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

Abstract

Purpose: 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.

Methods: Social networking among families, clinicians, and researchers was used to identify three children with variants of unknown significance in KDM1A and similar phenotypes.

Results: De novo variants in KDM1A underlie a new syndrome characterized by developmental delay and distinctive facial features.

Conclusion: 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.

Figure 1. Phenotypic characteristics of children with a mutation in KDM1A

All three individuals (A–C) with a mutation in KDM1A share a prominent forehead, slightly arched eyebrows, elongated palpebral fissures, a wide nasal bridge, thin lips, and wide-spaced teeth. Case identifiers correspond to those in Table 1, where a detailed description of the phenotype of each person is provided. C-1 and C-2 are pictures of the same child at 3 years 8 months and 8 years of age, respectively.

Figure 2. Genomic structure of KDM1A, predicted KDM1A protein, and spectrum of mutations that cause developmental delay

A) KDM1A is composed of 21 exons including protein-coding (blue) exons and non-coding (orange) exons. Lines with attached dots indicate the approximate locations of the three different de novo variants that we report to underlie developmental delay. The color of each dot reflects the domain/subdomain containing the corresponding mutated residue. B) Protein domain structure of KDM1A. KDM1A has three domains—SWIRM (pink), Amine-Oxidase Domain (AOD, blue and teal), and Tower (yellow)—as well as an unstructured N-terminal flexible region and C-terminal tail (gray). The amine-oxidase domain (AOD) is comprised of two subdomains, the FAD-binding and substrate-binding functional subdomains. The active site cavity of KDM1A is within the substrate-binding subdomain and is required for KDM1A to demethylate H3K4me1/2 and repress transcription. Both the Tower and SWIRM domains have been shown to be necessary for the catalysis of histone demethylation by KDM1A.

Figure 3. Effects of increasing number of trios sequenced and specificity of phenotype on power to detect significant association between putative mutations and phenotype

Assuming a de novo missense rate of 3.46×10⁻⁵/chromosome, as increasing numbers of trios (x-axis) are tested by exome sequencing, the power to detect a significant association (ranges of possible p values represented by different shades of green; darker indicates smaller and more significant p values) between de novo variants in a gene and the phenotype of interest increases. Additionally, as the specificity of the phenotype of interest increases, the proportion of individuals tested who have the phenotype (y-axis) naturally decreases, also resulting in increased power. A small decrease (60% to 50%) in the proportion of individuals who have the phenotype of interest can increase power more than sequencing 10,000 additional trios.