Unique Capabilities of Genome Sequencing for Rare Disease Diagnosis.

Background: Causal variants underlying rare disorders may remain elusive even after expansive gene panels or exome sequencing (ES). Clinicians and researchers may then turn to genome sequencing (GS), though the added value of this technique and its optimal use remain poorly defined. We therefore investigated the advantages of GS within a phenotypically diverse cohort.

-associated congenital fiber-type disproportion and cardiomyopathy with variants in additional neuromuscular disease genes; the dilemma of panel testing.

Next-generation sequencing has led to transformative advances in our ability to diagnose rare diseases by simultaneously sequencing dozens, hundreds, or even entire genomes worth of genes to efficiently identify pathogenic mutations. These studies amount to multiple hypothesis testing on a massive scale and not infrequently lead to discovery of multiple genetic variants whose relative contributions to a patient's disease are unclear. Panel testing, in particular, can be problematic because each of the many genes being sequenced might represent a plausible explanation for a given case.