Adressing the scenerio of 05 years old girl called Fatima:
Fatima is 05 years old and has been
diagnosed with Phenylketonuria since birth. She has demonstrated complex responses to multiple
medications and have multiple clinical conditions that are not explained by the
disease variant or by 1 year of traditional diagnostic testing.
Phenylketonuria (PKU) is one of the
common of the 300 inherited metabolic disorders. It caused by the deficiency of
phenylalanine hydroxylase (PAH) enzyme in liver or rarely absence of a
cofactor, tetrahydrobiopterin (BH4), as a result the essential amino acid phenylalanine
is not metabolized in tyrosine. The blood levels are high in phenylalanine
which is broken down into phenylketones especially phenylpyruvate which is
excreted in urine and gives it a musty odor.
If undiagnosed or untreated high blood level of phenylalanine can lead
to the infant’s brain damage, intellectual abnormalities, seizures,
microcephaly, and skin rashes by the end of first year of life.
PKU is an autosomal recessive
condition, therefore, in order to have a clinical presentation the person has to be
homozygous for the allelic variant, if a person has only one allele present the
person is the carrier for the condition. PKU is commonly included in newborn
screening panel in USA, Canada, many countries in Europe, Australia, New
Zealand, Japan, Taiwan, South Korea, and Philippines etc. The PKU screening has
not been established in Hong Kong, and India/Pakistan/Bangladesh/Indonesia.
Thus less than 15% of the total newborns are tested for PKU around the world. The blood
from the heel of the baby is taken for the phenylalanine assay.
PKU is classified under 04
phenotypes. The
blood levels of phenylalanine (Phe) of patients with classical PKU is >1200
(μmol/L), atypical
or mild PKU Phe levels 600-1200 (μmol/L)
in benign hyperphenylalaninemia Phe level 200-600(μmol/L) and lastly Biopterin deficiency variable.
Higher
degrees of consanguinity in Middle East can lead to the genetic disorders in offspring’s.
The comprehensive analysis of genotypes and phenotypes lasting for 02 years study of 27 Kurdish patients born with PKU
showed specific mutations in PAH gene among these patients prevalent in the
ethnical area. Consanguinity was positive in 85% of marriages. All except one
were not diagnosed with PKU at birth due to the absence of the PKU screening
test at birth.
In
classical PKU there is defective functioning of PAH enzyme in liver. The
genetics of BH4 is complex and more than one enzymes are involved,
malfunctioning of BH4 enzymes produce the biopterin deficiency variants.
Genotypes of PAH
deficiency:
Majority
of defects in 500 allelic variants range from defects as missense mutations,
non-sense, splice site, silent, frame shift, larger deletions and insertions
may occur.The mainstay of treatment in PKU is dietary restriction of Phenylalanine.
Whole
genome sequencing/ Whole exome sequencing is especially useful in patients with
congenital disorders especially if the consanguinity is presented (Berg et al., 2012).
Fatima’s who is 05 year
old
has PKU since birth, her parents are first cousins, she has been having complex
pattern of illness which is not responsive to the general management of diet
restriction rich in Phenylalanine all
the genetic variants needs to be evaluated to see if they are the distinctive
features of another congenital disorder associated with PKU.
Since
Fatima has demonstrated complex clinical conditions and responses to medication
their whole genome sequencing/whole exome sequencing provider (WGS/WES)
provider should be notified with the situation so that the due attention is paid
to the incidental findings of genetic variants and label them a potential
disease causing mutation (DM) before labeling them as likely polymorphism or variants
of uncertain significance (VUS). The DM
variants in Fatima’s case need to be reviewed manually and less stringent filtering criteria should be used and applied to remove the majority of missense
mutations need to be re-evaluated. The provider should not exclude the
novel missense mutations, synonymous and non-coding variations in the genome
sequencing evaluation.
The exome sequencing is
a powerful and cost-effective tool of investigating the congenital conditions
that effect the protein coding region of the human genetic code(Bamshad et al., 2011).
Reference:
Alibakhshi, R., Moradi, K., Mohebbi, Z., &
Ghadiri, K. (2014). Mutation analysis of PAH gene in patients with PKU in
western Iran and its association with polymorphisms: identification of four
novel mutations. Metabolic Brain Disease, 29(1), 131–138.
Berg, J. S., Adams, M., Nassar, N., Bizon, C., Lee,
K., Schmitt, C. P., … Evans, J. P. (2012). An informatics approach to analyzing
the incidentalome. Genetics in Medicine, 15(1), 36–44.
Bick, D., & Dimmock, D. (2011). Whole exome and
whole genome sequencing. Current Opinion in Pediatrics, 23(6),
594–600.
Centerwall, S. A., & Centerwall, W. R. (2000). The
discovery of phenylketonuria: the story of a young couple, two retarded
children, and a scientist. Pediatrics, 105(1), 89–103.
Hanley, W. B. (2012). Phenylketonuria (PKU)–A Success
Story. Latest Findings in Intellectual and Developmental Disabilities
Research. Retrieved from
http://www.intechopen.com/source/pdfs/28170/InTech-Phenylketonuria_pku_a_success_story.pdf
Hanley, W. B. (2013). Phenylketonuria (PKU)-What Next?
Mini-Review. J Genet Disor Genet Rep 2, 2, 2.
Wolf, S. M., Kahn, J. P., Lawrenz, F. P., &
Nelson, C. A. (2006). The incidentalome. JAMA, 296(23),
2798–2802.
Some videos of patients with PKU;
http://www.bing.com/videos/search?q=phenylketonuria&FORM=VIRE3#view=detail&mid=22E0CA49C9EF2172A38E22E0CA49C9EF2172A38ENational PKU alliance created by the people affected by PKU : http://npkua.org/
The phenylketonuria genotype database: http://www.pahdb.mcgill.ca/
Part 2 - Convert variant to VCF format
·
OMIM identification of the “rs ID” for the
variant of PAH gene.
![]() |
PAH-Gene-Refseq |
![]() |
The 0.0002 variant of PAH with ID rs5090858 |
·
OMIM rsID
(5030858) identified for Phenylketonuria disease (0.0002) variant, zoomed
in until the DNA sequence is shown.
![]() |
Rs5030858 variant of PAH with its beginning position 82110 |
·
The
beginning position is 82110 relative
to position 1 for the chromosome 12 on
which the PAH gene is located.
![]() |
rs5030858 variant of PAH with its position 82110 at exon 12 |
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