Chapter 064. The Practice of Genetics in Clinical Medicine (Part 7) pdf

Chapter 064. The Practice of Genetics
in Clinical Medicine
(Part 7)

Therapeutic Interventions Based on Genetic Risk for Disease
Specific treatments are now available for an increasing number of genetic
disorders, whether identified through population-based screening or directed
testing (Table 64-2). Although the strategies for therapeutic interventions are best
developed for childhood hereditary metabolic diseases, these principles are
making their way into the diagnosis and management of adult-onset disorders.
Hereditary hemochromatosis illustrates many of the issues raised by the
availability of genetic screening in the adult population. For instance, it is
relatively common (approximately 1 in 200 individuals of northern European
descent are homozygous), and its complications are potentially preventable
through phlebotomy (Chap. 351). The identification of the HFE gene, mutations of
which are associated with this syndrome, has sparked interest in the use of DNA-
based testing for presymptomatic diagnosis of the disorder. However, up to one-
third of individuals who are homozygous for the HFE mutation do not have
evidence of iron overload. Consequently, in the absence of a positive family
history, current recommendations include phenotypic screening for evidence of
iron overload followed by genetic testing. Whether genetic screening for
hemochromatosis will someday be coupled to assessment of phenotypic
expression awaits further studies. In contrast to the issue of population screening,
it is important to test and counsel other family members when the diagnosis of
hemochromatosis has been made in a proband. Testing allows the physician to
exclude family members who are not at risk. It also permits presymptomatic
detection of iron overload and the institution of treatment (phlebotomy) before the
development of organ damage.
Table 64-2 Examples of Genetic Testing and Possible Interventions
Genetic Disorder

Inherita
nce
Genes Interventions
Oncologic

Hereditary
nonpolyposis colon
AD MSH2,
MLH1, MSH6,
Early endoscopic
cancer P
MS1, PMS2,
TGFBR2
screening
Familial
adenomatous polyposis
AD APC
Early endoscopic
screening
Nonsteroidal
anti-inflammatory
drugs
Colectomy
Familial breast and
ovarian cancer
AD BRCA1
, BRCA2
Estrogen
receptor antagonists
Early scree

ning
by exams and
mammography
Consideration of
prophylactic surgery
Familial AD CDKN
Avoidance of
melanoma 2A UV light
Screening and
biopsies
Basal cell nevus
syndrome
AD PTCH

Avoidance of
UV light
Screening and
biopsies
Hematologic

Factor V Leiden AD F5
Avoidance of
thrombogenic risk
factors and oral
contraceptives
Hemophilia A XL F8C
Factor VIII
replacement
Hemophilia B XL F9
Factor IX

replacement
Possible gene
therapy
Glucose 6-
PO4
dehydrogenase deficiency

XL G6PD
Avoidance of
oxidant drugs
Cardiovascular

Hypertrophic
cardiomyopathy
AD MYH7,
MYBPC3,
TMSA,
TNNT2,
TPM1
Echocardiograph
ic screening
Early
pharmacologic
intervention
Myomectomy
Long QT
syndrome
AD KCNQ
1, SCN5A,
HERG,

MiRP1,
Electrocardiogra
phic screening
Early
KCNE1,
KCNE2
pharmacologic
intervention
Implantable
cardioverter
defibrillator devices
Marfan syndrome AD FBN1 Echocardiograph
ic screening
Prophylactic
beta blockers
Gastrointestinal

Familial
Mediterranean fever
AR MEFV

Colchicine
treatment
Hemochromatosis

AR HFE Phlebotomy
Pulmonary

α
1

Antitrypsin
deficiency

AR PI
Avoidance of
smoking
Avoidance of
occupational and
environmental toxins
Primary
pulmonary hypertension
AD BMPR2

Treatment with
pulmonary vasodilators

Renal

Polycystic kidney
disease
AD PKHD
1, PKHD2
Preventio
n of
hypertension
Prevention of
urinary tract infections
Kidney
transplantation
Nephrogenic XL, AR

AVPR2,
Fluid
diabetes insipidus
AQP2
replacement
Thiazides,
amiloride
Endocrine

Neurohypophyseal
diabetes insipidus
AD AVP Replace
vasopressin
Maturity-onset
diabetes of the young
AD Multipl
e genes
Screen and treat
for diabetes
Familial
hypocalciuric
hypercalcemia
AD CASR
Avoidance of
parathyroidectomy
Kallmann
syndrome
XL KAL
Induction of
puberty with hormone

replacement
Multiple endocrine
neoplasia type 2
AD RET Prophylactic
thyroidectomy
Screening for
pheochromocytoma and
hyperparathyroidism
21-hydroxylase
deficiency
AR CYP21

Glucocorticoid
and mineralocorticoid
treatment
Neurologic

Malignant
hyperthermia
AD RYR1
Avoidance of
precipitating anesthetics

Hyperkalemic
periodic paralysis
AD SCN4A

Acetazolamide
Adrenoleukodystr
ophy

XL ABCD1

Possible bone
marrow transplant for
severe childhood CNS
form
Duchenne and
Becker muscular
dystrophy
XL DMD Corticosteroids
Possible future
myoblast transfer
Familial Parkinson
disease
AD SNCA,
PARK2
Amantadine,
anticholinergics,
levodopa, monoamine
oxidase B inhibitors
Wilson disease AR ATP7B

Zinc, trientene
Abbreviations: AD, autosomal dominant; AR, autosomal recessive; CNS,
central nervous system; XL, X-linked