MLD Genetic Sequencing

Genetic sequencing (testing) looks for specific inherited changes (variants) in a person’s genes. Genetic variants can have harmful, beneficial, neutral (benign/no effect), or unknown/uncertain significance (VoUS) on the risk of developing a given disease.

Genetic sequencing analyzes a small bit of saliva, or sometimes blood, to examine the DNA for mutations – defective genes.

MLD is an autosomal recessive genetic disease. Your affected loved one received one bad gene from mom and one from dad. Mom and dad must both be carriers to pass along a bad gene. Carriers have a good gene and a bad gene. There is a 50% (2 in 4) chance their child will be a carrier, a 25% chance ( 1 in 4) that the child will be affected, and a 1 in 4 that the child will be free form MLD and not a carrier (MLD cannot be passed on).

Your DNA can mutate in many ways… causing the proteins (enzymes) to function improperly – or not at all.

• Missense mutation …  a change in one DNA base pair that results in the substitution of one amino acid for another in the protein made by a gene.
• Nonsense mutation … is also a change in one DNA base pair where the altered DNA sequence prematurely signals the cell to stop building a protein. This type of mutation results in a shortened protein that may function improperly or not at all.
• Insertion … changes the number of DNA bases in a gene by adding a piece of DNA. As a result, the protein made by the gene may not function properly.
• Deletion … changes the number of DNA bases by removing a piece of DNA. Small deletions may remove one or a few base pairs within a gene, while larger deletions can remove an entire gene or several neighboring genes. The deleted DNA may alter the function of the resulting protein(s).
• Duplication … consists of a piece of DNA that is abnormally copied one or more times. This type of mutation may alter the function of the resulting protein.
• Frameshift mutation … This type of mutation occurs when the addition or loss of DNA bases changes a gene’s reading frame. The resulting protein is usually nonfunctional. Insertions, deletions, and duplications can all be frameshift mutations.
• Repeat expansion … Nucleotide repeats are short DNA sequences that are repeated a number of times in a row. This type of mutation can cause the resulting protein to function improperly.

What is Genotype/Phenotype Correlation?

The genotype is the genetic makeup of an individual. The phenotype is the observable clinical, physical, or biochemical characteristics.

A disease phenotype may be modulated by genetic and non-genetic modifiers. The correlation between genotype and phenotype is a statistical relationship that predicts a physical trait, abnormality, or progression in a patient with a given mutation or a group of similar mutations.* 

This means two individuals with similar genotypes may present and progress differently.  There is much to learn in this regard. Gathering patient genotype and phenotype (clinical presentation and progression) data is the key to improving our understanding of these correlations.

The Sequencing Report

The report you will get back will indicate which genes are defective, and what the experts, publications, and case studies know about the implication of those mutations.  Remember that there are over 90,000 combinations of mutations known to cause MLD.  Fortunately, a small number of those mutations are much more common (prevalent) than the rest so there can be greater insight if the mutations or the combination of the two mutations has been studied in other patients.  However, this also means that hundreds of the mutations and tens of thousands of possible permutations are not as well understood.

Please moderate your expectations until you see the report. Regardless of the ability to correlate genotype and phenotype, the report will be valuable for improving our disease understanding, and to identify carriers and potential at-risk individuals in your extended family.