Understanding the Genetics of CSID

To review basic genetics, each individual has 22 non-sex (autosomal) chromosomes and one sex chromosome (X or Y) from each parent, for a total of 46 chromosomes. All of our genes are located on these chromosomes, which are located in every one of our cells. These genes are the blueprints that code for how your bodies grow, develop, and function.

When the information in a gene is altered, the information sent to your cells is coded differently. A variation in a gene on one of the first 22 non-sex chromosomes can lead to an autosomal (non-sex) disorder. Recessive inheritance means both genes in a pair must be altered in the same way to cause the inherited disease. Individuals with only one altered gene in the pair are considered heterozygotes. When the variation is associated with a recessive disorder, these heterozygotes would be expected to be silent carriers of the disorder, but the altered gene could be passed on to their children.

Congenital Sucrase-Isomaltase Deficiency (CSID) is considered an autosomal recessive disorder of the sucrase-isomaltase gene (SI).

If you are born to parents who are both heterozygotes, with one SI variation associated with CSID, you have a 1 in 4 chance of inheriting an altered gene from each parent and having CSID. In this example, you would have a 50% (1 in 2) chance of inheriting one altered gene associated with CSID.

In other words, if four children are born to two people who both carry a gene variation associated with CSID, the expected pattern of inheritance is:

• One child is born with two functional genes (has full sucrase function, and no CSID symptoms would be expected)
• Two children are born with one functional and one altered gene (are heterozygotes for CSID)
• One child is born with two altered genes (are homozygotes for CSID, and would be expected to have diminished or absent sucrase function and GI symptoms associated with CSID)

Among the 46 chromosomes, the sucrase-isomaltase (SI) gene is located on chromosome 3. On the SI gene, one part of the gene contains the genetic code for making the sucrase enzyme and another part of the gene contains the genetic code for making the isomaltase enzyme. In a recent study, 31 individuals with CSID had their SI gene sequenced to look for mutations of the SI gene.¹

Genetic mutations that cause CSID do so by altering the structure, disrupting the production, or impairing the function of sucrase-isomaltase. In the study, 27 different mutations were identified, with four of these 27 mutations detected more frequently than the other 23. The four most common SI gene mutations were G1073D, F1745C, V577G, and R1124X.¹

A majority of the mutations were present in the sucrase area of the SI gene (57%) compared to the number of mutations in the isomaltase area (43%), even though the isomaltase area is larger than the sucrase domain.¹ Based on a model that assumes these mutations do not evolve, there is an 83% probability that in the US population, symptomatic individuals diagnosed with CSID who have European ancestry will have at least one of these four common SI mutations for CSID.¹

The SI gene of an individual with CSID contains genetic variations that cause functional gastrointestinal problems such as diarrhea, recurrent abdominal pain, and bloating. Because these symptoms are similar to many other gastrointestinal disorders, such as irritable bowel syndrome (IBS), some scientists believe a small percentage of those who are diagnosed with IBS may actually have CSID.

Due to the relatively large number of genetic variations that were discovered in a relatively small sample size, significant differences in symptoms are experienced by individuals with CSID. These differences in symptoms are known as phenotypic variations. All those with CSID have diminished sucrase activity, but some have normal isomaltase activity, some have only traces of isomaltase activity, and others have reduced, but sufficient isomaltase activity.