool designed to facilitate cross-disciplinary collaborations, especially between scientists and other stakeholders of rare and undiagnosed disease research. ModelMatcher is integrated into the Rare Diseases Models and Mechanisms Network and Matchmaker Exchange, allowing users to identify potential collaborators in other registries. This living database decreases the time from when a scientist or clinician is making discoveries regarding their genes of interest, to when they identify collaborators and sponsors to facilitate translational and therapeutic research.

Nemaline Myopathy: A Case Report

Generalized weakness in the pediatric and adolescent population is caused by many disorders that affect the neuromuscular axis. As next-generation sequencing (NGS) is becoming of high yield in replacing more invasive procedures, that is, muscle and nerve biopsy, more previously undiagnosed diseases of the muscles are now labeled with specific pathogenicity. A 16-year-old-girl diagnosed with nemaline myopathy but previously was misdiagnosed with congenital myasthenia and put-on unnecessary medications. Clinicians should be aware of congenital diseases that affect the muscles and know the importance of the NGS in reaching the correct diagnosis more so when there is a history of consanguinity.

Impacto de un programa de equitación adaptada en la actividad física y en el sueño de un grupo de niños con enfermedades raras (Impact of an adaptive riding program on the physical activity and sleep in a group of children diagnosed with rare diseases)

El objetivo de este trabajo fue verificar el impacto de un programa de equitación adaptada en un grupo de niños con enfermedades raras y comprobar su repercusión en la actividad física y en algunos parámetros del sueño. Se realiza un diseño experimental de caso único, de reversión múltiple intrasujetos. La muestra está compuesta por cinco niños/as que presentan enfermedades de baja frecuencia. Para evaluar la actividad física y el tiempo de sueño se ha utilizado un acelerómetro triaxial. Con carácter descriptivo, a fin de valorar las características habituales del sueño se ha empleado una escala de trastornos del sueño. En términos generales se observa que la participación como usuario en sesiones de equitación adaptada supone un incremento de actividad física apreciable respecto a la actividad física media del propio usuario. No hemos encontrado una prolongación en la duración de sueño. === The aim of this work is to verify the impact of a adaptive riding program to promote physical activity and sleep in a group of children with rare diseases. A single-case, reversal and intrasubject experimental design has been implemented. The sample was composed of five children with low-frequency or undiagnosed diseases. To measure physical activity and sleep an triaxial accelerometer has been used. Additionally, a sleep disorder scale has been employed in order to assess the usual sleep characteristics. In general terms, we can point out that participating as a user in adaptive riding sessions produces an increase in daily physical activity, which is appreciable compared to the average physical activity of the user.