SNP Shot: Genomic Insights

Familial Mediterranean fever (FMF) is a genetic disorder marked by recurring episodes of painful inflammation. These episodes typically affect the abdomen, chest, or joints and are often accompanied by fever. Rashes or headaches can also occur. Less commonly, inflammation may involve other areas, such as the heart, the membranes around the brain and spinal cord, or, in males, the testicles. Before an attack, roughly half of those affected experience a prodrome, characterized by mild discomfort in the area that will become inflamed or a general feeling of unease.

The first FMF episode usually occurs during childhood or adolescence, although it can sometimes happen later in life. Episodes typically last between 12 and 72 hours, and their severity can vary. They often occur monthly, and in women, may coincide with menstruation or ovulation. The time between episodes can vary widely, from days to years. Between episodes, individuals are usually symptom-free. However, without treatment to prevent attacks and complications, amyloidosis can develop. Amyloidosis involves the buildup of protein deposits in organs and tissues, particularly the kidneys, potentially leading to kidney failure.

Inheritance:

FMF typically follows an autosomal recessive inheritance pattern. This means that both copies of the MEFV gene in each cell must have variants for the condition to manifest. Individuals with this pattern inherit one copy with a variant from each parent, who are typically carriers and do not exhibit symptoms themselves. Research suggests that approximately one-third of FMF patients have only one identified MEFV gene variant, leading experts to believe a second, undetected variant exists elsewhere in the gene. Rarely, FMF can be inherited in an autosomal dominant manner. This pattern requires only one copy of the altered gene in each cell to cause the disorder, and affected individuals often inherit the variant from an affected parent.

However, another explanation exists for some cases initially thought to be autosomal dominant. A common gene variant within a population can lead to an autosomal recessive disorder appearing across multiple generations, mimicking autosomal dominant inheritance. This is known as pseudodominance. For example, if one parent has FMF (with variants in both MEFV gene copies) and the other is an unaffected carrier (with a variant in one MEFV gene copy), the affected child might appear to have inherited the disorder solely from the affected parent. This apparent autosomal dominant inheritance pattern is, in reality, an autosomal recessive pattern.