Nonsyndromic holoprosencephaly (nonsyndromic holoprosencephaly) - Genes SHH, ZIC2, SIX3 or homeobox protein tgif1.
Nonsyndromic holoprosencephaly is a developmental abnormality of the brain that also affects the head and face. Holoprosencephaly occurs when the brain does not divide properly in the right and left hemispheres during development. This alteration is called nonsyndromic to distinguish it from other types of holoprosencephaly caused by genetic syndromes, chromosomal abnormalities, or substances that cause birth defects. The severity of the disease varies widely among affected individuals, even within the same family.
Nonsyndromic holoprosencephaly can be grouped into four types according to the degree of division of the brain. Unless more severe types are known as alobar, semi - lobar, lobar, and the average interhemispheric variant (MIHV). In the most severe forms of non - syndromic holoprosencephaly, the brain is not divided at all. These affected individuals have ciclopía and proboscis above the eye. Most newborns die before birth or shortly thereafter.
In less severe forms, the brain is partially divided and in general, the eyes are too close together (hypotelorism). The life expectancy of these people varies depending on the severity of symptoms. Other features of the disease may include microcephaly or macrocephaly due to hydrocephalus, cleft palate, with or without cleft lip, a single central incisor instead of two and a flat bridge. In addition, the eyes may be too small or absent. Some affected individuals have a distinctive pattern of facial features, including a narrowing of the head at the temples, oblique palpebral fissures up, large ears, a short nose with nostrils up and philtrum. Some people have no apparent structural brain abnormalities, but have some of the facial features associated with the disease. It is considered that these individuals have a form of the disease known as microform holoprosencephaly and are generally identified after birth of an affected too familiar. Most people with holoprosencephaly have non - syndromic developmental delay, intellectual disability and malfunction of the pituitary. Dysfunction in other parts of the brain can cause seizures, feeding difficulties, problems regulating body temperature, heart rate and breathing, hyposmia or anosmia.
About 25 percent of people with non - syndromic holoprosencephaly have a mutation in one of these four genes: SHH, ZIC2, SIX3 or homeobox protein tgif1. Mutations in other non - syndromic holoprosencephaly related genes are found in only a small percentage of cases. Many people with this disease have a genetic mutation identified. In these individuals, the cause of the disease is unknown.
The SHH gene, located on the long arm of chromosome 7 (7q36), encoding the protein "Sonic Hedgehog". This protein functions as a chemical signal that is essential for embryonic development. The protein plays a role in cell growth, cell specialization, and the normal conformation of the organism. This protein is important for the development of the brain and spinal cord, eyes, limbs and many other parts of the body. This protein, and other signaling proteins, are required to form the brain hemispheres. It also has an important role in the formation of the eyes.
They have identified more than 100 mutations in the SHH gene cause non - syndromic holoprosencephaly. Mutations in this gene are the most common cause of impaired. These mutations reduce or eliminate the activity of the protein "Sonic Hedgehog". Without proper activity of this protein, the eyes are not formed normally and the brain is not separated into two hemispheres. If the eyes do not move to the correct position, the development of other parts of the face is affected.
The SIX3 gene, located on the short arm of chromosome 2 (2p21), encodes a protein that plays an important role in the development of eyes and forebrain. This protein is a transcription factor, meaning that binds to specific DNA regions and helps control the activity of certain genes. The protein regulates genes involved in several signaling pathways that are important for embryonic development. Also it regulates genes involved in the formation of the lens and retina.
We found at least 60 mutations in the gene SIX3 in people with non - syndromic holoprosencephaly. Although mutations in this gene can cause mild forms of the disease, general signs and tend to cause more serious than the symptoms mutations in other genes. Mutations in the gene change the structure of the protein in different ways SIX3 disrupting the ability of the protein to bind to DNA. As a result, the genes involved in the normal development of the eye and forebrain are not properly activated. Without proper activity of these genes, the eyes are not formed normally and the brain is not separated into two hemispheres.
The homeobox protein tgif1 gene, located on the short arm of chromosome 18 (18p11.3), encoding the protein TG. This protein is important for the normal development of the forebrain. The TG protein is a transcription factor that regulates signaling pathways that are important for embryonic development. It acts by blocking the retinoic acid molecule that regulates gene activity. Retinoic acid, a form of vitamin A, joins a group of transcription factors that regulate a number of important genes for early development.
They have identified at least 13 mutations in the gene cause the disease homeobox protein tgif1. Mutations in this gene are the fourth most common cause of non - syndromic holoprosencephaly. These mutations alter the ability of the protein to bind to DNA or interact with other proteins. If the signals involved in the development of forebrain are not properly regulated, the brain is not separated into two hemispheres.
The ZIC2 gene, located on the long arm of chromosome 13 (13q32), encodes a protein that plays an important role in the development of the forebrain. This protein is a transcription factor. The protein regulates genes involved in both early and late stages of development of the forebrain.
They have identified more than 80 mutations in the gene cause non - syndromic ZIC2 holoprosencephaly. Mutations in this gene are the second most common cause of the disease. The facial features of individuals with mutations in the gene ZIC2 are different from those in which the disease is caused by mutations in other genes. These distinctive facial features include a narrowing of the head at the temples, oblique palpebral fissures up, big ears, short nose with nostrils up and philtrum. Mutations in the gene, reduce or eliminate the activity of the protein. Without enough functional protein, genes involved in the normal development of the forebrain not controlled properly. As a result, the brain does not separate into two hemispheres.
This disease is inherited as an autosomal dominant, which means that an alteration in a copy of a gene in each cell is generally sufficient to cause disease. However, not all people with a mutation of the gene develop signs and symptoms of the disease. In some cases, an affected person inherits the mutation from one parent who may or may not have mild disease characteristics. Other cases are the result of a new genetic mutation and occur in people with no history of disease in your family.
Tests in IVAMI: in IVAMI perform detection of mutations associated with non - syndromic holoprosencephaly, by complete PCR amplification of the exons of SHH, ZIC2, SIX3 and homeobox protein tgif1 genes, respectively, and subsequent sequencing.
Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).