Genetic Mutations Can Be Risk Factors for Pediatric Sarcoidosis, Study Finds

Ana Pena, PhD avatar

by Ana Pena, PhD |

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Several mutations found in 37 genes were reported to be possible genetic risk factors for pediatric sarcoidosis, according to researchers.

The report, “Whole exome sequencing in three families segregating a pediatric case of sarcoidosis,” was published in the journal BMC Medical Genomics.

Sarcoidosis is an inflammatory disease that can affect multiple organs and whose origin is poorly understood. The disease usually develops before the age of 50, but very rarely affects children — with an estimated prevalence of 0.4 to 1.2 per 100,000 children. 

When it does affect children, the disease is often severe, impacting different organs, causing frequent relapses, and increasing the risk of lung fibrosis.

Some researchers have suggested sarcoidosis is caused by a dysfunction in the immune system that happens in people with a genetic predisposition to the condition. But the contribution of environmental and genetic factors is unclear.

Most sarcoidosis cases are sporadic, meaning they don’t have a family history. But 3 percent to 5 percent of patients display familial sarcoidosis, having a first or second degree relative also affected by the disease. 

In fact, studies demonstrating that identical twins are 80 times more likely to develop sarcoidosis suggests a genetic background has a strong influence.

The identification of genetic risk factors is challenging given that sarcoidosis is a complex disease that likely involves many different genes. In fact, many gene variants have been associated with sarcoidosis.

Now, researchers investigated genetic variants linked to pediatric sarcoidosis. They examined families with a child diagnosed with exceptionally severe sarcoidosis before the age of 15, but whose parents did not have the disease.

Three family trios were selected from a large French study on familial sarcoidosis, called SARCFAM (NCT02829853).

Researchers searched for mutations in children and their healthy parents using whole exome sequencing, a technique that sequences only DNA that provides instructions for the production of proteins.

Mutations in 37 genes were found, carried by both the parents and child or only present in the child.

Six mutations previously unreported were present only in children, and not overlapping between them, which indicates they appeared spontaneously and were not inherited.

The others were potentially disease-causing mutations, either rare or common in the population, and carried by both children and parents.

The identified genes are predicted to have several different functions including cell replication, communication, transport, and immune system activation.

Of the 37 genes identified, 29 may be related directly or indirectly to pathways linked to immunity and related processes. The team focused closely on 10 of those genes, which had mutations recurrent in at least two family trios.  

Based on what is known about the role of these genes, researchers hypothesized that the characteristic granulomas (small areas of inflammation in tissue) occurring in sarcoidosis may be related, with specific cellular functions such as autophagy (a type of cellular recycling), cell transport, and replication and activation of T-cells (a key subset of immune cells).

Taken together, researchers identified several genetic variants possibly linked to pediatric sarcoidosis.

“Whole exome analysis of case-parent trios is useful for the identification of genes predisposing to complex genetic diseases [such] as sarcoidosis. Our data identified 37 genes that could be putatively linked to a pediatric form of sarcoidosis in three trios,” the researchers wrote. 

“The characterization of a very broad panel of genes associated with the different clinical forms of sarcoidosis will ultimately not only define the relative risk of disease occurrence in families at risk, but also better characterize the evolutionary profiles and help to optimize therapeutic strategies,” the team added.