iRHOM2 Deficiency Causes Environmentally Directed Immunodysregulatory Disease

RHBDF2 that encodes the protein iRHOM2. Whole exome (kindred 1) and whole genome sequencing (kindred 2) have uncovered the first human loss-of-function mutations of RHBDF2 in 4 individuals. The affected patients are all children, 8 years old or younger, and were brought to our attention initially due to their suffering recurrent infections. Sequencing of their family members revealed parents with heterozygous RHBDF2 mutations, and heterozygous and wild type siblings – all of which were unaffected by this disease. A comprehensive investigation of this gene mutation through in vivo and in vitro experiments revealed that a loss of the protein iRHOM2 impairs the activity of the protease ADAM17 and subsequently compromises immune responses. This condition leads to the afflicted patients becoming vulnerable to different infections based on their unique environment and presenting with diverse clinical phenotypes. ]]>
Inclusion criteria: Patients known to have, or suspected of having, an inherited disease of the immune system are eligible for enrollment. Because of the intensive time and labor required for research laboratory testing, patients are enrolled only if there is high index of suspicion in the opinion of the investigator. Biological relatives of enrolled patients are eligible for enrollment. There is no limit as to age, sex, race, or disability.

Exclusion criteria: The presence of an acquired immune abnormality, such as HIV, cytotoxic chemotherapy, or malignancy may be grounds for possible exclusion, if the investigator feels the presence of such abnormalities has interfered with evaluation. Severely debilitated health status or poor venous access may also preclude acquisition of adequate specimens for analysis. Within the limits of maximal acceptable blood draw volumes and minimum requirement for key laboratory tests, the cutoff weight for infants permitted in this protocol is 3 kg and above. ]]>