Monogenic diseases are rare! But presentations of many of them overlap with, or are similar to those of common
non-genetic or multifactorial disorders. Studies on novel genes of autoinflammatory disorders described in the GenExpress
in this issue highlight the same point. These papers talk about gain-of-function mutations in genes involved in innate
immunity. The presenting features of these monogenic autoinflammatory disorders are fever and ‘--itis’, associated with
haematological markers of inflammation; the features are similar to those of infections or autoimmune disorders.
Recurrent episodes in the absence of immunodeficiency make one suspect that these can be autoimmune disorders. More
than 100 autoimmune disorders are delineated, many of them with overlapping features. Development of the speciality of
clinical immunology and expert management by the specialists has improved the outcomes of autoimmune disorders. But
rarely the auto-antibodies are conspicuous by their absence in clinically suspected autoimmune disorders and in
such scenarios, testing of multiple genes in one go clinches the diagnosis of monogenic auto-inflammatory
disorders.
Autoinflammatory and autoimmune disorders are inflammatory disorders due to defects in the immune system. The
autoinflammatory disorders are due to defects in the genes involved in innate immunity and its pathways. The
inflammation starts by itself without known external triggers like microorganisms. On the other hand, autoimmune
disorders are due to abnormalities of adaptive immunity where the body mistakes a cell type that is actually “self” as
“other”. These are akin to ‘learning mistakes’, while in autoinflammatory disorders the ‘mistakes are in the basic
knowledge’ of the immune competent cells. As mentioned previously, the resulting symptoms are very similar. Presence of
family history or consanguinity can help in clinical suspicion in addition to documented absence of autoantibodies. Some
autoimmune disorders also have family history of other autoimmune disorders as they also have multifactorial etiology
which includes a genetic component. Some autoinflammatory disorders manifest during fetal life or infancy
and have overlapping features with infective disorders. This group includes pseudo-TORCH syndrome and
Aicardi-Goutieres syndrome for which 3 and 9 causative genes are known till date. Correct diagnosis is important
not only for appropriate management but also for genetic counseling as there may be 25 or 50% risk of
recurrence in the family members. For severe disorders with early lethality and neurological involvement,
the option of prenatal diagnosis also may be useful for the families. Specific targeted therapies also may
become available as the genetic diagnosis provides knowledge of the molecular pathways involved in disease
pathogenesis.
The monogenic autoinflammatory disorders should open our minds to rare monogenic causes of common presentations
and stress the need for considering these etiologies in common presentations. Similar overlap is seen in other diseases with
heterogeneous etiologies like diabetes mellitus, nephrotic syndrome, cardiomyopathy, hypertension, cataract, etc. In
fact, there are monogenic causes for each of these clinical conditions, even though more often they are
associated with multifactorial etiology. Understanding the genetics of rare monogenic disorders also paves the
way for obtaining insights into the pathogenesis of common multifactorial disorders, which in turn helps
in identifying therapeutic targets for novel drug development. It is thought that the genetic variants in
the genes for monogenic disorders may be contributing as susceptibility loci for common multifactorial
disorders.
Don’t think of rare diseases rarely if you don’t want to miss any diagnosis!
