Gene discovery for Mendelian conditions via social networking: de novo variants in KDM1A cause developmental delay and distinctive facial features

Abstract

PurposeThe pace of Mendelian gene discovery is slowed by the “n-of-1 problem” – the difficulty of establishing 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 is often impeded by lack of a convenient or widely-available way to share data on candidate variants / genes among families, clinicians and researchers.MethodsSocial networking among families, clinicians and researchers was used to identify three children with variants of unknown significance in KDM1A and similar phenotypes.ResultsDe novo variants in KDM1A underlie a new syndrome characterized by developmental delay and distinctive facial features.ConclusionSocial networking is a potentially powerful strategy to discover genes for rare Mendelian conditions, particularly those with non-specific 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). Design and development of a web-based tool, MyGene2, 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 underway.

Model Organisms Facilitate Rare Disease Diagnosis and Therapeutic Research

“…Use of integrated match-making programs that comprise the Matchmaker Exchange (MME) ( Philippakis et al 2015 ) allows the identification of patients with similar phenotypes and genotypes across different platforms. In Matchmaker Exchange, databases such as GeneMatcher ( Sobreira et al 2015b ), PhenomeCentral ( Buske et al 2015 ), DECIPHER (DatabasE of genomiC varIation and Phenotype in Humans using Ensembl Resources) ( Chatzimichali et al 2015 ), MyGene2 ( Chong et al 2016b ), matchbox/seqr , and Australian Genomics Health Alliance (AGHA) Patient Archive are connected to one another, thereby supporting queries of data from >20,000 unrelated patients, and facilitating prioritization of genes and variants.…”

Lsd1 interacts with cMyb to demethylate repressive histone marks and maintain inner ear progenitor identity

“…Many factors within this module are involved in other biological processes, cancer and/or mutated in human syndromes. Thus, from a therapeutic perspective, this study may provide insights into the mechanisms underlying the human syndromes caused by mutations in LSD1 (Chong et al, 2016;Tunovic et al, 2014), such as cleft palate, psychomotor retardation and distinct facial features (CPRF; OMIM # 616728), as well as overlapping features with Kabuki syndrome (OMIM # 300867).…”

Novel bioinformatic developments for exome sequencing

“…This should hopefully inspire more researchers to contribute to these databases and facilitate the identification of the genetic cause for their patients. By contributing these data to public databases they do not only become available to researchers and physicians but also to the patients themselves (Chong et al 2015 ; Kirkpatrick et al 2015 ). A nice illustration of this is the case of Massimo Damiani who suffered from an unclassified form of leukoencephalopathy and whose parent’s efforts resulted in the genetic diagnosis (Lambertson et al 2015 ).…”