Table 2

ACMG actionable genes and possible courses of clinical action in the elderly

DiseaseGene(s)Approximate age of onset (years)Incidence (estimate)Clinical action (for child or younger adult)Likely clinical action (for elderly)Implication for family
Hereditary breast and ovarian cancerBRCA1, BRCA2, PALB, ATM30–80 1:800 Surgery, chemoprevention, screening Annual mammography, MRI; possible bilateral salpingooophorectomy or prophylactic mastectomy Predictive test for first-degree relative (50:50 risk)
Lynch syndrome—hereditary non-polyposis colorectal cancerMLH1, MSH2, MSH6, PMS235 1:800 Primary prevention (Nonsteroidal anti-inflammatory drugs), screening, early colonoscopy Colonoscopy, gynae surveillance Predictive test for first-degree relative (50:50 risk)
Romano-Ward, Long QT syndrome (LQTS) types 1, 2 and 3, Brugada syndrome (cardiac)KCNQ1, KCNH2, SCN5A<18 for LQTS; infant to >80 for Brugada 1:8000 Antiarrhythmic drugs Exercise test, flecainide challenge Predictive test for first-degree relative (50:50 risk)
Familial hypercholesterolaemiaLDLR, APOB, PCSK9Mid-20s to late adulthood 1:1000 Diet/lifestyle changes, statins Statins Predictive test for first-degree relative (50:50 risk)
Dilated cardiomyopathyTPM1, MYL3, ACTC1, PRKAG2, GLA, MYL2, LMNAHighly variable 1:2500 Pharmacological, surgical, pacemakers, implantable defibrillators Echocardiogram Predictive test for first-degree relative (50:50 risk)
Marfan syndrome, Loeys-Dietz syndrome, familial thoracic aortic Aneurysms and DissectionsFBN1, TGFBR1, TGFBR2, SMAD3, ACTA2, MYLK, MYH11Highly variable 1:10 000 Surgery, chemoprevention, screening Echocardiogram Predictive test for first-degree relative (50:50 risk)
retinoblastomaRB1<5 1:30 000 Ophthalmology, paediatric oncology, pathology and radiation oncology Minimal––possibly eye exam Predictive test for first-degree relative (50:50 risk)
Hypertrophic cardiomyopathyMYBPC3, MYH7, TNNT2, TNNI3Adolescence to 70+ <1:50 000 Pharmacological, surgical, pacemakers, implantable defibrillators Echocardiogram Predictive test for first-degree relative (50:50 risk)
Li-Fraumeni syndrome (heritable cancer)TP53 (and CHEK2) Children and young adults, before 45 <1:50 000 Standard cancer treatment, avoiding radiation therapy Avoid irradiation, surveillance Predictive test for first-degree relative (50:50 risk)
Peutz-Jeghers syndrome (polyps)STK11Young adulthood <1:50 000 Endoscopic surveillance with polypectomy, family testing Endoscopy surveillance Predictive test for first-degree relative (50:50 risk)
Familial adenomatous polyposis of the colon (APC, Gardner syndrome)APC (and MUTYH) 20 <1:100 000 Colectomy Colonoscopy Predictive test for first-degree relative (50:50 risk)
Tuberous sclerosis complex (TSC)TSC1, TSC2Childhood–30 1:100 000 Mechanistic target of rapamycin (mTOR) inhibitors, neurosurgery, antiepileptic drugs Renal scans Predictive test for first-degree relative (50:50 risk)
Neurofibromatosis type 2NF218–24 1:100 000 Surgical, MRI screens MRI Predictive test for first-degree relative (50:50 risk)
Catecholaminergic polymorphic ventricular tachycardiaRYR2 (and CALM1) 7–12; rare cases >30 1:100 000 Antiarrhythmic medication Echocardiogram Predictive test for first-degree relative (50:50 risk)
Arrythmogenic right ventricular dysplasia/cardiomyopathyPKP2, DSP, DSC2, TMEM43, DSG232–40 1:100 000 Antiarrhythmic medication, implantable cardioverter-defibrillators Echocardiogram, MRI Predictive test for first-degree relative (50:50 risk)
Malignant hyperthermia susceptibilityRYR1, CACNA1SOnly after anaesthetic 1:100 000 Ventilation, dantrolene, cooling Anaesthetic advice Predictive test for first-degree relative (50:50 risk)
Von Hippel Lindau syndromeVHLYoung adulthood 1 in 36 000; high penetrance; so estimate <1:100 000 Screening Surveillance evidence based- renal scans, plasma metanephrine Predictive test for first-degree relative (50:50 risk)
Multiple endocrine neoplasia type 1 (MEN1)MEN120–25 <1:300 000 Parathyroidectomy, biochemical screening Surveillance Predictive test for first-degree relative (50:50 risk)
Hereditary paraganglioma- pheochromocytoma syndromeSDHD, SDHAF2, SDHC, SDHB30 <1:300 000 Early surveillance, followed by pharmacological adrenergic receptor blockade and surgery Surveillance Predictive test for first-degree relative (50:50 risk)
Multiple endocrine neoplasia type 2:RET50–70 <1:350 000 Parathyroidectomy, biochemical screening Surgery––thyroidectomy Predictive test for first-degree relative (50:50 risk); surgery––thyroidectomy in childhood—consider grandchildren
Familial medullary thyroid cancerRET (and NTRK1) 0–70 <1:350 000 Parathyroidectomy, biochemical screening Surgery––thyroidectomy Predictive test for first-degree relative (50:50 risk); surgery––thyroidectomy in childhood—consider grandchildren
PTEN hamartoma tumour syndromePTEN20–30 <1:400 000 Screening Imaging Predictive test for first-degree relative (50:50 risk)
Ehlers-Danlos syndrome––vascular typeCOL3A130–40 1:500 000 Medical, surgical management of pain Clinical assessment Predictive test for first-degree relative (50:50 risk)
  • ACMG, American College of Medical Genetics.