Structure of DUX4 protein full-length (FL), with short (S) version indicated. The genetics of<unk>  is complex.<unk>  and the myotonic dystrophies have unique genetic mechanisms that differ substantially from the rest of genetic myopathies. The DUX4 gene is the focal point of<unk>  genetics. Normally, DUX4 is expressed during embryogenesis and later repressed in all tissues except the testes. In<unk> , there is failure of DUX4 repression and continued production of DUX4 protein, which is toxic to muscles. The mechanism of failed DUX4 repression is hypomethylation of DUX4 and its surrounding DNA on the tip of chromosome 4 (4q35), allowing transcription of DUX4 into messenger RNA (mRNA). Several mutations can result in disease, upon which<unk>  is sub-classified into<unk>  type 1 <unk> 1) and<unk>  type 2 <unk> 2). Disease can only result when a mutation is present in combination with select, commonly found variations of 4q35, termed haplotype polymorphisms. There are at least 17 4q35 haplotype polymorphisms, roughly dividable into the groups 4qA and 4qB. A 4qA haplotype polymorphism, often referred to as a 4qA allele, is necessary for disease, as it contains a polyadenylation sequence that allows DUX4 mRNA to resist degradation long enough to be translated into DUX4 protein. DUX4 and the D4Z4 repeat array centromeric end TEL telomeric end NDE box non-deleted element PAS polyadenylation site triangle D4Z4 repeat trapezoid partial D4Z4 repeat white box pLAM gray boxes DUX4 exons 1, 2, 3 arrows corner promoters straight RNA transcripts black sense red antisense blue DBE-T dashes dicing sites DUX4 resides within the D4Z4 macrosatellite repeat array, a series of tandemly repeated DNA segments in the subtelomeric region (4q35) of chromosome 4. Each D4Z4 repeat is 3.3 kilobase pairs (kb) long and is the site of epigenetic regulation, containing both heterochromatin and euchromatin structures. In<unk> , the heterochromatin structure is lost, becoming euchromatin. The subtelomeric region of chromosome 10q contains a tandem repeat structure highly homologous (99% identical) to 4q35, containing "D4Z4-like" repeats with protein-coding regions identical to DUX4 (D10Z10 repeats and DUX4L10, respectively). Because 10q usually lacks a polyadenylation sequence, it is usually not implicated in disease. However, chromosomal rearrangements can occur between 4q and 10q repeat arrays, and involvement in disease is possible if a 4q D4Z4 repeat and polyadenylation signal are transferred onto 10q, or if rearrangement causes<unk> 1. DUX4 consists of three exons. Exons 1 and 2 are in each repeat. Exon 3 is in the pLAM region telomeric to the last partial repeat. Multiple RNA transcripts are produced from the D4Z4 repeat array, both sense and antisense. Some transcripts might be degraded in areas to produce si-like small RNAs. Some transcripts that originate centromeric to the D4Z4 repeat array at the non-deleted element (NDE), termed D4Z4 regulatory element transcripts (DBE-T), could play a role in DUX4 derepression. One proposed mechanism is that DBE-T leads to the recruitment of the trithorax-group protein Ash1L, an increase in H3K36me2-methylation, and ultimately de-repression of 4q35 genes.<unk> 1<unk>  involving deletion of D4Z4 repeats (termed 'D4Z4 contraction') on 4q is classified as<unk> 1, which accounts for 95% of<unk>  cases. Typically, chromosome 4 includes between 11 and 150 D4Z4 repeats. In<unk> 1, there are 1–10 D4Z4 repeats. The number of repeats is roughly inversely related to disease severity. Namely, those with 8 - 10 repeats tend to have the mildest presentations, sometimes with no symptoms; those with 4 - 7 repeats have moderate disease that is highly variable; and those with 1 - 3 repeats are more likely to have severe, atypical, and early-onset disease. Deletion of the entire D4Z4 repeat array does not result in<unk>  because then there are no complete copies of DUX4 to be expressed, although other birth defects result. One contracted D4Z4 repeat array with an adjoining 4qA allele is sufficient to cause disease, so inheritance is autosomal dominant. De novo (new) mutations are implicated in 10 - 30% of cases, 50% of which exhibit somatic mosaicism. It has been proposed that<unk> 1 undergoes anticipation, a trend primarily associated with trinucleotide repeat disorders in which disease manifestation worsens with each subsequent generation. As of 2019, more detailed studies are needed to definitively show whether or not anticipation plays a role. If anticipation does occur in<unk> , the mechanism is different than that of trinucleotide repeat disorders, since D4Z4 repeats are much larger than trinucleotide repeats, an underabundance of repeats (rather than overabundance) causes disease, and the repeat array size in<unk>  is stable across generations. D4Z4 array examples, with each D4Z4 repeat representated by a triangle. The circles above the triangles represent DNA methylation, which determine DNA packaging as represented by the circles in line with the triangles.<unk> 2<unk>  without D4Z4 contraction is classified as<unk> 2, which constitutes 5% of<unk>  cases. Various mutations cause<unk> 2, all resulting in D4Z4 hypomethylation, at which the genetic mechanism converges with<unk> 1. Approximately 80% of<unk> 2 cases are due to deactivating mutations in the gene SMCHD1 (structural maintenance of chromosomes flexible hinge domain containing 1) on chromosome 18. SMCHD1 is responsible for DNA methylation, and its deactivation results in hypomethylation of the D4Z4 repeat array. Another cause of<unk> 2 is mutation in DNMT3B (DNA methyltransferase 3B), which also plays a role in DNA methylation. As of 2020, early evidence indicates that a third cause of<unk> 2 is mutation in both copies of the LRIF1 gene, which encodes the protein ligand-dependent nuclear receptor-interacting factor 1 (LRIF1). LRIF1 is known to interact with the SMCHD1 protein. As of 2019, there are presumably additional mutations at other unidentified genetic locations that can cause<unk> 2. Mutation of a single allele of SMCHD1 or DNMT3B can cause disease. Mutation of both copies LRIF1 has been tentatively shown to cause disease in a single person as of 2020. As in<unk> 1, a 4qA allele must be present for disease to result. However, unlike the D4Z4 array, the genes implicated in<unk> 2 are not in proximity with the 4qA allele, and so they are inherited independently from the 4qA allele, resulting in a digenic inheritance pattern. For example, one parent without<unk>  can pass on an SMCHD1 mutation, and the other parent, also without<unk> , can pass on a 4qA allele, bearing a child with<unk> 2. Two ends of a disease spectrum Initially,<unk> 1 and<unk> 2 were described as two separate genetic causes of the same disease. However, they can also be viewed not as distinct causes, but rather as risk factors. Not rarely do both contribute to disease in the same individual. In those with<unk> 2, although they have do not have a 4qA allele with D4Z4 repeat number less than 11, they still often have one less than 17 (relatively short compared to the general population), suggesting that a large number of D4Z4 repeats can prevent the effects of an SMCHD1 mutation. Further studies need to be done to determine the upper limit of D4Z4 repeats in which<unk> 2 can occur. In those with a 4qA allele and 10 or fewer repeats, an additional SMCHD1 mutation has shown to worsen disease, classifying them as both<unk> 1 and<unk> 2. In these<unk> 1/FSHD2 individuals, the methylation pattern of the D4Z4 repeat array resembles that seen in<unk> 2. This combined<unk> 1/FSHD2 presentation is most common in those with 9 - 10 repeats, and is seldom found in those with 8 or less repeats. The relative abundance of SMCHD1 mutations in the 9 - 10 repeat group is likely because a sizable portion of the general population has 9 - 10 repeats with no disease, yet with the additive effect of an SMCHD1 mutation, symptoms develop and a diagnosis is made. In those with 8 or fewer repeats, symptoms are more likely than in those with 9 - 10 repeats, leading to diagnosis regardless of an additional SMCHD1 mutation. The apparent frequency of<unk> 1/FSHD2 cases in the 9 - 10 repeat range, combined with the<unk> 2-like methylation pattern, suggest the 9 - 10 repeat size to be an overlap zone between<unk> 1 and FSDH2.
Facioscapulohumeral muscular dystrophy
Limb–girdle muscular dystrophy
Becker muscular dystrophy
Ullrich congenital muscular dystrophy
Fukuyama congenital muscular dystrophy
Spinal muscular atrophy
Duchenne muscular dystrophy
Jokela type spinal muscular atrophy