Figure 3. Models of Disease Allele Transmission.

(A) In classical Mendelian disease, for a recessive, monogenic disease, at that single locus there is biallelic inheritance (highlighted in box). Examples could be either Stargardt macular dystrophy or cystic fibrosis, which are both due to point mutations in ATP-binding cassette (ABC) transporter genes. However, at some loci in the human genome, imprinting results in monoallelic expression, and the disease phenotype will occur in a manner dependent on the parent of origin of the specific mutation, either by deletion copy number variants (CNV) or uniparental disomy (UPD). The example given is the Angelman syndrome with point mutations in the UBE3A gene. The CMT1A locus (17p12) represents a triallelic locus whereby because of the duplication, there are three copies of the PMP22 gene. None of the copies have point mutations in them, but it takes three copies to convey the clinical phenotype. Other examples of disease allele transmission include interactions between two or potentially more genes. In the classic model of digenic inheritance, the phenotype of retinitis pigmentosa has been shown to be due to heterozygous point mutations in the ROM1 gene in combination with heterozygous point mutations at the RDS locus. Thus there is biallelic digenic inheritance. Note that a genomic deletion CNV renders a locus monoallelic, whereas a duplication CNV results in a triallelic locus.

(B) Bardet-Biedl syndrome (BBS), traditionally thought of as a recessive trait, can sometimes result from three mutant alleles, two of which come from one locus, and one from another locus. This is an example of digenic triallelic inheritance.

(C) A single pedigree illustrates triallelic inheritance for BBS. Standard pedigree symbols are used; filled squares, affected with BBS. Alleles segregating at two distinct loci (BBS2 and BBS6) are shown, one in each pedigree. WT, wild-type or normal allele.