What does my child’s GRIN diagnosis mean?
Identification of specific gene mutations in a genetic report is so far the only way to know if a child suffers from a GRIN disorder. To try to help you understand what your child’s genetic diagnosis and genetic report means, we would like to explain what the most common words used to classify GRIN disorders really mean.
DNA consists of four building blocks, which are called nucleotides. The nucleotides are indicated with the letters C (Cytosine), G (Guanine), A (Adenine), and T (Thymine). The order of the nucleotides encodes for the building of proteins. The GRIN genes encode (i.e., contain the code) for building proteins that form the NMDA receptors.
A mutation is a change in the genetic code (recipe), that leads to the production of a variant (a different structure from the expected one) of a protein codified by that gene. It can be caused by the alteration of single nucleotide in the gene´s DNA, or the deletion, insertion, or rearrangement of larger sections of genes or massive changes across entire portions of chromosomes.
Heterozygous, missense, nonsense (truncation), duplication and deletion:
Heterozygous: A gene consists of two alleles (or “copies”), which stem from your mother and father, respectively). If a mutation is heterozygous, this means that a child carries one mutated copy and one non-mutated copy of the GRIN gene. So, for that reason ALL GRIN children are thought to have heterozygous mutations.
Missense mutations: This refers to a change in the genetic code in the gene (i.e. the letters in the sequence of the DNA code are different from what they should be). This then leads to a change in the single units (amino acid) of the protein, with this yielding an abnormal GRIN protein product.
Nonsense mutations (or truncation): These types of mutations are also caused by as little as a single letter change in the genetic code, but they lead to the production of a shorter fragment of the GRIN protein. This protein is said to be incomplete or truncated, and it is usually nonfunctional.
Duplication: meaning that the child has an extra copy or copies of the abnormal GRIN gene.
Deletion: This refers to the deletion of 1 or more gene units (nucleotides, i.e. A,C,T, G), which leads to a deformed or non-viable GRIN protein.
Most GRIN mutations are described as de novo, meaning they are NOT inherited from either parent but have happened by chance at the time of conception or shortly thereafter.
Inherited GRIN mutations are rare because GRIN mutations are, for the most part, disease causing mutations. This means that whoever carries the mutation will have some or all the GRIN clinical symptoms and oftentimes will not have children of their own. For this reason, it is very important that inherited mutations are studied thoroughly. On rare occasions, a parent may carry a GRIN mutation, but the parent will only be very mildly affected. In the child, this mutation, in combination with other mutations in other genes, may however cause much more severe diseases. That is why a full genetic test like WES (Whole Exome Sequencing) is strongly recommended for the diagnosis and to rule out other genes as the potential cause of your child’s clinical symptoms.
Please Keep in Mind: If you have a child with a de novo GRIN mutation and are considering having another child, it is very important to discuss this with your geneticist/genetic counselor. This is because, in rare cases, something called Germline cell mosaicism can occur. This means that even if the genetic mutation is not found in the parent’s blood (the cells most used when genetic testing is done) it could still be found in either sperm or egg cells from either one of the parents. In these rare cases, the parent could pass along the GRIN mutation even without him/her being affected. In this case further testing should be done for both parents.
If Germline cell mosaicism is ruled out and the GRIN mutation was de novo, parents have a less than 1% chance of having another baby with a GRIN mutation.
Sometimes your genetic report may also mention whether your child’s mutation is deemed to be pathogenic (disease causing) and can consequently account for your child’s symptoms. A mutation can also be non-pathogenic (not disease causing), or a mutation can be of “unknown significance”. The latter means that, at this point in time, it is not yet clear whether the mutation is disease causing and can account for your child’s symptoms. Sometimes a mutation of “unknown significance” can at a later point in time be redefined as pathogenic or non-pathogenic. If the report does not specify if the mutation your child carries, is pathogenic, please refer to the GRIN database.