One in four – the carrier rate of recessive diseases

How frequent? With all the genetic information around, we are often wondering how much genetic morbidity is really hidden in our genomes. Yes, everybody is a knock-out for 1-3 genes, but in most cases, these variants do not cause disease. However, what happens if you apply genomics to estimate the burden of known disease variants? Now in a recent paper in Genetics in Medicine by Lazarin and colleagues, the carrier frequency for ~400 variants known to cause ~100 recessive disorders is investigated. 24% of all individuals are carriers for at least one recessive disorder.

Carrier screening. Some recessive diseases are quite common in certain populations and for some of these disorders, the case can be made for carrier screening. In the US, in contrast to many European countries, carrier screening for Cystic Fibrosis and Spinal Muscular Atrophy (SMA) is recommended for individuals of European descent. The US-based company Counsyl offers direct-to-consumer marketing for carrier screening by looking at a panel of 417 validated variants known to cause recessive disorders. In total, 108 recessive disorders are covered with their panel. Counsyl now presents an analysis of ~23,000 individuals screened for these variants.

The 10 most common diseases screened for with the Counsyl array based on the paper by Lazarin and colleagues. The frequency (1 in) might be slightly unusual, as we normally deal with percentages, but it is represented in a way that is used in genetic counseling.

The 10 most common diseases screened for with the Counsyl array based on the paper by Lazarin and colleagues. The frequency (1 in) might be slightly unusual, as we normally deal with percentages, but it is represented in a way that is used in genetic counseling.

One in four. They find that 24% of all individuals, irrespective of ethnicity, are carriers for at least one pathogenic variant involved in recessive disease. Up to 5% of patients carry two variants. The most common diseases that the individuals were carriers for included alpha-1-Antitrypsin deficiency, a condition that usually leads to progressive lung disease in adults, Cystic Fibrosis and non-syndromic deafness due to mutation in GJB2 (DFNB1).

What else is out there? The publication by Lazarin and colleagues offers a good estimate on established variants involved in recessive disease. These variants are known to cause recessive disorders and genetic counseling based on these findings is straightforward at least from the genetic point of view. Given that the Counsyl array is variant-based and not gene-based, a “negative” array does not rule out disease, not even the diseases tested for. And of course the Counsyl array only investigates inherited recessive disorders, which might be less relevant for epilepsies compared to de novo mutation, dominant mutations and copy number variations. Nevertheless, in some fields, genetic carrier screening is a success story. Tay-Sachs disease, which has a particularly high carrier rate in individuals of Ashkenazi Jewish descent, is virtually extinct in this population due to carrier screening.

6 thoughts on “One in four – the carrier rate of recessive diseases

  1. Pingback: Dealing with the genetic incidentaloma – the ACMG recommendations on incidental findings in clinical exome and genome sequencing | Beyond the Ion Channel

  2. As an OB, this is just another reason I tell every one of my patients that they absolutely need to take the Counsyl test. This kind of testing should be instituted at the high school level. If people know their carrier status, and can be proactive about it when thinking about having children, it could save the health care system billions of dollars annually.

  3. Dear Dr. James,
    thank you for your comment. I don’t think that a general recommendation for this can be made. This is actually a very complex matter with many different aspects to consider. First, this is a matter of patient autonomy and patients may have many different reason to take or not to take such a test. More importantly, there is very little knowledge on many of these disorders if they are discovered on a genetic basis. Traditionally, we have the clinical manifestation of disorders and confirm them genetically afterwards. There is very little experience on the penetrance of many disorders when starting from the population, at least insufficient experience to issue general recommendation. This insecurity increases exponentially when we move from particular variants to predictions made from the exome or genome level, as emphasized in the recent ACMG guidelines.

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  6. Pingback: Microcephaly, WDR62, and how to analyze recessive epilepsy families | Beyond the Ion Channel

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