Available Assays

Several methods are currently used for the molecular detection of mutations in PAH associated with PKU. These methods include:

• Testing for a panel of common mutations with a detection rate of approximately 50%, depending on the number of mutations included.

• Mutation scanning of all 13 exons and the intron-exon junction regions. DNA sequencing detects approximately 94% of mutations; however, this method can be expensive.3 A recently developed system for mutation scanning, denaturing high-performance liquid chro-matography (DHPLC), which also has a high detection rate (~96%) and is more cost-effective than DNA sequencing,4 may be the method of choice for PKU molecular testing.

• Finally, when molecular analysis fails to detect one or both mutant alleles, linkage studies can be performed and are highly accurate if polymorphic markers within or very closely linked to the PAH gene are used.

Table 8-1. Genotype-Phenotype Correlations

for the Most

Common PAH Mutations

PAH Activity

Mutation

Prevalence

in COS Cells

Phenotype

R408W

31%

<1%

Classic PKU

IVS12+nt1G^A

11%

<1%

Classic PKU

IVS10-11G^A

6%

Not available

Classic PKU

I65T

5%

26%

Classic PKU

Variant PKU

Non-PKU PAH

Y414C

5%

50%

Variant PKU

Non-PKU PAH

R261Q

4%

<30%

Classic PKU

Variant PKU

Source: "PAH Activity in COS Cells" and "Phenotype" from the

PAHdb Phenylalanine Hydroxylase Locus Knowledgebase [data

base online]. Available at: http://www.pahdb.mcgill.ca/.

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