Greig Cephalopolysyndactyly Syndrome (GCPS) is caused by a deletion of the GLI3 gene [Medical review]

There are various causes of congenital malformation syndromes, but many of them are due to chromosomal or genetic abnormalities. It is very important to identify the abnormal chromosomes or genes, and if these are identified, diagnosis can be made through prenatal chromosomal or genetic screening.

Greig Cephalopolysyndactyly Syndrome , which we will introduce here , is a congenital malformation syndrome caused by a genetic abnormality.

What is Greig Cephalopolysyndactyly Syndrome (GCPS)?

Greig Cephalopolysyndactyly Syndrome (GCPS) is a genetic disorder for which the causative gene has been identified. It is named after David Middleton Greig, author of a 1926 book about patients with the disorder. 

Some sources estimate the incidence to be one in a million .

Cases and Diagnosis

As the name suggests, this is a disease in which there are mutations in the brain and fingers, and many patients have common deformities of the limbs, face, and head. The limbs show preaxial polydactyly with cutaneous syndactyly, the face shows hypertelorism, and the head shows macrocephaly with protruding forehead.

In addition, although not common, central nervous system abnormalities and cognitive impairments have also been reported. 

It is somewhat difficult to diagnose this condition clinically. Polydactyly may be due to other conditions, eye hypertelorism is difficult to judge, and the location of onset varies from person to person. In most cases, a provisional diagnosis of GCPS is made if the three previously mentioned characteristics are present.

Treatment and Prognosis

Treatment is symptomatic and varies depending on the condition of the disease. In cases where limb deformities are severe, orthopedic surgery may be required.

The prognosis is generally very good, although there is a slight risk of developmental delay and cognitive impairment due to the disease, which can be accompanied by neurological abnormalities, as mentioned above.

The prognosis after treatment also depends on the size of the deletion in the GLI3 gene, and there have been reports of a poor prognosis when the deletion is large.

As with any genetic disease, it is extremely difficult to treat the disease from its roots. However, a technology that could be a fundamental treatment for genetic diseases is currently being developed. This technology is called genome editing . Genome editing is a technology that uses RNA called a guide and scissors (restriction enzymes) that cut DNA to edit the desired part of the genome. However, its application to medical treatment is still in its infancy, and there is also the off-target effect that cuts parts of genes that are not the target, so it is a technology that is expected to be developed in various fields in the future.

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GCPS is caused by a partial deletion in the GLI3 gene.

A study conducted in 1997 showed that GCPS is caused by a loss-of-function mutation in a gene called GLI3 (GLI-Kruppel family member 3, glioblastoma transcription factor 3).

The GLI3 gene is located at chromosome 7p14.1, and is a loss of function that the gene should have, resulting in the onset of the disease.

Furthermore, even among patients with the same GCPS, the size and location of the deletion varies from person to person. In addition, there is another disease (Pallister-Hall syndrome) that is caused by the same deletion of the GLI3 gene.

Why does deletion of the GLI3 gene cause GCPS?

So what is the original role of the GLI3 gene, whose function is lost in GCPS?

Although the full picture is still unknown, it is known that the GLI3 gene is involved in the function of Sonic hedgehog (Shh), a protein that plays a very important role in morphogenesis.

Shh is an extracellular signaling factor (protein) involved in cell differentiation and limb development during embryonic development. The GLI3 gene is known to act as a factor that suppresses the transcription of Shh. In other words, when a mutation occurs in the GLI3 gene, it results in an enhanced phenotype of the Shh protein, which affects morphogenesis. The regions where GLI3 is expressed also support its function, and GLI3 is expressed in areas distant from the Shh expression region, anteriorly in the limb buds (cells that differentiate into limbs) and dorsally in the neural tube.

There are several Sonic Hedgehog signaling pathways (signaling pathways centered on Shh), but the pathway in which GLI3 is involved is called the Ptc-Smo-Gli pathway, which involves the membrane proteins Ptc and Smo, as well as the GLI family (GLI1-GLI3). It has been revealed that these signaling pathways act as the most important morphogens in development.

In addition to research targeting GCPS, research on GLI3 is also being conducted on sonic hedgehog signaling and hypothalamic hamartomas that cause drug-resistant epileptic seizures.

This gene mutation also brings us closer to understanding the mechanism by which morphological abnormalities, or deformities, are induced, so further research is needed to be done.

What is the chromosomal deletion site “7p14.1”?

Let me explain what the chromosomal deletion site “7p14.1” that causes GCPS indicates.

As mentioned above, the GLI3 gene is located in this area. “7p14.1” is information that indicates where on which chromosome the deletion is located. To do this, we first need to know the rules for chromosome numbering. 

First of all, humans have 22 pairs (44 autosomes). Each one is numbered from 1 to 22. This is the first number, so “7p14.1” means chromosome number 7.

Next, chromosomes are long and thin, with a “constricted” part called the centromere. This is the boundary between the short arm (p) and the long arm (q), which are written as symbols. In other words, “7p14.1” is p, so it is on the short arm.

The numbers that follow indicate the order of numbers assigned to chromosomes, starting from the one closest to the centromere in the center. These numbers are assigned according to the bands that are visible when the chromosomes are stained.

In other words, “7p14.1” means that it is located in region 14.1 of the p (short arm) of chromosome 7. 

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What is a chromosome (gene) deletion?

So far, we have explained that GCPS is caused by a partial deletion of the GLI3 gene, but what exactly is a deletion?

First of all, genetic diseases are largely divided into chromosomal abnormalities and genetic abnormalities. Chromosomal abnormalities are cases where a chromosome that should normally be paired in two is missing three or one chromosome is missing. A typical example is the so-called Down syndrome (trisomy 21, where chromosome 21 is paired in three, i.e., a duplication of the chromosome) . On the other hand, genetic abnormalities refer to the deletion or duplication of a part of a chromosome, rather than the entire chromosome.

GCPS is a genetic disorder in which part of the GLI3 gene on chromosome 7 is deleted. However, it has been found that even in the same GCPS case, the size of the deleted area varies from patient to patient. However, since GCPS is caused by the loss of function of the GLI3 gene, there is no doubt that a deletion large enough to cause the GLI3 gene to lose its function has occurred, even if the size of the deleted area varies.

One might imagine that the deletion that would cause the GLI3 gene to lose its function would not be just one base, but this is not necessarily the case. This is because a single base deletion can cause a frameshift mutation. A frameshift mutation is a mutation in which the codon (so-called triplet code) is shifted due to the deletion or insertion of a base, resulting in amino acids not being synthesized according to the genetic code.

In fact, it has been reported that Pallister-Hall syndrome, which also develops due to loss of function of the GLI3 gene, is caused by this frameshift.

Chromosome and gene deletions can happen to anyone. However, if the gene in question is essential for human life, it can prevent the baby from being born and can even cause a miscarriage. Even if the baby is born, it can cause a congenital disorder.

Although a small number of GCPS patients have been reported with point mutations, most patients appear to have mutations in a wider region of the GLI3 gene rather than a single-base deletion (point mutation).

Autosomal dominant and haploinsufficiency

Human chromosomes are made up of two chromosomes. These two chromosomes are passed down from the father and mother to the child, one each. In other words, even if the GLI3 gene is deleted on one chromosome of the father or mother, the other GLI3 gene may not be mutated. In that case, will GCPS not develop?

No, unfortunately, it has been found that if one of the parents has a deletion in the GLI3 gene that causes GCPS and the child inherits that chromosome, the child will also develop GCPS.

If that is the case, why does the other GLI3 gene, which should be intact, not function? This question can be explained by the phenomena of autosomal dominant and haploinsufficiency.

In general, even if only one of two chromosomes has a mutation, as long as the function of the other chromosome is intact, the disease will not develop in most cases. However, the GLI3 gene is a gene that is prone to show the characteristics of only one gene, so the characteristics of the gene with the mutation will be seen. In other words, even if the two chromosomes are heterozygous (one has a GLI3 mutation and the other does not), the abnormal chromosome with the mutation will be “dominant” and the disease will develop. This is called autosomal dominant.

This phenomenon in which a heterozygous gene results in a defective function is called haploinsufficiency.

In the case of autosomal dominant genetic disorders, if either parent has GCPS, there is a 50% chance that the child will have the same phenotype and develop the same disease.

Differences from Pallister-Hall syndrome

Pallister-Hall Syndrome (PHS) is a congenital malformation syndrome caused by a deletion of the GLI3 gene, the same gene as GCPS.

PHS shares clinical similarities with GCPS in limb, head, and facial anomalies. The difference is that most polydactyly in GCPS is preaxial (polydactyly with extra thumbs), whereas in PHS it is central (polydactyly with extra index to ring fingers) or postaxial (polydactyly with extra little fingers). However, there are also postaxial cases of GCPS, and other genetic diseases with similar symptoms are known, so it is difficult to judge from these clinical cases, and in most cases it is diagnosed genetically by looking at the deletion site of the GLI3 gene.

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GCPS and its methods in prenatal testing

By checking for mutations in the GLI3 gene, it is possible to detect the presence or absence of GCPS before birth.

There are several methods that can detect GCPS, including FISH, next-generation sequencers, microarrays, and real-time PCR . If only GCPS is to be identified in prenatal testing, any of the above methods except FISH is theoretically possible. However, for prenatal screening tests that check for various diseases at once, next-generation sequencers and microarrays, which can comprehensively detect genes, are often used.

As the name suggests, a next-generation sequencer is the next generation of sequencers (devices that read gene sequences), and it fragments DNA and reads millions or tens of millions of fragmented gene sequences in parallel. This makes it possible to read a large number of genes at speeds that were unimaginable with conventional sequencers, which makes it possible to perform prenatal genetic testing.

Microarrays are a technology that can find mutations by mounting mutation probes (probes: gene fragments) or standard probes of known genes on a chip and checking the intensity and color of the fluorescence. Compared to next-generation sequencers, which can also check unknown genes, microarrays only check for known genes, but they are used as a detection method that is easier to analyze than next-generation sequencers.

The FISH method is a traditional method that can detect copy number variation (CNV) and is also called fluorescent in situ hybridization. Mutations are detected by creating a fluorescent probe that recognizes the target region and checking it with a fluorescent microscope. However, there are limitations to the method of viewing the fluorescence on chromosomes with a microscope, and while it is possible to check large mutations, the resolution of the FISH method is said to be around 100kb (100,000 bases), making it difficult to detect small mutations. Therefore, it is not suitable for comprehensive genetic testing.

Real-time PCR is a type of equipment that is also used to diagnose viruses for which no established diagnostic methods have been established, such as COVID-19. It uses gene fragments called probes and primers and is used for a variety of purposes, including identifying mutations and validating screening results. 

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summary

GCPS is caused by a partial deletion of the GLI3 gene, which plays an important role in morphogenesis. Because it is an autosomal dominant condition, if one parent has the disease, there is a 50% chance that the child will inherit it. However, since the deletion locus has been identified, prenatal diagnosis is possible.

At Hiro Clinic NIPT , prenatal testing for such autosomal partial deletion disorders is possible. Although it is rare for the condition to become a life-threatening serious disease, the severity varies depending on the size of the deletion, so prenatal genetic testing allows individual measures for treatment and prognosis to be established in advance.