Back in 2009, as a fresh-faced young editor, I attended the second Cold Spring Harbor Personal Genomes meeting. Nowadays medical and individual genomes are 10-a-penny (well, not quite), but four years is a long time in genomic technologies and the atmosphere at that meeting was one of excitement and anticipation. I shared a room with Elizabeth Worthey, who was to publish the clinical genome that saved the life of a child later named as Nicholas Volker, while others spoke about genomic analyses of patients with Miller syndrome and melanoma that have also become classics of the medical genomics literature.
Many speakers at that meeting reported patient genome sequencing, but James Lupski’s talk in the Ethics session was particularly memorable because the patient genome in question was his own. The Lupski family, including Jim himself, are affected by a recessive form of Charcot-Marie-Tooth neuropathy, and despite years of classical genetic analysis and Jim’s own expertise in genomic disorders, the causal gene was unknown. Richard Gibbs, also from Baylor College of Medicine, undertook whole genome sequencing (WGS) of his colleague and looked at mutations in the genes associated with this condition, tracking it down to compound heterozygous mutations in the SH3TC2 gene. They also reported other, more unexpected findings, including mutations thought to be pathogenic in patients with other Mendelian conditions.
This week in Genome Medicine we publish a multi-platform reanalysis of this genome. Claudia Gonzaga-Jauregui, Richard Gibbs and colleagues carried out six independent exome assays and an additional WGS, showing reasonably high concordance for single nucleotide calls, and lower concordance for insertions and deletions. While the first analysis of this genome used WGS in order to avoid missing non-coding mutations, the authors now find that the increased depth of the exome sequencing allowed resolution of some of the secondary findings originally reported, as well as identifying an additional potentially causative mutation in SH3TC2.