The pace of Mendelian gene discovery is slowed by the “n-of-1 problem”—the difficulty of establishing the causality of a putatively pathogenic variant in a single person or family. Identification of an unrelated person with an overlapping phenotype and suspected pathogenic variant in the same gene can overcome this barrier, but it is often impeded by lack of a convenient or widely available way to share data on candidate variants/genes among families, clinicians, and researchers.
Social networking among families, clinicians, and researchers was used to identify three children with variants of unknown significance in KDM1A and similar phenotypes.
De novo variants in KDM1A underlie a new syndrome characterized by developmental delay and distinctive facial features.
Social networking is a potentially powerful strategy to discover genes for rare Mendelian conditions, particularly those with nonspecific phenotypic features. To facilitate the efforts of families to share phenotypic and genomic information with each other, clinicians, and researchers, we developed the Repository for Mendelian Genomics Family Portal (RMD-FP; http://uwcmg.org/#/family). Design and development of MyGene2 (http://www.mygene2.org), a Web-based tool that enables families, clinicians, and researchers to search for gene matches based on analysis of phenotype and exome data deposited into the RMD-FP, is under way.
Genet Med 18 8, 788–795.
developmental delay; Internet-driven patient finding; KDM1A; Mendelian gene discovery; social networking
At a glance
- The genetic basis of mendelian phenotypes: discoveries, challenges, and opportunities. Am J Hum Genet 2015;97:199–215. , , , et al.; .
- Guidelines for genetic studies in single patients: lessons from primary immunodeficiencies. J Exp Med 2014;211:2137–2149. , , , ,
- Guidelines for investigating causality of sequence variants in human disease. Nature 2014;508:469–476. , , , et al.
- Molecular genetic testing and the future of clinical genomics. Nat Rev Genet 2013;14:415–426. ,
- ClinGen–the clinical genome resource. N Engl J Med 2015;372:2235–2242. , , , et al.; .
- PhenomeCentral: a portal for phenotypic and genotypic matchmaking of patients with rare genetic diseases. Hum Mutat 2015;36:931–940. , , , et al.
- GeneMatcher: a matching tool for connecting investigators with an interest in the same gene. Hum Mutat 2015;36:928–930. , , ,
- GenomeConnect: matchmaking between patients, clinical laboratories, and researchers to improve genomic knowledge. Hum Mutat 2015;36:974–978. , , , et al.; .
- DECIPHER: database of chromosomal imbalance and phenotype in humans using ensembl resources. Am J Hum Genet 2009;84:524–533. , , , et al.
- Facilitating collaboration in rare genetic disorders through effective matchmaking in DECIPHER. Hum Mutat 2015;36:941–949. , , , et al.
- The matchmaker exchange: a platform for rare disease gene discovery. Hum Mutat 2015;36:915–921. , , , et al.
- Discovering new diseases with the internet: how to find a matching patient. 2015. http://matt.might.net/articles/rare-disease-internet-matchmaking/. Accessed 10 June 2015.
- Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway. Genet Med 2014;16:751–758. , , , et al.; .
- The shifting model in clinical diagnostics: how next-generation sequencing and families are altering the way rare diseases are discovered, studied, and treated. Genet Med 2014;16:736–737. ,
- One of a kind. The New Yorker, 21 July 2014:32–38.
- De novo ANKRD11 and KDM1A gene mutations in a male with features of KBG syndrome and Kabuki syndrome. Am J Med Genet A 2014;164A:1744–1749. , , ,
- Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Lancet 2012;380:1674–1682. , , , et al.
- Autosomal-Dominant Multiple Pterygium Syndrome Is Caused by Mutations in MYH3. Am J Hum Genet 2015;96:841–849. , , , et al.; .
- A framework for the interpretation of de novo mutation in human disease. Nat Genet 2014;46:944–950. , , , et al.
- Mutations in ANKRD11 cause KBG syndrome, characterized by intellectual disability, skeletal malformations, and macrodontia. Am J Hum Genet 2011;89:289–294. , , , et al.
- Characterization of ANKRD11 mutations in humans and mice related to KBG syndrome. Hum Genet 2015;134:181–190. , , , et al.
- Further delineation of the KBG syndrome phenotype caused by ANKRD11 aberrations. Eur J Hum Genet 2015;23:1176–1185. , , , et al.
- Evolution and functional impact of rare coding variation from deep sequencing of human exomes. Science 2012;337:64–69. , , , et al.; .
- KBG syndrome: report of twins, neurological characteristics, and delineation of diagnostic criteria. Am J Med Genet A 2007;143A:292–300. , ,
- Histone demethylases in development and disease. Trends Cell Biol 2010;20:662–671. ,
- Opposing LSD1 complexes function in developmental gene activation and repression programmes. Nature 2007;446:882–887. , , , et al.
- Regulation of neuronal traits by a novel transcriptional complex. Neuron 2001;31:353–365. , , , et al.
- Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 2004;119:941–953. , , , et al.
- Alternative splicing of the histone demethylase LSD1/KDM1 contributes to the modulation of neurite morphogenesis in the mammalian nervous system. J Neurosci 2010;30:2521–2532. , , , et al.
- Histone demethylase LSD1 is required to induce skeletal muscle differentiation by regulating myogenic factors. Biochem Biophys Res Commun 2010;401:327–332. , , , , ,
- A hypomorphic lsd1 allele results in heart development defects in mice. PLoS One 2013;8:e60913. , , , et al.
- Crystal structure of human histone lysine-specific demethylase 1 (LSD1). Proc Natl Acad Sci USA 2006;103:13956–13961. , , , et al.
- Research 2.0: social networking and direct-to-consumer (DTC) genomics. Am J Bioethics 2009;9:35–44. ,
- The impact of parent advocacy groups, the Internet, and social networking on rare diseases: the IDEA League and IDEA League United Kingdom example. Epilepsia 2011;52 Suppl 2:102–104. ,
- Research led by participants: a new social contract for a new kind of research. J Med Ethics 2015:1–4. , , , et al.
- PatientsLikeMe the case for a data-centered patient community and how ALS patients use the community to inform treatment decisions and manage pulmonary health. Chron Respir Dis 2009;6:225–229. ,
- The human phenotype ontology: semantic unification of common and rare disease. Am J Hum Genet 2015;97:111–124. , , , et al.
- Mitigating false-positive associations in rare disease gene discovery. Hum Mutat 2015;36:998–1003. , , ,
- Enhanced utility of family-centered diagnostic exome sequencing with inheritance model-based analysis: results from 500 unselected families with undiagnosed genetic conditions. Genet Med 2015;17:578–586. , , , et al.
- Participant-driven matchmaking in the genomic era. Hum Mutat 2015;36:965–973. , , , ,