Expanded Carrier Screening

Every person is a carrier of AR/XLR mutations

Pathogenic mutations causing autosomal recessive (AR) and X-linked recessive (XLR) genetic diseases are rare, but each of us is a healthy carrier of at least 5 AR/XLR conditions, according to estimates. So, we are all potentially exposed to specific reproductive risks for rare disorders, although such risks depends on the genetic status of our partner.

Basically two questions arises:

1. Do we want to know these mutations?

2. How many of these AR/XLR mutations can we unveil today?

Let’s try to answer:

1. In our experience, when coming to reproductive risk calculations, some couples are willing to achieve the largest information possible, whereas others prefer to ignore the risk (the majority of patients falling in the first group).

The scientific community tended to recommend carrier screening only for specific risks based on (A) family history or (B) ethnicity (e.g.: Tay-Sachs disease in Ashkenazi or β-thalassemia in Mediterranean populations). However, most AR/XLR conditions remain unseen under these recommendations.

Eventually, it’s a question of personal sensitivity, where the Geneticist is invited to inform and consult without forcing decisions.

2. In our exomes and genomes, we usually detect from 0 to 5-6 mutations for AR/XLR conditions. This value comes from 1st level carrier screening (i.e. when filtering only pathogenic mutations deposited in ClinVar), usually increasing from 0 to 2-3 mutations when performing 2nd level carrier screening (i.e. when looking for new, loss-of-function mutations).

For sure, the yield and quality of Expanded Carrier Screening (ECS) enabled by whole exome and whole genome sequencing is mostly depending on the time and knowledge dedicated to the clinical interpretation of variants.

ECS – advantages:

– Increases autonomous reproductive decisions
– Greater awareness of the carrier status

ECS – caveat:

– Semidominant conditions may be included in ECS
– Knowledge in Medical Genetics is still incomplete
– De novo mutations cannot be seen in ECS
– Missense variants remains uncertain if not previously characterized
– Couple reproductive risks for newborn congenital disease remains consistent even after ECS

ECS – Resources:

– Policy proposed by ESHG about a responsible implementation of ECS: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4867464/

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Antonarakis SE. Carrier screening for recessive disorders. PMID: 31142809
Gregg A. Expanded Carrier Screening. PMID: 29428278
Kraft et al. The evolving landscape of expanded carrier screening: challenges and opportunities. PMID: 30245516
Henneman et al. Responsible implementation of expanded carrier screening. PMID: 26980105
Taber et al. A guidelines-consistent carrier screening panel that supports equity across diverse populations. PMID: 34906503
Gregg et al. Screening for autosomal recessive and X-linked conditions during pregnancy and preconception: a practice resource of the American College of Medical Genetics and Genomics (ACMG). PMID: 34285390
Gabriel A. Lazarin, MS et al, An empirical estimate of carrier frequencies for 400+ causal Mendelian variants: results from an ethnically diverse clinical sample of 23,453 individuals. PMID: 22975760


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