Contiguous gene syndromes (CGS) are disorders caused by chromosomal abnormalities, such as deletions and duplications, which result in an alteration of normal gene dosage. Clinically, each CGS is characterized by a specific and complex phenotype, which was recognized in most cases as a genetic syndrome before knowledge of their cytogenetic etiology. The responsible chromosomal segment is usually small on a cytogenetic scale (<5 Mb), but encompasses multiple genes, some of which are dosage sensitive, and contribute to the phenotype independently.

CGS may be due to deletions of the X chromosome in males, with resulting structural and functional nullisomy. CGS associated with deletions of Xp22.3 and Xp21 are good examples of regions containing multiple disease genes. Some of the disorders included in these CGS are well-known disease entities due to single gene defects (e.g., Duchenne muscular dystrophy, adrenal hypoplasia congenita, glycerol kinase deficiency).

For most autosomal loci, deletion causes a reduction of gene dosage to structural and functional monosomy. Haploinsufficiency for specific genes in the critical interval is implicated for del(7)(q11.23q11.23) in Williams syndrome, for del(8)(q24.1q24.1) in Langer-Giedion syndrome, del(17)(p13.3) in Miller-Dieker syndrome, and for del(22)(q11.2q11.2) in DiGeorge syndrome and velocardiofacial syndrome.

Some human genes show exclusive expression from a single parental homologue and no expression from the other homologue (i.e., genomic imprinting). Imprinting can be tissue-specific, as is the case for the major gene causing Angelman syndrome. Deletion of a chromosome segment containing the active allele of an imprinted gene results in structural monosomy but functional nullisomy (e.g., paternal del(15)(q11.2q13) in Prader-Willi syndrome and maternal del(15)(q11.2q13) in Angelman syndrome). Uniparental disomy for the homologue containing the inactive allele results in structural disomy but functional nullisomy (e.g., maternal disomy 15 in Prader-Willi syndrome and paternal disomy 15 in Angelman syndrome).

Duplication of chromosomal segments causes increased dosage and gene expression. Beckwith-Wiedemann syndrome can be caused by paternal duplications of 11p15.5 or by paternal uniparental disomy 11. Charcot-Marie-Tooth disease type 1A is caused by duplications within 17p12 including the dosage-sensitive PMP22 gene. For most cases, Pelizaeus-Merzbacher disease results from duplication of the dosage sensitive PLP gene.

Mechanisms for terminal deletions include telomere healing and telomere capture. Several interstitial deletions and duplications have been shown to result from unequal crossing over between large (>20 kb), low-copy region-specific repeat sequences. The underlying genome architecture likely facilitates large rearrangements of other regions of the genome.

Molecular technologies, primarily PCR and fluorescence in situ hybridization (FISH), have been key to the characterization of CGS and provide powerful and sensitive diagnostic capabilities. For X-linked CGS, multiplex PCR analysis of nullisomic males and FISH analyses of carrier females are efficient strategies for deletion detection. FISH is the method of choice for detection of deletions and translocations in autosomal CGS. Interphase FISH and pulsed-field gel electrophoresis have been used to diagnose chromosomal duplications.