Genetic types of FSHD
There are two genetically distinct FSHD subtypes - FSHD1 (OMIM: 158900) and FSHD2 (OMIM: 158901), described. The basis of pathogenesis in both types of disease is ectopic expression of the DUX4(MIM: 606009) retrogene in skeletal muscles. This is only possible by hypomethylation (chromatin relaxation) of the polymorphic D4Z4 macrosatellite repeat array at chromosome 4q35, which in turn provides DUX4derepression. This is because each D4Z4 unit in array contains the sequence of polyadenylation signal for DUX4 mRNA.
To make this bit more complicated, several population studies have established that immediately distal to the D4Z4 array are two 4q subtelomeric haplotypes - designated as 4qA and 4qB. Both FSHDs types develop only with disease-permissive 4qA haplotype.
Therefore, it is essential not only to rely on the length D4Z4 array but always to evaluate the 4q subtelomeric haplotype. This is well illustrated by the example described in the 55 Chinese patients diagnosed with FSHD without 4q subtelomeric haplotype assessment. After re-evaluation, the FSHD-d D4Z4 repeats in four of them were found to be a nonpathogenic 4qB variants. Further molecular analyses established the true causes of their symptoms: limb-girdle muscular dystrophy or myotonic dystrophy.
Although the ultimate mechanism of pathology is the same for both types of FSHD, they differ in the path that leads to this.
FSHD1 is associated with partial deletion of the D4Z4 array. Shortening the length of the D4Z4 repeat array is one of the ways to cause its hypomethylation. Most healthy people will have D4Z4 repeats ranging from 11 to 150. While in FSHD1 patients D4Z4 repeats array is lower than 11. Although, at least one D4Z4 repetition is required for developing FSHD1. FSHD1 accounts for ~95% of cases.
In FSHD2 D4Z4 array is within the normal range. However, mutations of the SMCHD1gene (chromosome 18p11), DNMT3B gene (chromosome 20q11) or LRIF1gene (chromosome 1p12) were described as another causative factors of D4Z4 array hypomethylation, and DUX4derepression. The SMCHD1gene mutation is currently seen as most common - accounting for approximately 80% of cases.
Diagnosis
Determining the partial deletion of the D4Z4 array (<11) in cis with the 4qA haplotype is not equal to FSHD1 diagnosis. A diagnosis of FSHD1 can only be made in conjunction with a complete clinical evaluation. This is because the frequency of pathogenic contraction of the D4Z4 array (4qA haplotype) can be found in approximately 1–3% of the healthy individual population.
There is also recent report stating that in rare situations, FSHD can occur on chromosome 10 due to an interchromosomal rearrangement with the FSHD locus on chromosome 4q (see Professionals Publications for more data).
Genotype-phenotype correlation
Unfortunately, in available reports, we can find some different results and some misconceptions. Thus we find that the best way to address this topic is Q&A.
Q: Is there any difference in clinical signs between FSHD type 1 and FSHD type 2?
A: No, there is not. The phenotypic manifestations for both types of FSHD are identical.
Q: Is there a correlation between the D4Z4 repeats number and the clinical symptoms?
A: Yes, but it is not as evident as it may seem.
People carrying 1-3 D4Z4 will usually have a worse course of the disease when compared to people carrying 4-10 D4Z4. It should be emphad here, however, that there is a large variability of clinical symptoms in both groups, which may lead to the opposite situations.
Another difference is that people carrying 1-3 D4Z4 will most often present symptoms earlier (<20 years of age or even <10) than people carrying 4-10 D4Z4 (>20 years of age). Thus, one may state that earlier onset means worse outcomes, but it is again not so obvious. For example, a study of patients carrying only 1-3 D4Z4 compared groups of early-onset symptoms (<10 years of age) with later onset symptoms (>10 years of age) and did not find differences in disease severity course in the long term. So overall, it is more about carrying 1-3 D4Z4 than exact symptoms start when considering disease outcome — bearing in mind that this would be only a prediction, not a rule.
One more thing is that people carrying 1-3 D4Z4 will more frequently present a classical phenotype of disease compared to people carrying 4-10 D4Z4.
Studies comparing disease severity between groups of patients with 7-8 D4Z4 and 9-10 D4Z4 did not find statistical differences. Due to the large variability of symptoms presented by patients with 4-10 D4Z4, some researchers conclude that this number of repeats does not have a definite prognostic value. Therefore, the only prediction that can be made now is that a patient carrying 1-3 D4Z4 probably will get worse disease outcomes than if he had had 4-10 D4Z4.
Q: Are there any other prognostic factors?
A: Yes, however, particular ones. In some rare cases, patients meeting the criteria for the FSHD1 diagnosis may also be carriers of the SMCHD1mutation, which can influence the disease severity.
Q: Is there a correlation between the D4Z4 repeats number and the probability of a family member developing disease?
A: Yes. The exact probability is shown in the table. Studies predict penetrance to be lower in patients with 9-10 D4Z4 (~47%) than those with 6-8 D4Z4 (~62%) or 1-3 D4Z4 (~90%).
That being said, it should be remembered that <11 D4Z4 is not pathognomonic for FSHD and a complete clinical evaluation is essential for diagnosis.
Differential diagnosis is vital for people carrying 9-10 D4Z4 with an atypical disease course.
