The Increasing Importance of Gene-Based Analyses

In recent years,genome and exome sequencing studies have implicated a plethora of new disease genes with rare causal variants. here,i review 150 exome sequencing studies that claim to have discovered that a disease can be caused by different rare variants in the same gene,and i determine whether their methods followed the current best-practice guidelines in the interpretation of their data. specifically,i assess whether studies appropriately assess controls for rare variants throughout the entire gene or implicated region as opposed to only investigating the specific rare variants identified in the cases,and i assess whether studies present sufficient co-segregation data for statistically significant linkage. i find that the proportion of studies performing gene-based analyses has increased with time,but that even in 2015 fewer than 40% of the reviewed studies used this method,and only 10% presented statistically significant co-segregation data. furthermore,i find that the genes reported in these papers are explaining a decreasing proportion of cases as the field moves past most of the low-hanging fruit,with 50% of the genes from studies in 2014 and 2015 having variants in fewer than 5% of cases. as more studies focus on genes explaining relatively few cases,the importance of performing appropriate gene-based analyses is increasing. it is becoming increasingly important for journal editors and reviewers to require stringent gene-based evidence to avoid an avalanche of misleading disease gene discovery papers. © 2016 elizabeth t. cirulli.