Congenital malformations - Edocr

CHAPTER 3 GENETIC COUNSELING: PRINCIPLES AND PRACTICES 27
Figure 3-6.
condition.
A typical pedigree of a Y-linked
Figure 3-7.
disorder.
A typical pedigree of an mtDNA
single cell generally has >1000 copies of the mitochondrial
genome dispersed in >100 mitochondria.
The mitochondrial genome is a circular chromosome
approximately 165 kb in size and contains
37 genes. 4 The encoded proteins are involved in
oxidative phosphorylation. The majority of proteins
required for normal mitochondrial function,
however, are encoded in the nuclear DNA and
therefore, mitochondrial disorders are also associated
with mendelian inheritance.
Mitochondrial DNA (mtDNA) disorders are
unique in that they are associated with maternal
inheritance only. A mature oocyte is felt to have
>100,000 copies of the mitochondrial genome
while sperm contain very few. A child, therefore,
inherits the mitochondrial genome from
the mother and not from the father. Mutations
and deletions in the mitochondrial DNA have
been identified to cause several disorders, such
as mitochondrial encephalopathy and ragged red
fibers (MERRF) and mitochondrial encephalopathy,
lactic acidosis, and stroke-like episodes
(MELAS). A typical pedigree (Fig. 3-7) is characterized
by the presence of both affected males
and females but no transmission of the disorder
through affected males. The number of mitochondrial
genome copies with a mutation can
vary in a given somatic cell or mature oocyte.
Most cells contain a mixture of both normal and
mutated mtDNA. The severity in manifestations
of the disorder is felt to be due to the percentage
of mutated mtDNA to normal mtDNA in
various tissues. 4 Therefore, an affected mother
has up to 100% risk of passing on the condition
to her child.
Complex Disorders
Disorders in which a combination of genetic and
environmental factors is involved in the manifestation
of the disease state are referred to as complex
or multifactorial disorders. Multifactorial
disorders, such as isolated congenital heart defects,
isolated cleft lip and/or palate, diabetes mellitus,
and hypertension, can be observed to aggregate
in a family but not follow a clear mendelian mode
of inheritance. The genes underlying the complex
disorder are transmitted following the mendelian
principles but the disease state occurs when the