Genetic Carrier Screening

Additional Reading
CO 690: Carrier Screening in the Age of Genomic Medicine
CO 691: Carrier Screening for Genetic Conditions
CO 816: Consumer Testing for Disease Risk

Previously on the podcast, we have talked through aneuploidy screening. But we’ve not talked in depth about carrier screening, so today’s podcast is dedicated to the other form of prenatal genetics we often consider! 

What is carrier screening?

• Aneuploidy screening: looking at some biochemical marker in an already pregnant individual to understand risk of trisomy (typically).

• Carrier screening: looking at genetics of parental contributions to assess potential risk in a current or hypothetical pregnancy. 

  • So this tells you - do you carry a condition that you are not affected by?

  • Only needs to be performed once in a lifetime - as opposed to aneuploidy screening, which needs to be re-performed with every pregnancy. 

• ACOG recommends that “information about carrier screening should be provided to every pregnant individual.” 

• Carrier screening most commonly looks for autosomal recessive conditions - that is, both parents need to be carriers in order for there to be a 25% risk of fetus being affected.

  • Certain X-linked conditions (i.e., hemophilia, Fragile X) can also be screened.

    • Information can be used in pregnancy planning, understanding risk of fetal condition that may impact life/lifespan of fetus, and choice for IVF with PGT or invasive testing in pregnancy.

  • Some other conditions may be discouraged from carrier screening (i.e., Huntington’s disease, BRCA genes) because of ethical concerns with doing carrier screening on fetuses, given these are adult-onset conditions. 

  • No “official threshold” for carrier screening generally, but most panels select conditions with a carrier frequency of ~1/100 or greater → generally a disease incidence of 1 in 40,000.

• There always remains some residual risk for carriage state/disease, even after carrier screening.

What strategies have been suggested for carrier screening?

• Historically, carrier screening was considered on an ethnicity basis (i.e., ethnic-based screening)

  • However, multiple limitations to this approach:

    • Challenging for individuals to define ancestry

    • Ancestral “mixing” between partners of different ethnicities causing different risks

    • The “pretest” probability of a positive is difficult to predict given these limitations

    • Couples with consanguinity may be at higher risk of recessive conditions being expressed in offspring, regardless of ethnic background.

• Current approaches favor panethnic or expanded carrier screening 

  • Panel of disorder screening is offered to all individuals regardless of ancestry.

  • The cost of screening has come down significantly, allowing for screening for hundreds of conditions at reasonable cost to patient.

• If family history of mutations/conditions are known, targeted screening can be considered to look for specific mutations.

What limitations are there in carrier screening? What does “residual risk” after carrier screening mean?

• These carrier screening panels look for known mutations in a population, based on a reference genome.

  • These reference genomes are overwhelmingly represented by White populations, so:

    • Carrier screening may not detect all mutant variants of an allele → residual risk

    • Carrier screening does not recognize new, potentially disease-causing variants.

      • Carrier testing is not sequencing! 

What conditions are recommended by ACOG to be screened for with carrier screening?

• Spinal muscular atrophy

  • Autosomal recessive disease with spinal cord motor neuron degeneration due to biparental inheritance of an SMN1 mutation/deletion.

  • Leading genetic cause of infant death.

  • Incidence of disease around 1 in 6-10k; carrier frequency in most populations around 1:40 to 1:60.

    • 2% of cases are the result of a new gene mutation. 

  • SMA has an interesting genetic profile:

    • There is generally one copy of SMN1 per chromosome, and a deletion/abnormality in each parental contribution leads to disease (again, autosomal recessive).

    • However, some of the population have two copies of SMN1 on a chromosome, and 0 copies on the other – so they are technically carriers (because of the chromosome with 0 copies).

    • Carrier screening tests for SMA generally look for the number of copies of SMN1 - so a patient with this particular variation (2+0) would be missed.

      • This 2+0 variation is much more common in African Americans - lowering the carrier detection rate of SMA from 95% in White patients to 71% in African Americans.

      • This leads to a higher residual risk from these tests as they may miss the 2+0 mutation.

• Cystic fibrosis

  • Most common life-threatening AR condition in White population.

    • Incidence 1/2500 in White; considerably less common in other ethnic groups.

  • Two copies of CFTR mutations (chromosome 7) cause the disease.

  • Most carrier screening looks for one of the 23 most common mutations that exist – again, predominantly in White populations.

    • But there are over 1700 CFTR mutations identified that can lead to CF!

    • Performance ranges from 94% sensitivity in Ashkenazi Jewish populations to less than 50% in Asian populations. 

    • Because of the number of mutations, some have advocated for CFTR sequencing to supplant panel testing as a way to determine carrier status and reduce residual risk amongst all populations. 

• Hemoglobinopathies

  • We have talked about these on the show before - thalassemias and sickle cell disease.

  • CBC and RBC indices should be performed in all pregnant persons to assess for anemia and risk of hemoglobinopathy.

    • Hb electrophoresis can be considered in all patients with anemia, particularly if there is family history or ethnicity-based risk factor, to screen for hemoglobinopathy.

    • Alpha thalassemias, though, can only be detected with molecular genetic studies - so if the electrophoresis is not conclusive, DNA-based testing should be pursued to assess for alpha thal. 

• Fragile X Syndrome

  • Most common inherited form of intellectual disability; distinctive facial features in males, enlarged testicles, delay in fine and gross motor skills are some manifestations.

  • 1 in 3600 males; 1 in 4k-6k females. 

  • Carrier frequency in the US around 1 in 250 for no known risk factors, or 1 in 86 for those with a family history of intellectual disability.

  • X-linked disorder of mutation in FMR1 gene.

    • The mutation is characterized by expansion of a trinucleotide repeat sequence (CGG); the more repeats, the more significant the mutation:

      • Intermediate (45-54 repeats)

      • Premutation (55-200 repeats)

      • Full mutation (>200 repeats)

    • Females carrying a premutation or full-mutation X chromosome are also at risk for premature ovarian insufficiency. Females with full mutation may also have fragile X characteristics of disease like in males, though with variable expression. 

We hear a lot about “Ashkenazi Judaism” and carrier screening. What does that mean and what conditions should be screened?

• Ashkenazi Jewish is defined in the committee opinions as individuals of Eastern and Central European Jewish descent.

  • Not a super accurate or helpful designation, as most individuals with Jewish ancestry in the USA are descended from these areas.

• Recommendations for specific screening:

  • Tay Sachs Disease - severe, progressive neurodegenerative disease with functional deficiency in the gene encoding the hexosaminidase A enzyme. 

    • Carrier rate in Ashkenazi Jewish populations around 1 in 30.

  • Cystic fibrosis

  • Canavan disease - severe degenerative neurologic disease

  • Familial dysautonomia - severe disorder of sensory and autonomic nervous systems

  • Multiple others are also considered, including Gaucher disease, Joubert syndrome, maple syrup urine disease, Niemann-Pick disease, and a few others. 

    • The panels developed for this population are very ethnicity-specific - so while great for this population, residual risk discussion can be complicated in non-Jewish individuals (as the incidence of carriage is often very low).

What about the genetic screening tests advertised to patients online?

• There are a whole host of “carrier screens” that are direct-to-consumer, and even some of the more reputable companies in this space have direct-to-consumer options given the decreasing expense of this technology. 

• However, these companies have varying degrees of privacy protections for genetic data.

• They also may have implications on patient’s eligibility for disability and other types of insurance; long-term care considerations; and ownership of one’s own genetic data.

• Some direct-to-consumer testing uses different kinds of technology to develop a picture of risk for a patient, that may or may not be helpful in their context. Abnormal results of concern should always be reviewed with a genetic counselor.

  • If you have any concerns or need more time for your patients to discuss whether they want to have carrier screening, it’s worthwhile to send them to a GC! They can help patients navigate targeted vs expanded carrier screening and help make decisions that are right for each individual patient.