but otherwise is no more common compared to the general population. Large 4q35 deletion can lead to various other rare manifestations. Scoliosis can occur, thought to result from weakness of abdominal, hip extensor, and spinal muscles. Conversely, scoliosis can be viewed as a compensatory mechanism to weakness. Breathing can be affected, associated with kyphoscoliosis and wheelchair use; it is seen in one-third of wheelchair-using patients. However, ventilator support (nocturnal or diurnal) is needed in only 1% of cases. Although there are reports of increased risk of cardiac arrhythmias, general consensus is that the heart is not affected. Genetics The genetics of FSHD is complex. FSHD 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 FSHD genetics. Normally, DUX4 is expressed during embryogenesis and later repressed in all tissues except the testes. In FSHD, 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 FSHD is sub-classified into FSHD type 1 (FSHD1) and FSHD type 2 (FSHD2). 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 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 FSHD, 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