2q37 deletion syndrome – HDAC4 gene, Chromosome 2

The 2q37 deletion syndrome, also known as 2q37-qter monosomy or Albright hereditary osteodystrophy type 3 syndrome, can affect many parts of the body. Common signs and symptoms include hypotonia at birth, mild to severe intellectual disability, delayed development of motor skills, and behavioral problems, including autism spectrum alterations. Other signs include unusual physical features, such as brachydactyly, short stature, obesity or shortage of hair; and characteristic facial features, such as a prominent forehead, low hairline, thin eyelids, epicantic folds, upwardly inclined palpebral fissures, small nose, small mouth with thin lips, smooth nasolabial groove, prominent cheekbones, large chin and small abnormalities in the ears In addition, individuals with 2q37 deletion syndrome may suffer from seizures and eczema. There have been cases of people with malformations in the brain, heart, gastrointestinal system, kidneys or genitals. Some affected people also develop a rare form of kidney cancer called Wilms tumor.

This process is due to deletions of the genetic material of a specific region on the long arm of chromosome 2. Deletions occur near the end of the chromosome at location 2q37. The size of the elimination varies among affected individuals, and most of the affected people lose from 2 to 9 Mb. Although there are many genes whose loss could be involved in the development of the disease, it is likely that the loss of the HDAC4 gene (histone deacetylase 4), located on the long arm of chromosome 2 (2q37.3), explain many of the characteristic signs of the syndrome (such as intellectual disability and skeletal abnormalities).

The HDAC4 gene encodes the histone deacetylase 4 enzyme, which is part of a group of histone modifying enzymes. Histones are structural proteins that bind to DNA and shape chromosomes. By removing an acetyl group from histones, histone deacetylases cause chromosome DNA to compress. As a consequence transcription factors, which bind to specific regions of the DNA and help control the activity of particular genes, cannot access the DNA. Through histone deacetylation, histone deacetylase 4 is able to regulate the activity of certain genes. Histone deacetylase 4 appears to be particularly important for regulating the activity of genes involved in the development of the heart and skeleton. This protein is also involved in the survival of nerve cells.

The chromosomal region that is removed in the 2q37 deletion syndrome varies among affected individuals and may contain many genes, but always includes the HDAC4 gene. As a consequence of the aforementioned elimination, people with this condition have only one copy of the HDAC4 gene in each cell instead of the usual two copies. The researchers believe that the elimination of the HDAC4 gene and reduction in the amount of histone deacetylase 4 produced, explain many of the characteristics of the 2q37 deletion syndrome. It is likely that histone deacetylase 4 enzyme deficiency disrupts the regulation of many genes and contributes to the characteristics of this syndrome.

Cases of individuals carrying a mutation in the HDAC4 gene that have brachydactyly without other health problems have been described, while others have many features of the 2q37 deletion syndrome. However, it is not clear why mutations in this gene can lead to a wide variety of signs and symptoms.

Most cases of 2q37 deletion syndrome are not inherited and are due to a chromosomal elimination that occurs as a random event during the formation of reproductive cells or early embryonic development, so affected people generally have no history of the disease in his family. However, rarely does an affected person inherit a copy of chromosome 2 with a segment removed from an affected parent. In these cases, the father is generally less affected than the child, for reasons that are unknown. When an affected child inherits a chromosomal elimination from a parent, it is inherited in an autosomal dominant pattern, which means that a copy of the altered chromosome in each cell is sufficient to cause the disorder.

Tests performed in IVAMI: in IVAMI we perform the detection of deletions in chromosome 2 associated with the 2q37 deletion syndrome, by means of the PCR quantification at real time.

Recommended samples: non-coagulated blood obtained with EDTA for separation of blood leucocytes, or a card with a dried blood sample (IVAMI can mail the card to deposit the blood sample).