  Despite advances in clinical genetic testing, including the introduction of
exome sequencing (ES), more than 50% of individuals with a suspected Mendelian
condition lack a precise molecular diagnosis. Clinical evaluation is
increasingly undertaken by specialists outside of clinical genetics, often
occurring in a tiered fashion and typically ending after ES. The current
diagnostic rate reflects multiple factors, including technical limitations,
incomplete understanding of variant pathogenicity, missing genotype-phenotype
associations, complex gene-environment interactions, and reporting differences
between clinical labs. Maintaining a clear understanding of the rapidly
evolving landscape of diagnostic tests beyond ES, and their limitations,
presents a challenge for non-genetics professionals. Newer tests, such as
short-read genome or RNA sequencing, can be challenging to order and emerging
technologies, such as optical genome mapping and long-read DNA or RNA
sequencing, are not available clinically. Furthermore, there is no clear
guidance on the next best steps after inconclusive evaluation. Here, we review
why a clinical genetic evaluation may be negative, discuss questions to be
asked in this setting, and provide a framework for further investigation,
including the advantages and disadvantages of new approaches that are nascent
in the clinical sphere. We present a guide for the next best steps after
inconclusive molecular testing based upon phenotype and prior evaluation,
including when to consider referral to a consortium such as GREGoR, which is
focused on elucidating the underlying cause of rare unsolved genetic disorders.
