SLC9A3 is located at chromosome 5p15.33 and encodes the sodium (Na⁺)/proton (H⁺) exchanger 3 isoform (NHE3). This ion transporter is located on the apical membrane surface of epithelial cells that line the lumen of the gastrointestinal tract and renal proximal tubules where it facilitates the (re)entry of luminal sodium and indirectly bicarbonate (HCO3-) and water (re)absorption into the body. This helps to control the body’s fluid levels (and consequently blood pressure) and acid–base (pH) homeostasis. It is also expressed in other epithelia, such as the male epididymis, vas deferens and testes where it plays important roles in seminal fluid levels and acidification essential for male reproductive health.
Usually, SLC9A3-related conditions are caused by a single ‘spelling’ variation in the gene, which means the message is not read or received properly, resulting in the production of a defective, non-functional protein. SLC9A3-related conditions are genetic conditions. This means that the condition was not caused by anything the mother or father did before the baby was conceived, during pregnancy or birth, or after the baby was born. SLC9A3-related conditions are extremely rare, although the precise prevalence of the disease is currently unknow. As the disorder is autosomal recessive (that is, the gene is located on one of the 22 pairs of numbered, non-sex chromosomes in humans—in this case chromosome 51—as opposed to the sex chromosomes X and Y), developing the disorder requires inheriting an abnormal gene from both parents and can affect males and females equally.
What is needed to confirm the diagnosis of SLC9A3-related syndrome?
The diagnosis of SLC9A3-related syndrome is confirmed by performing genetic testing in an affected individual, which enables the detection of a disease-causing change in the SLC9A3gene.
There are two possible strategies to identify a SLC9A3change:
• If the individual’s characteristics are not sufficient to raise the suspicion of SLC9A3-related syndrome (for example, because they overlap with the characteristics observed in other genetic disorders), the DNA sequence of multiple genes, including SLC9A3, will be analysed using a multi-gene panel or exome sequencing.
• If the individual’s characteristics raise the suspicion of SLC9A3-related syndrome, only the DNA sequence of the SLC9A3 gene will be analysed.
The genetic testing can be arranged by a clinical geneticist and involves the collection of a sample of blood or saliva from the affected individual (and eventually the parents). Analysing the DNA of the patient and comparing it with the parents’ DNA may facilitate the detection of a disease-causing change in the SLC9A3 gene that is not present in the healthy parents (i.e. a “de novo” change).
SLC9A3