17.2 Genetic Principles: Inheritance Patterns, Carrier Screening & Hereditary Cancer Risk Assessment
Key Takeaways
Autosomal dominant conditions (BRCA, Lynch, familial hypercholesterolemia) give each child a 50% risk; when both parents carry an autosomal recessive condition (CF, SMA, sickle cell), each child has a 25% risk of being affected.
In X-linked recessive disorders such as hemophilia and Duchenne muscular dystrophy, a carrier mother passes the condition to half her sons and carrier status to half her daughters; an affected father has no affected sons and all carrier daughters.
An FMR1 premutation (55–200 CGG repeats) causes primary ovarian insufficiency in about 20% of female carriers and can expand to a full mutation (>200) when passed through a mother.
The USPSTF recommends that women with a personal or family history of breast, ovarian, tubal, or peritoneal cancer, or Ashkenazi Jewish ancestry, be assessed with a brief risk tool and referred for genetic counseling if positive.
The Genetic Information Nondiscrimination Act (2008) protects against discrimination in health insurance and employment, but not in life, disability, or long-term care insurance.
Patterns of Inheritance
| Pattern | Transmission | Examples |
|---|---|---|
| Autosomal dominant | One altered copy causes the trait; each child of an affected parent has a 50% risk; males and females equally affected; appears in every generation (variable penetrance) | BRCA1/2, Lynch syndrome, familial hypercholesterolemia, Marfan syndrome, Huntington disease |
| Autosomal recessive | Two altered copies needed; two carrier parents: 25% affected, 50% carriers, 25% unaffected noncarriers per pregnancy; often no family history; more common with consanguinity | Cystic fibrosis, spinal muscular atrophy, sickle cell disease, thalassemias, Tay-Sachs disease |
| X-linked recessive | Carrier mother: 50% of sons affected, 50% of daughters carriers; affected father: all daughters carriers, no sons affected (no male-to-male transmission) | Hemophilia A and B, Duchenne muscular dystrophy, G6PD deficiency |
| X-linked dominant | Affected father passes it to all daughters and no sons | Fragile X (with anticipation), vitamin D–resistant rickets |
| Mitochondrial | Passed only through the mother to all her children | MELAS, Leber hereditary optic neuropathy |
| Multifactorial | Genes plus environment; recurrence about 2%–5% after one affected child | Neural tube defects, cleft lip and palate, many congenital heart defects |
| Chromosomal | Nondisjunction (risk rises with maternal age), translocations, deletions | Trisomies 21, 18, and 13; Turner syndrome; 22q11.2 deletion; a balanced Robertsonian translocation causes familial Down syndrome |
Fragile X and the FMR1 Gene
| CGG Repeats | Category | Significance |
|---|---|---|
| Fewer than 45 | Normal | — |
| 45–54 | Intermediate | Small expansion risk |
| 55–200 | Premutation | Primary ovarian insufficiency in about 20% of female carriers; tremor/ataxia syndrome in older carriers; can expand to a full mutation when passed by a mother |
| More than 200 | Full mutation | Fragile X syndrome (most common inherited intellectual disability) |
ACOG recommends fragile X carrier testing for people with a family history of fragile X or unexplained intellectual disability and for women with unexplained POI or elevated FSH before 40.
Carrier Screening Strategy
- Offer to everyone considering pregnancy or currently pregnant (ACOG): cystic fibrosis and spinal muscular atrophy, plus a CBC (with hemoglobin electrophoresis based on indices and ancestry) for hemoglobinopathies.
- Ancestry-based panels (for example, Ashkenazi Jewish: Tay-Sachs, Canavan, familial dysautonomia) or expanded panels for everyone are both acceptable. ACMG (2021) recommends a tiered expanded panel for all.
- If one partner is a carrier, offer testing to the reproductive partner promptly; if both are carriers, refer to genetic counseling to discuss prenatal diagnosis (CVS or amniocentesis) or preimplantation genetic testing in future IVF.
- Explain residual risk: a negative screen lowers but does not eliminate carrier probability.
- Prenatal aneuploidy screening and diagnostic testing are covered in the obstetric diagnostics section.
Hereditary Cancer Risk Assessment
USPSTF (2019, Grade B)
Assess women with a personal or family history of breast, ovarian, tubal, or peritoneal cancer, or an ancestry associated with BRCA1/2 variants (such as Ashkenazi Jewish), with a brief familial risk tool: the Ontario Family History Assessment Tool, Manchester Scoring System, Referral Screening Tool, Pedigree Assessment Tool, 7-Question Family History Screen, or the Tyrer-Cuzick (IBIS) model. A positive result leads to genetic counseling, then testing if indicated. Routine assessment, counseling, or testing is not recommended for women without these histories (grade D).
Red Flags for Genetic Referral
- Breast cancer at 50 or younger, triple-negative breast cancer at 60 or younger, or bilateral or multiple primary cancers.
- Ovarian, tubal, or peritoneal cancer at any age.
- Male breast cancer, pancreatic cancer, or metastatic prostate cancer in the family.
- Two or more relatives on the same side with breast, ovarian, pancreatic, or prostate cancer.
- Ashkenazi Jewish ancestry with any of these cancers.
- A known pathogenic variant in the family.
- Lynch indicators: colorectal or endometrial cancer before 50, a mismatch-repair–deficient tumor, or the Amsterdam II "3-2-1" pattern (three relatives with Lynch cancers, two generations, one diagnosed before 50).
Cancer Risks and Management
| Syndrome | Key Risks | Risk-Reducing Management |
|---|---|---|
| BRCA1 | Breast about 55%–72% lifetime; ovarian about 39%–44% | Annual breast MRI from 25, mammography from 30 (often alternating every 6 months); risk-reducing salpingo-oophorectomy (RRSO) at 35–40 after childbearing; consider risk-reducing mastectomy |
| BRCA2 | Breast about 45%–69%; ovarian about 11%–17% | Same screening; RRSO at 40–45 |
| Lynch syndrome (MLH1, MSH2, MSH6, PMS2, EPCAM) | Colorectal and endometrial (up to roughly 40%–60% depending on the gene), ovarian, and others | Colonoscopy every 1–2 years from 20–25; hysterectomy with BSO after childbearing (often in the 40s) |
| Li-Fraumeni (TP53) | Very early breast cancer, sarcomas, brain tumors | MRI-based screening; avoid radiation when possible |
| Cowden (PTEN) | Breast, thyroid, and endometrial cancers | Enhanced screening |
| PALB2, CDH1, and others | Elevated breast risk; CDH1 adds diffuse gastric cancer and lobular breast cancer | Gene-specific plans |
Combined oral contraceptives lower ovarian cancer risk in BRCA carriers and can be used for contraception.
Chemoprevention (USPSTF 2019, Grade B)
Offer risk-reducing medications to women at increased breast cancer risk (for example, a 5-year risk of 3% or higher) with low adverse-effect risk:
- Tamoxifen (premenopausal or postmenopausal): Increases VTE, endometrial cancer, and cataracts.
- Raloxifene (postmenopausal): Increases VTE but not endometrial cancer, and protects bone.
- Aromatase inhibitors (postmenopausal): Cause bone loss and arthralgias.
Ethics and Privacy of Genetic Information
- Pretest counseling covers benefits, limitations, possible variants of uncertain significance, and implications for relatives; post-test counseling covers cascade testing of family members.
- The Genetic Information Nondiscrimination Act (GINA, 2008) prohibits genetic discrimination in health insurance and employment (for employers with 15 or more employees), but not in life, disability, or long-term care insurance.
- Direct-to-consumer tests may check only a few variants (for example, three Ashkenazi founder BRCA variants) and should not replace clinical testing when the history is concerning.
A woman is a known carrier of hemophilia A. Her partner does not have hemophilia. What is the risk for each pregnancy?
Each son has a 25% chance of being affected, and each daughter has a 25% chance of being affected.
All sons will be affected, and all daughters will be carriers, because the mother carries the gene.
Each son has a 50% chance of being affected; each daughter has a 50% chance of being a carrier.
There is no risk to her children, because hemophilia can be inherited only from an affected father.
A 33-year-old has primary ovarian insufficiency with FSH of 58 IU/L and 6 months of amenorrhea. Her karyotype is 46,XX. Her brother's son has intellectual disability. Which genetic test is most appropriate?
BRCA1 and BRCA2 sequencing
Cystic fibrosis carrier screening only
Factor V Leiden testing
FMR1 testing for fragile X premutation
A 41-year-old woman's mother had ovarian cancer at 58, and her maternal aunt had breast cancer at 44. She has no personal cancer history. According to the USPSTF, what is the most appropriate next step?
Use a brief familial risk tool and, if positive, refer her for genetic counseling and possible testing.
Order BRCA1/2 testing directly today, without pretest genetic counseling or a familial risk assessment.
Reassure her that cancers on her mother's side of the family do not affect her own risk.
Begin annual CA-125 and transvaginal ultrasound screening for ovarian cancer starting now.
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