Table 4.

Examples of successful studies that used reverse phenotyping. Abbreviations: BMPR2—Bone morphogenic protein receptor type 2; PAH—pulmonary arterial hypertension; WES—whole-exome sequencing, * denotes allele number.

Gene	Condition	Study Design	Data Sources	Results	References
HLA-DRB1*0301/DQB1*0201	Sarcoidosis	Mix of retrospective and prospective cases with acute onset sarcoidosis	Health records	Patients with acute onset sarcoidosis carrying HLA-DRB1*0301/DQB1*0201 genotype have good prognosis, manifestations of Lofgren’s syndrome differ between man and woman.	[278,302]
BMPR2	PAH	Retrospective analysis of 169 PAH patients	WES & Health records	Patients with missense mutations that escape nonsense-mediated decay have more severe disease than those with truncating mutations.	[296]
BMPR2	PAH	Retrospective analysis of 171 patients		Missense variants in the cytoplasmic tail appear to confer less severe phenotype than other BMPR2 variants with a later age of onset, milder haemodynamics, and more vasoreactivity.	[297]
BMPR2	PAH	A large individual participant data meta-analysis	Literature review	Patients harbouring deleterious BMPR2 mutations have earlier disease onset, worse haemodynamics, are less likely to respond to NO challenge and have lower survival when compared to those without BMPR2 mutations.	[180]
BMPR2	PAH	Retrospective analysis of 44 PAH patients who underwent lung transplantation between 2005 and 2014	Histology, immunohistochemistry, morphometry of explanted lungs; French registry database	BMPR2 mutation carriers are more prone to haemoptysis; haemoptysis is closely correlated to bronchial arterial remodelling and angiogenesis; pronounced changes in the systemic vasculature correlate with increased pulmonary venous remodelling, creating a distinctive profile in PAH patients harbouring a BMPR2 mutation.	[295]
multiple genes	Nephrotic syndrome	A retrospective analysis of all patients diagnosed with nephrotic syndrome between 2000 and 2018	WES & personalised diagnostic workflow	Reverse phenotyping after WES increased the diagnostic accuracy in patients referred with the diagnosis of steroid-resistant nephrotic syndrome.	[279]