Kym Boycott is a Clinical Geneticist at the Children’s Hospital of Eastern Ontario (CHEO), Senior Scientist at the CHEO Research Institute, and Professor of Pediatrics at the University of Ottawa. Dr. Boycott’s research program in rare diseases bridges clinical medicine to basic research and is focused on understanding the molecular pathogenesis of these disorders to improve patient care and family well-being. She is the Principal Investigator of Care4Rare Canada, a pan-Canadian platform integrating genomic and other –omic technologies to improve our understanding of rare disease, with a particular focus on solving the unsolved and most difficult rare diseases. She is co-Principal Investigator of the Rare Diseases: Models & Mechanisms Network, established to catalyze connections between clinical investigators discovering new genes and basic scientists who can analyze equivalent genes and pathways in model organisms. Dr. Boycott moves the international rare disease agenda forward through her role as the Chair of the Diagnostics Committee of the International Rare Diseases Research Consortium, a member of the Steering Committee of the Global Alliance for Genomics and Health and as a member of the Global Commission to End the Diagnostic Odyssey for Children.
Addressing Challenges in the Diagnosis and Treatment of Rare Genetic Diseases
Here, we discuss the increasing opportunity for diagnosis and therapy of rare diseases and how to tackle the associated challenges.
International Cooperation to Enable the Diagnosis of All Rare Genetic Diseases
Provision of a molecularly confirmed diagnosis in a timely manner for children and adults with rare genetic diseases shortens their "diagnostic odyssey," improves disease management, and fosters genetic counseling with respect to recurrence risks while assuring reproductive choices.
Utility of whole‐exome sequencing for those near the end of the diagnostic odyssey: time to address gaps in care
In the next decade we will witness a paradigm shift in the way we care for patients with rare genetic diseases, addressing a significant gap in the management of individuals with rare diseases. The diagnostic journey for patients will include clinical genomic sequencing, which in the not too distant future will be WGS as costs decrease with new platforms. The accessibility of WGS‐based diagnostics for patients will be central to understanding the complete compendium of human genetic pathology. Strategies and infrastructure should be put in place to facilitate discovery in clinical settings, and to further mine large phenotypic and genomic datasets for disease mechanisms. As we understand the etiology of more rare diseases, it is probable that we will increasingly implicate known genes and that the approach to the completion of the complete Mendelian dataset will be asymptotic. There will be a subset of rare diseases that are due to non‐coding mutations in regulatory regions that may be more readily identified with the imminent use of WGS and RNA sequencing, and to implicate and understand this type of variation will require large‐scale data sharing at an impressive level. Ultimately, such datasets will be instrumental in identifying modifiers of disease, providing insight into phenotypic variability, prognosis, and for a subset of diseases, identifying drug targets. Finally, NGS technologies are providing significant opportunities to implement personalized health strategies including prevention or early detection of disease, improved health maintenance, and development of tailored therapy for patients with rare genetic diseases.
Biallelic Mutations in BRCA1 Cause a New Fanconi Anemia Subtype
The proband presented at birth with microsomia and dysmorphic features (Fig. 1A). Growth parameters were less than the 0.4 percentile at term (birth weight 1990g, height 40.5 cm, head circumference (HC) 27 cm), and subsequent catch-up growth was not evident at 25 years of age (weight 40 kg, −3.03 S.D.; 135 cm tall, −4.35 S.D.; HC 48.5 cm, approx.−4 to −5 S.D.). Additional congenital abnormalities included sparse hair, upslanted palpebral fissures, blepharophimosis, a narrow palate, dental malocclusion, a high-pitched and hoarse voice, hyper and hypopigmented skin lesions, duodenal stenosis and a slightly enlarged left kidney. She has proximally inserted thumbs (Fig. 1A), 2nd digit camptodactyly, 2–3 toe syndactyly and hyperextensible knees as well as a history of hip dislocation. Conductive hearing loss was diagnosed at 4 years of age. Bone age at 2y 3m was delayed (1y and 6m (−2S.D.)), but had normalized by 9 years. The patient also has mild intellectual disability with significantly delayed speech. At 23 years of age she was diagnosed with ductal breast carcinoma that was estrogen and progesterone receptor positive and Her2 negative. Mastectomy was performed followed by treatment with docetaxel, fluorouracil-epirubicin-cyclophosphamide and radiation therapy. A prophylactic mastectomy was performed on the contralateral breast at age 25. The patient did not experience unusual treatment associated toxicity and has not been diagnosed with bone marrow failure to date.
Resolution of refractory hypotension and anuria in a premature newborn with loss-of-function of ACE
Vasopressin was used to successfully treat refractory hypotension and anuria in the neonate born at 27 weeks of gestation.