By sequencing all genes (exome/genome sequencing), we might find disease-causing mutations in genes unrelated to the patient’s actual phenotype, which may cause severe health problems (e.g., mutations causing susceptibility to cancer or certain heart diseases). These are called incidental findings (or secondary findings). For example, we might find a breast cancer-predisposing mutation in a patient tested for thoracic aortic aneurysm (e.g., a BRCA1 mutation). If the patient has previously given consent, the breast-cancer mutation will also be reported in such a case. Incidental findings are relatively infrequent, as they may be detected in just 1-3% of patients. It should be reminded that an incidental finding may be of relevance also for the patient’s consanguineous (e.g., parents and siblings), as they may carry the same genetic variant.
The American College of Medical Genetics has issued a list of genes for which incidental findings should be reported. The last update includes the following genes:
Clinical conditions | Typical on set | Gene | Transmission |
Familial adenomatous polyposis | Infancy/adult | APC | AD |
Familial medullary thyroid cancer | Infancy/adult | RET | AD |
Hereditary breast and/or ovarian cancer | Adult | BRCA1, BRCA2, PALB2 | AD |
Hereditary paraganglioma–pheochromocytoma syndrome | Infancy/adult | SDHD, SDHAF2, SDHC, SDHB, MAX, TMEM217 | AD |
Juvenile polyposis syndrome | Infancy | BMPR1A, SMAD4 | AD |
Li–Fraumeni syndrome | Infancy/adult | TP53 | AD |
Lynch syndrome | Adult | MLH1, MSH2, MSH6, PMS2 | AD |
Multiple endocrine neoplasia type 1 | Infancy/adult | MEN1 | AD |
MUTYH-associated polyposis | Adult | MUTYH | AR |
Neurofibromatosis type 2 | Infancy/adult | NF2 | AD |
Peutz–Jeghers syndrome | Infancy/adult | STK11 | AD |
PTEN hamartoma tumor syndrome | Infancy/adult | PTEN | AD |
Retinoblastoma | Infancy | RB1 | AD |
Tuberous sclerosis complex | Infancy | TSC1, TSC2 | AD |
von Hippel–Lindau syndrome | Infancy/adult | VHL | AD |
WT1-related Wilms tumor | Infancy | WT1 | AD |
Aortopathies | Infancy/adult | FBN1, TGFBR1, TGFBR2, SMAD3, ACTA2, MYH11 | AD |
Arrhythmogenic right ventricular cardiomyopathy | Infancy/adult | PKP2, DSP, DSC2, TMEM43, DGS2 | AD |
Catecholaminergic polymorphic ventricular tachycardia | Infancy/adult | RYR2, CASQ2, TRDN | AD, AR |
Dilated cardiomyopathy | Infancy/adult | TNNT2, LMNA, FLNC, TTN | AD |
Ehlers–Danlos syndrome, vascular type | Infancy/adult | COL3A1 | AD |
Familial hypercholesterolemia | Infancy/adult | LDLR, APOB, PCSK9 | AD |
Hypertrophic cardiomyopathy | Infancy/adult | MYH7, MYBPC3, TNNI3, TPM1, MYL3, ACTC1, PRKAG2, MYL2 | AD |
Long QT syndrome types 1 and 2 | Infancy/adult | KCNQ1, KCNH2 | AD |
Long QT syndrome 3; Brugada syndrome | Infancy/adult | SCN5A | AD |
Biotinidase deficiency | Infancy | BTD | AR |
Fabry disease | Infancy/adult | GLA | XL |
Ornithine transcarbamylase deficiency | Infancy/adult | OTC | XL |
Pompe disease | Infancy/adult | GAA | AR |
Hemochromatosis | Adult | HFE | AR |
Hereditary hemorrhagic telangiectasia | Infancy/adult | ACVRL1, ENG | AD |
Malignant hyperthermia | Infancy/adult | RYR1, CACNA1S | AD |
Maturity-onset diabetes of the young | Infancy/adult | HNF1A | AD |
RPE65-related retinopathy | Infancy | RPE65 | AR |
Wilson disease | Infancy/adult | ATP7B | AR |