Table 1.

Case examples of diagnoses made by NGS, providing insights into pathogenicity

Gene	Insights into pathogenesis of rare disorder	Details of diagnosis	Details of pathogenesis
MYBPC1 (MIM 160794)	Demonstrated a novel and expanded phenotype associated with this known gene (PMID 31264822)	Protein modeling and biochemical and kinetic studies demonstrated effect of variant on muscle structure/function	Novel phenotype for gene
SETBP1 (MIM 611060)	Demonstrated a forme fruste presentation for a well-described and neurologically progressive disorder (PMID 32445275)	Documentation of a patient with a previously observed variant within a gene hotspot with a much milder phenotype/disease course than previously described	Novel phenotype–specific variant
KMT2D (MIM 602113)	Novel, and substantially different, phenotype associated with pathogenic variants within a 40-amino-acid region of the gene previously established to be associated with a different and well-described genetic syndrome (PMID 32083401)	Region of particular interest identified via variant sharing and review of data from both control databases and published cases	Novel phenotype–specific gene region
IRF2BPL (MIM 611720)	Novel disease gene reported in 2018, in which clinical phenotype significantly varies based on type of genetic change (PMID 30057031)	LOF variants cause severe neurodevelopmental regression, and missense variants cause a milder neurologic phenotype	Novel phenotype–specific type of variant
SCN8A (MIM 600702)	Individuals identified with variants resulting in protein LOF or GOF and different clinical presentations (PMID 25725044)	GOF variants cause severe early-infantile epileptic encephalopathy 13, while LOF variants cause intellectual disability with or without seizures	Novel phenotype–specific molecular consequence

Abbreviations: GOF, gain of function; LOF, loss of function; MIM, Mendelian Inheritance in Man; NGS, next-generation sequencing; PMID, PubMed reference number.