Congenital malformations - Edocr

28 PART I GENERAL CONSIDERATIONS
combination of predisposing gene mutations and
other environmental factors are present or encountered.
3 Risks for these disorders are generally
based on empiric data and depend upon the
given population, number of affected family
members, and the degree of relationship to the
affected family members. The risk increases if the
number, of affected family members increases,
if the manifestation of the disorder is more severe
and if the affected member is of the less
commonly affected sex. 3 The empiric risks will
vary based on the specific disorder, but for many
complex disorders a couple who has had one
affected child has a 2–6% risk of recurrence in
another pregnancy.
Penetrance and Expressivity
Risks for genetic disorders can be modified by
penetrance or expressivity. Penetrance is defined
as the proportion of individuals with a gene
mutation for a known condition that manifest
any features of the disorder. If some individuals
with a gene mutation have no clinical features
of the disorder, the disorder is stated to have reduced
penetrance. If all individuals who have
the gene mutation manifest features of the condition,
the condition is stated to have full penetrance.
Reduced penetrance can therefore alter
the risks that a person manifests features of the
condition, but the risks of transmitting the gene
mutation do not vary from the principles of
mendelian inheritance and segregation of genes.
Expressivity is defined as the extent to which an
individual manifests features of the disorder.
Thus, expressivity describes the variability and
level of severity of the disorder in a given affected
person.
Estimation of Risk When a Specific
Diagnosis Is Unknown
One of the most challenging aspects of genetic
counseling is discussing recurrence risks with
parents when a specific diagnosis for their
child’s findings is not evident. The risk of recurrence
is then estimated based on the clinical
presentation, known family history, and exclusion
of possible etiologies, such as chromosome
anomalies. In general, for a couple who has had
one affected child, a negative family history of
similar findings, and no known consanguinity,
the risk of recurrence is estimated at a range of
≤1% up to 25%. This range would account for the
possibility that the condition is associated with
de novo autosomal dominant, autosomal recessive
or multifactorial inheritance. If consanguinity
is known, the parents are generally quoted a
recurrence risk of 25% due to the increased probability
of shared alleles in consanguineous
unions. If more than one affected family member
is known, the risk should be determined on the
most likely mode of inheritance that would explain
the pattern of affected family members. For
example, if only males are observed affected in
the family, and women are the connecting members
between the affected male relatives; the
most likely possibility is an X-linked recessive
pattern of inheritance. If the parents have had
at least two affected children, the most likely
mode of inheritance is autosomal recessive and
the couple should be quoted a 25% risk of recurrence.
Parents should always be counseled
that this is an estimated risk and that the exact
risk of recurrence is unknown without a specific
diagnosis and known mode of inheritance
associated with the disorder.
GENETIC SCREENING AND
PRENATAL DIAGNOSIS
Carrier Screening
The prevalence of some genetic disorders varies
by ethnic group and populations due to factors
such as the founder effect and genetic drift. Current
practices of standard care recommend
screening for carrier status of certain genetic
disorders given a person’s ethnicity. Due to the