1.

9 Discussion

• Early diagnosis of HNPCC in families can be extremely effective in reducing the

mortality rates in individuals at risk from colon cancer; this is due to early and
appropriate initiation of preventative measures and regular screening. The
Bethesda guidelines and Amsterdam criteria provide diagnostic guidelines for
HNPCC. Despite their usefulness they are not predictive in up to 30% of
HNPCC cases.

• In this case, the mutation is in MSH6; a gene involved in mismatch repair. The
loss or reduction in mismatch repair capability leads to an inability to correct the
errors that occur normally during DNA replication (DNA proofreading).
Mismatch repair is a highly conserved process found in prokaryotes and
eukaryotes.

• The HNPCC trait is autosomal dominant and so can be inherited with one
defective allele. However, both copies of a mismatch-repair gene must be
altered, or mutated, before a person will develop cancer. An individual may
inherit a mutated copy of one of these genes from each parent. Alternatively,
inheritance of a germline mutation from one patient, may be followed by a
somatic mutation in the “good copy”. Where the cancer develops depends upon
where the second mutation occurs. For example, if the second mutation is in the
ovary, ovarian cancer may develop. Furthermore, the presence of two mutated
copies of a mismatch repair gene in an individual does not 100% predict
progression to cancer; cancer is caused through accumulation of errors in genes
controlling cell growth due to a lack of proofreading. If these genes do not pick
up errors, the individual will not develop cancer through this mechanism.

2.8 Discussion

• Not all variations are mutations; some are simply polymorphisms (or different
versions) of the sequence. Many DNA sequence variations cause no significant
detrimental effect on the phenotype of the individuals bearing the variant. Some
variations occur outside of regions capable of exerting significant effect on
phenotypes and others may be found within genes (or within other critical
regions such as regulatory elements), but may influence characteristics such as
height and hair color rather than characteristics of medical importance. Thus,
even after identifying a variation in a patient, additional studies need to be
carried out in order to determine whether the variation is deleterious and causing
the phenotype or disease under analysis. One way to determine whether an
identified variation is a polymorphism or a mutation is to confirm that the
variant has been previously shown to be associated with the disease. The Human
Gene Mutation Database is a valuable resource for such studies. In addition, it
can be valuable to determine whether the variation of interest is present in
related individuals without a disease phenotype. In this case it is less likely that
 the variation is the disease-causing mutation.

• In disorders such as Marfan, confirmation of genetic testing with appropriate

clinical examination for potential life-threatening conditions is critical.

• Since there is redundancy in the genetic code, differences at the nucleotide level
within coding regions of the genome do not always translate to differences at the
amino acid level. Such differences that do not alter the amino acid are termed
synonymous differences, as opposed to non-synonymous changes, which do
affect the sequence of the resultant protein. Synonymous changes within coding
regions are significantly less likely than non-synonymous changes to result in a
change in phenotype or to be associated with a disease.

3.6 Discussion

• HPFH is a benign disorder that is often undetected. However, when coupled with
homozygosity for sickle cell disease, it completely masks the severely
debilitating symptoms of sickle cell disease.

• While this child has been protected, the parents should be made aware that they
are both carriers of sickle cell trait and additional children might inherit the
sickle cell disease and not the HPFH mutation. Pre-implantation diagnosis might
be an option for the couple to consider if they are planning to have more
children.

• A large number of diseases are associated with mutations in the hemoglobin

genes (see review of Lab Section 3.1 for specifics on these disorders). These
include:
o Alpha thalassemia
o Beta thalassemia
o Sickle cell Disease

• Over 800 hemoglobin variants have been identified; approximately 500 are due
to mutations in the ß-globin gene, the remainder being in the α gene.

• Mutations occurring in either the γ-globin gene promoter result in the continued
expression of the γ gene in the adult, a condition termed non-deletion hereditary
persistence of fetal hemoglobin (HPFH). In individuals carrying a disease-
causing mutation in the β-globin gene, the HPHF mutation is protective, and
associated with reduced morbidity. This condition is found in 1/188,000
individuals with sickle cell disease.

• Although in this case the child had both the sickle cell and HPFH mutations and
was therefore protected from Sickle Cell Disease, the parents should be made
aware that additional children might not inherit the HPFH mutation, and would
then be susceptible to sickle cell disease. Pre-implantation diagnosis might be an
option for the couple to consider if they are planning to have more children.