Incidental findings | Breda Genetics srl

By sequencing all genes (exome/genome sequencing) we might find disease-causing mutations also in genes unrelated to the phenotype in question, but 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). In such a case, if the patient has previously given consent, the breast-cancer mutation will also be reported. Incidental findings are relatively infrequent, as they may be detected in just 1-3% patients. It should be reminded that an incidental finding may be of relevance also for patient’s blood relatives (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. As of 30.04.2015, this list includes the following genes:

Condition	Typical Age of Onset	Gene	Inheritance
Hereditary breast and ovarian cancer	Adult	BRCA1 BRCA2	Autosomal dominant
Li–Fraumeni syndrome	Child/adult	TP53	Autosomal dominant
Peutz–Jeghers syndrome	Child/adult	STK11	Autosomal dominant
Lynch syndrome	Adult	MLH1 MSH2 MSH6 PMS2	Autosomal dominant
Familial adenomatous polyposis	Child/adult	APC	Autosomal dominant
MYH-associated polyposis; adenomas, multiple colorectal, FAP type 2; colorectal adenomatous polyposis, autosomal recessive, with pilomatricomas	Adult	MUTYH	Autosomal recessive
Von Hippel–Lindau syndrome	Child/adult	VHL	Autosomal dominant
Multiple endocrine neoplasia type 1	Child/adult	MEN1	Autosomal dominant
Multiple endocrine neoplasia type 2	Child/adult	RET	Autosomal dominant
Familial medullary thyroid cancer	Child/adult	RET	Autosomal dominant
PTEN hamartoma tumor syndrome	Child/adult	PTEN	Autosomal dominant
Retinoblastoma	Child	RB1	Autosomal dominant
Hereditary paraganglioma– pheochromocytoma syndrome	Child/adult	SDHD SDHAF2 SDHC SDHB	Autosomal dominant
Tuberous sclerosis complex	Child	TSC1 TSC2	Autosomal dominant
WT1-related Wilms tumor	Child	WT1	Autosomal dominant
Neurofibromatosis type 2	Child/adult	NF2	Autosomal dominant
Ehlers–Danlos syndrome, vascular type 1	Child/adult	COL3A1	Autosomal dominant
Marfan syndrome, Loeys–Dietz syndromes, and familial thoracic aortic aneurysms and dissections	Child/adult	FBN1 TGFBR1 TGFBR2 SMAD3 ACTA2 MYLK MYH11	Autosomal dominant
Hypertrophic cardiomyopathy, dilated cardiomyopathy	Child/adult	MYBPC3 MYH7 TNNT2 TNNI3 TPM1 MYL3 ACTC1 PRKAG2 GLA MYL2 LMNA	Autosomal dominant / X-linked
Catecholaminergic polymorphic ventricular tachycardia		RYR2	Autosomal dominant
Arrhythmogenic right-ventricular cardiomyopathy	Child/adult	PKP2 DSP DSC2 TMEM43 DSG2	Autosomal dominant
Romano–Ward long QT syndrome types 1, 2, and 3, Brugada syndrome	Child/adult	KCNQ1 KCNH2 SCN5A	Autosomal dominant
Familial hypercholesterolemia	Child/adult	LDLR APOB PCSK9	Autosomal dominant / Semidominant
Malignant hyperthermia susceptibility	Child/adult	RYR1 CACNA1S	Autosomal dominant

Condition

Typical Age of Onset

Gene

Inheritance

Hereditary breast and ovarian cancer

Adult

BRCA1

BRCA2

Autosomal dominant

Li–Fraumeni syndrome

Child/adult

TP53

Autosomal dominant

Peutz–Jeghers syndrome

Child/adult

STK11

Autosomal dominant

Lynch syndrome

Adult

MLH1

MSH2

MSH6

PMS2

Autosomal dominant

Familial adenomatous polyposis

Child/adult

APC

Autosomal dominant

MYH-associated polyposis; adenomas, multiple colorectal, FAP type 2; colorectal adenomatous polyposis, autosomal recessive, with pilomatricomas

Adult

MUTYH

Autosomal recessive

Von Hippel–Lindau syndrome

Child/adult

VHL

Autosomal dominant

Multiple endocrine neoplasia type 1

Child/adult

MEN1

Autosomal dominant

Multiple endocrine neoplasia type 2

Child/adult

RET

Autosomal dominant

Familial medullary thyroid cancer

Child/adult

RET

Autosomal dominant

PTEN hamartoma tumor syndrome

Child/adult

PTEN

Autosomal dominant

Retinoblastoma

Child

RB1

Autosomal dominant

Hereditary paraganglioma– pheochromocytoma syndrome

Child/adult

SDHD

SDHAF2

SDHC

SDHB

Autosomal dominant

Tuberous sclerosis complex

Child

TSC1

TSC2

Autosomal dominant

WT1-related Wilms tumor

Child

WT1

Autosomal dominant

Neurofibromatosis type 2

Child/adult

NF2

Autosomal dominant

Ehlers–Danlos syndrome, vascular type 1

Child/adult

COL3A1

Autosomal dominant