Definition

Contiguous gene syndromes (CGS) are disorders caused by chromosomal structural abnormalities such as deletions and duplications which affect a number of physically contiguous genes and that result in alteration of the normal gene dosage.

Background

The chromosomal structural abnormalities responsible for Contiguous Gene Syndromes (CGS) -- deletions which are missing a portion of a specific chromosome or duplications which have an extra copy of a portion of a specific chromosome -- were not detected until advances in cytogenetic techniques enabled one to detect small chromosomal rearrangements. Although these rearrangements are small on the scale of a specific chromosome, they are very large in terms of their molecular contents and the number of base pairs of DNA that may be involved. Generally speaking, approximately three million base pairs of DNA (3 Mb) must be altered in order to visualize this as a chromosomal structural abnormality by routine G-band staining in a clinical cytogenetics laboratory.

It is more difficult to recognize duplication of a segment than it is to recognize deletion of a specific site. Some rearrangements, in fact, are smaller than can be detected by routine chromosome staining. In order to detect submicroscopic rearrangements the technology of fluorescence in situ hybridization (FISH) is utilized (see Cyberounds® Medical Genetics discussion, The Human Genome Project for a more detailed discussion of this technique). However, such a technique requires that the clinician prompt a specific investigation of a particular region of the genome based on his or her clinical impression of what the phenotype seems to represent. In other words, it is the practitioner who directs the cytogenetics laboratory as to where to look in the human genome. The cytogenetics laboratory then uses DNA probes that are labeled with a fluorphore that fluoresces under fluorescence microscopy and uses these probes to investigate the specific region of interest.

Contiguous gene syndromes are recognizable syndromes and comprise microdeletion and microduplication syndromes.(4) Specific features of these syndromes may occur individually in families, as phenotypes segregating in a Mendelian fashion. Complex phenotypic abnormalities may result from DNA rearrangements involving several contiguous genes. These syndromes are typically described as clinical entities prior to the establishment of a chromosomal etiology.

A classic example is the DiGeorge syndrome with its recognizable clinical triad of:

1. hypocalcemic seizures secondary to absent parathyroids
2. immunodeficiency secondary to absent thymus
3. congenital heart disease (in particular, interrupted aortic arch).

All of these findings can be explained by an embryological defect of the fourth branchial arch and derivatives of the third and fourth pharyngeal pouches. In the last decade, this has been shown to result from a specific deletion on chromosome 22 -- del22q11.2. Thus, this region of chromosome 22 must encode genes that are important for branchial arch development. In the CGSs, the cytogenetic is consistently small and may not be detectable by routine methods. Some patients with the complete clinical phenotype demonstrate no visible cytogenetic abnormality even after high resolution chromosomal analysis, suggesting a nonvisible microdeletion or microduplication.

Interestingly, some human genes show exclusive expression from a single parental homologue (one of the two chromosomes in a pair each of which is inherited from a different parent) and no expression from another homologue -- a phenomenon known as genomic imprinting. This phenomena clearly demonstrates that it is not only important that we inherit the proper amount of genetic information but it is also important to have contribution of our genetic information from both parents. The deletion of a chromosome segment containing the active allele of an imprinted gene can give two completely distinct phenotypes depending on from which parent the deletion originated. An example is if you have a deletion 15q11 to q13 on the paternally inherited chromosome the Prader-Willi syndrome (mental retardation, obesity, uncontrollable appetite, hypogonadism, dysmorphic facies) occurs, while deletion 15q11 to q13 on the maternally inherited chromosome results in a completely distinct clinical entity known as Angelman syndrome (mental retardation, absent speech, seizures, unusual gait, inappropriate laughter).

There is some controversy regarding the term contiguous gene syndromes, for the name implies that several genes may be involved in bringing about the specific clinical phenotype. While these genes are physically contiguous on the segment of the chromosome that is either deleted or duplicated, in the case of some of these syndromes only one of the genes within the region of rearrangement is primarily responsible for the multiple phenotypic features in the disease entity. In these instances, a more proper term is perhaps microdeletion or microduplication syndrome because instead of there being a series of contiguous genes involved there is only one gene that may be responsible for the multiple phenotypic effects. This has recently been demonstrated quite clearly for the Rubenstein-Taybi syndrome. Some patients identified with this syndrome had a microdeletion involving chromosome 16 band p13.3; however, there was a subset of patients who, instead of having visible deletion, had specific point mutations (base pair changes in a gene resulting in an alteration of the encoded protein) involving a gene for a transcription factor (a protein which activates transcription or "turns on" a gene).(10)

On the basis of a theoretical estimation of the number of genes in the human genome (0.5-1 x 105 genes/3 x 109 base pairs), 1 Mb [Mb = 1x106 base pairs] of DNA may encode as many as 16-33 genes. Since a cytogenetically visible deletion encompasses greater than 2-3 Mb, it is likely that deletion of multiple genes occurs in the visible microdeletion syndromes and that a number of these genes may be involved in eliciting the specific phenotype. However, it has been shown that the phenotype of a contiguous gene syndrome can be due to the dosage effect of one or a few dosage-sensitive genes. Dosage-sensitve genes are those that elicit a phenotype when there is one extra copy (due to either microduplication or trisomy) or one missing copy (due to either microdeletion or monosomy) of the two copies in the normal pair. There is no abnormal gene or gene product, rather an alteration in the copy number or dosage is responsible for the clinical phenotype. For instance, hemizygosity (loss of one copy) of LIS1 is implicated as the cause of type 1 lissencephaly in Miller-Dieker syndrome. Patients with lissencephaly (smooth brain or absence of gyri) without visibly detectable cytogenetic deletion in 17p13 were found to have structural alterations of LIS1.

Another interesting example of the role of a single gene in a phenotypic manifestations of a contiguous gene syndrome is exemplified by studies of mutations in the elastin (ELN) gene. Supravalvular aortic stenosis (SVAS) is an autosomal dominant trait that causes hemodynamically significant narrowing of large elastic arteries. The gene for SVAS has been mapped to chromosome 7 at the ELN locus. In a family in which there was observed cosegregation of a balanced translocation involving chromosome 7 and the SVAS phenotype, the translocation breakpoint was shown to disrupt the ELN gene. Subsequently, hemizygosity of the ELN locus was found in the majority of patients with Williams syndrome. Williams syndrome is a contiguous gene deletion syndrome with developmental delay, distinct facial and ocular features, hypercalcemia, gregarious personality and SVAS.

Perhaps one of the most well-documented cases of haplo-insufficiency of a specific gene leading to a specific clinically entity is the case of hereditary neuropathy with liability to pressure palsies (HNPP) and the PMP22 gene. HNPP is an autosomal dominant demyelinating polyneuropathy associated with a 1.5 Mb deletion in 17p11.2p12 including the PMP22  gene.(7) It has been reported that rare families do not carry the 1.5 Mb deletion but instead have a PMP22 point mutation resulting in a frame shift mutation which leads to a nonsense codon and thus loss-of-function allele (a protein that can no longer function properly). Remarkably, although the HNPP deletion spans 1.5 Mb which may theoretically encompass some 30-50 genes, it appears that haploinsufficiency of a single gene, PMP22, is entirely responsible for the clinical phenotype. These data suggest that gene dosage effects of a limited number of genes mapping within a microdeletion interval may contribute in a major way to the observed clinical phenotype. An extension of this concept would suggest that Down syndrome associated with trisomy 21 may actually result from the gene dosage effects of perhaps only a few dosage sensitive genes.

The molecular mechanisms for generating the DNA rearrangements which lead to the classical contiguous gene syndromes have not been elucidated. As an aggregate, these disorders affect a non-trivial portion of the human population. The recent findings with Williams syndrome raise the likelihood that additional recognizable patterns of human malformation will be shown to be contiguous gene syndromes resulting from microdeletion or microduplication of specific regions of the human genome. Furthermore, the recent elucidation of the mechanism for Charcot-Marie-Tooth disease and hereditary neuropathy with liability to pressure palsies suggest that other dominantly-inherited disorders may be due to submicroscopic duplication or deletion of specific regions of the genome. Moreover, there may be specific structural features of the human genome that lend themselves to recurrence of DNA rearrangements because of repeat sequences in these regions of the genome.

In the majority of cases, to date, knowledge of the particular genomic regions involved has led immediately to a specific diagnostic test through the application of fluorescence in situ hybridization (FISH). An objective diagnostic test is particularly useful for malformation syndromes where a diagnosis can often be difficult even for a trained clinical dysmorphologist. In addition, the diagnostic probes may clarify questions of mosaicism (in which two or more cell lines with different genetic make ups occur in a single organism as seen, for example, in classic 46 XX/ 45,X Turner mosaic) versus smaller deletion beyond the resolution of conventional cytogenetics.