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 . 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. 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. (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.