Key Points

• Health care providers should recognize when genetic factors contribute meaningfully to risk assessment, diagnosis, or disease management for rare conditions as well as common multifactorial conditions.

• Staying current with advances in diagnosis and treatment of genetic conditions challenges both genetic specialists and family physicians.

• Family physicians should identify and utilize credible and current information resources to support their care of patients with heritable conditions because proper diagnosis and management can be lifesaving.

Table 44-5 lists examples of multifactorial, single-gene, and chromosomal disorders seen in family medicine, including genetic information about each disease (Acheson and Wiesner, 2004; Christiansen et al., 2005; Gaston et al., 1986). In aggregate, single-gene and chromosomal disorders are relatively common. Physicians should remain alert for

Table 44-5 Multifactorial, Single-Gene, and Chromosomal Disorders Seen in Family Medicine

Condition

Inheritance Pattern

Genes Involved*

Single-gene diseases

Early-onset Alzheimer's disease

Autosomal dominant

APP, PSEN1, PSEN2

Breast cancer

Autosomal dominant with incomplete penetrance

BRCA1, BRCA2

Colon cancer (Lynch syndrome)

Autosomal dominant with incomplete penetrance

MLH1, MSH2, MSH6, and PMS2

Cystic fibrosis

Autosomal recessive

CFTR

Hemochromatosis, adult

Autosomal recessive

HFE

Marfan's syndrome

Autosomal dominant

FBN1, TGFBR2

Sickle cell disease

Autosomal recessive

HBB

Tay-Sachs disease

Autosomal recessive

HEXA

^-Thalassemia

Autosomal recessive

HBB

Familial hypercholesterolemia

Various

LDLR, ApoB, PCSK9, LDLRAP1

Chromosomal diseases

Down syndrome

Sporadic

Trisomy 21

Fragile X syndrome

X-linked dominant with incomplete penetrance

FMR1, with >200 CGG repeats

Turner' syndrome

Sporadic

XO karyotype

XXY Males (Klinefelter's syndrome)

Sporadic

XXY karyotype

Multifactorial diseases

Alzheimer's disease

Multifactorial

APOE E4, multiple SNPs

Asthma

Multifactorial

Multiple SNPs

Coronary artery disease

Multifactorial

Multiple SNPs

Depression

Multifactorial

Multiple SNPs

Diabetes type 2

Multifactorial

Multiple SNPs

Diabetes, type I

Multifactorial

HLA variants and multiple SNPs

Venous thromboembolism

Multifactorial/autosomal dominant

Factor V Leiden FVL, proteins C and S, prothrombin G20210A, antithrombin III

Data from Gene Tests (www.genetests.org); Online Mendelian Inheritance in Man (http://www.ncbi.nlm.nih.gov/omim/); and NHGRI GWAS catalog (http://www.genome.gov/26525384). *Most common mode of inheritance for each condition listed; for many common multifactorial conditions, there are rare instances of mutations in single genes causing a similar disease.

SNPs, Single nucleotide polymorphisms.

single-gene diseases when seeing patients, which can include causes of cancers, anemia, liver disease, developmental delay, and deep vein thrombosis. Making a correct genetic diagnosis can lead to lifesaving interventions for affected patients and their families.

Much research is needed regarding the genetics of multi-factorial disorders, and predispositional genetic testing for such conditions using newer markers (e.g., disease-associated SNPs) is not currently recommended. A few examples illustrate what can currently be done with genetics and genomics in primary care.

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