Genetic lupus-like syndrome [77 genes]

Monogenic forms of SLE are rare and are usually known as lupus-like syndromes, which manifest some typical clinical characteristics of SLE. These are the result of deregulation of T or B lymphocytes, decontrol in the inflammatory response or defects in the mechanisms of immune tolerance. Only a few cases of familial lupus caused by pathogenic mutations have been published in the scientific literature, although other autoimmune diseases could have overlapping phenotypes with SLE, or other diseases related to the immune system can present with symptoms compatible with SLE. Accurate genetic interpretation is important to evaluate familial forms, which could modify patient management and direct genetic counseling.

• Lupus perniosis
• Vasculitis
• Arthralgia
• Chronic autoinflammation
• Lupus-like symptoms
• Multisystemic manifestations

• Unknown (rare monogenic forms)
• ~0.5% of general population (SLE)

• Diagnosis and genetic counseling
• Anti-inflammatories
• Immunosuppressants
• Monoclonal antibodies
• Immunomodulators

Identifying a genetic defect responsible for the disease would allow a precise molecular diagnosis to be issued and make it possible to provide genetic counseling to the patient and their family members. In some cases, detecting a genetic variant can help explore specific treatment options.

Not all cases diagnosed with SLE are susceptible to genetic study because it is an autoimmune disorder of multifactorial origin. In those cases in which “lupus-like” is suspected, or there is an early presentation with severe expression, there may be an intrinsic genetic cause causing the disease. This set of genes includes those whose genetic defects can be a sufficient cause of autoimmune diseases that manifest overlapping characteristics with lupus. Here we find genes encoding the classical complement pathway, complement regulators, and some of the alternative pathways that are related to glomerulonephritis.

Within this panel, genes with the following functions are included:

• Genes involved in DNA repair processes, whose loss of function is prone to developing high titers of ANA, anti-dsDNA, anti-histone, and anti-Ro autoantibodies: DNASE1, DNASE1L3, TREX1, RNASEH2A/B/C
• Genes related to interferonopathies: TMEM173, IFIH1, SAMHD1
• Genes involved in STAT pathways and regulators of TLR-mediated signals: TLR5, TLR7, BANK1, BLK
• Genes whose defects lead to the development of primary immunodeficiencies with susceptibility to developing autoimmunity and overlapping characteristics with lupus: PRKCD, CTLA4, NCF2, CYBB, RAG2, IKZF1, TYK2…
• Genes encoding TNF-mediated proinflammatory receptors and regulators: TNFAIP3