The field of genetics/genomics centers on an ever-expanding area of knowledge.  This expansion and change is rapidly improving clinicians’ ability to identify genetic variants of significance. These can be used to guide patient care and make critical decisions aimed at improving and lengthening our lives.  This is very good news, of course.  However, the complexity of genetics coupled with frequent improvements in technology has caused a major hurdle in terms of most physicians’ understanding of genetic testing and its implications.

The Clinician Knowledge Gap

This knowledge gap should not come as a surprise, as according to a study conducted in 2015, most medical schools in the U.S. and Canada teach the majority of genetics content during the first 2 years of school.  The average number of total contact hours for genetics instruction (including biochemical genetics) was 36 hours, which means that about half the schools provide less than 36 total hours.  Only 25% of the schools taught genetics as a stand-alone course, as opposed to incorporating genetics content into other courses and clerkships.¹

In addition to the relatively low amount of genetics education offered early during one’s four years in medical school, many physicians in practice are focused on and overloaded by the daily care tasks that are required of their patients.  For example, in the fields of primary care and obstetrics and gynecology, they are managing chronic conditions, diagnosing flus/viruses, taking care of pregnancies, delivering babies, etc. – leaving them little time or bandwidth for further education or consideration of the complex nuances of genetics.  As such, many studies have shown a deficiency of knowledge of genetics and genetic tests amongst various physician specialties as well as a lack of confidence and comfort with incorporating genetic testing into their daily practice. ², ³, ⁴, ⁵

We will illustrate how the above deficiencies in physician education and general discomfort with implementing genetics show up in practice through a recent case referred to Metis Genetics.

A Case Study

A couple (we will call them April and Malcolm) was referred to Metis Genetics for genetic counseling.  April was 17 weeks pregnant when she met with the Metis genetic counselor.  Both April and Malcolm had received genetic carrier screening - a gene panel examining parental carrier status for over 200 conditions, through their obstetrician.  The test results had been given to the couple 3 days prior to their meeting with the genetic counselor.  The results showed that both parents were carriers of the R229Q variant in the NPHS2 gene. Pathogenic (disease causing) variants in this gene can cause nephrotic syndrome. This condition is a kidney disorder that begins in infancy and typically leads to irreversible kidney failure (end-stage renal disease) by early childhood. Mutations in this gene appear to be the most frequent cause of congenital nephrotic syndrome. Different NPHS2 gene mutations can also cause other forms of nephrotic syndrome that develop later in life.⁶

In order for a recessive condition to be passed on to one’s children, both parents need to be carriers of the condition, and the child needs to receive the genetic disease-causing variant from each parent.  When a couple are both unaffected carriers of the same recessive genetic condition, there is a 25% chance that this situation can occur (i.e., each will pass the disease causing variant to their offspring), and that the child will actually be affected with the condition in question.  In the case of April and Malcolm, when the obstetrician delivered these test results, he told them; “Since you are both carriers, you have a 25% chance of having a child affected with this condition.  You may want to schedule an amniocentesis to find out the diagnosis.”  His assumption was that because they both carried the R229Q variant in this gene (NPHS2) that can cause congenital nephrotic syndrome – they had a 25% chance of having a child affected with this disease. This assumption was incorrect.  It is not surprising that the clinician made this error, as he thought back to the model of recessive inheritance that we discussed above.  However, the R229Q variant alone in this gene is not sufficient to cause the disease. ⁷, ⁸

Having two copies of the R229Q variant (being homozygous for R229Q) is not enough to cause congenital nephrotic syndrome.  If the R229Q variant is inherited from one parent, and another different disease-causing variant is inherited from the other parent, the child will have a congenital kidney disease of varying severity and age of onset, based upon the particular, second disease-causing variant that is inherited. ⁷, ⁸, ⁹, ¹⁰, ¹¹ However, neither April nor Malcolm were carriers of a different, disease-causing variant.  They were both carriers of R229Q, which is a benign variant when inherited from both parents.  We acknowledge that this is a bit of a more complicated situation than standard recessive inheritance.  However, there was language in the genetic testing report that explained these test results, and that the fetus was not at risk for this syndrome.  The clinician in question did not understand the laboratory report language and did not have a good understanding of the inheritance of this condition.  Therefore, April and Malcolm spent 3 days before they met with the genetic counselor in turmoil and panic about their pregnancy.  April was planning on having an amniocentesis, which is an invasive procedure to obtain amniotic fluid from the fetus that is associated with a low risk of miscarriage.  It is possible, depending upon the genetic results of the amniocentesis (if the fetus carried two copies of R229Q), that the couple could have chosen to terminate the pregnancy if no other clinicians or healthcare providers stepped in to explain the true significance of the test results.  They could have ended the pregnancy of a healthy fetus based on this misinformation.

April and Malcolm were extremely relieved after their discussion with the genetic counselor.  The genetic counselor explained the inheritance of this condition and the significance of the R229Q variant.  She pointed out the test report language that explained that the fetus was not at risk for this disease.  The couple chose not to have an amniocentesis and to move forward with the pregnancy, with a great emotional burden now lifted.  The emotional trauma these patients underwent was not necessary.  This type of situation is not rare, unfortunately, as many clinicians do not have an adequate understanding of the nuances of genetics to be counseling patients through these risk situations.  Just examining the case of this condition and the gene NPHS2, there is a high carrier frequency in the population - 1/13 individuals of European descent are carriers of a mutation for steroid-resistant nephrotic syndrome. 1/9 individuals of Ashkenazi Jewish descent are carriers.¹² Therefore, similar situations to this have a high chance of arising, particularly as more couples receive expanded carrier testing for recessive conditions.

The Importance of Genetic Counselors

This case study illustrates the vital importance of genetic counselors in the management of genomic healthcare.  Genetic counselors receive master’s degrees and clinical training focused solely on the medical and psychosocial implications of genetics in people’s lives.  They take a standardized board certification exam before practicing and are required to participate in continuing education to keep their certification current, as the field of genetics is rapidly evolving.  These experts are skilled and ready to help patients respond to situations of genetic risk such as the one discussed above.  We cannot expect all physicians to be experts in genomic medicine, in addition to the rigorous daily demands of their specialty, particularly in light of the relatively low amount of genetics education they receive during their training and the fact that the field is changing at such a swift pace.

Genetic counselors are at the forefront of genomic medicine and helping to implement its promise for patients.  It is incumbent upon us in the field to spread awareness of the existence of genetic counselors and the value they can provide.  You can learn more about what genetic counselors do and connect with one at https://www.aboutgeneticcounselors.org/.

References:

1.     Plunkett-Rondeau, J., Hyland, K. & Dasgupta, S. Training future physicians in the era of genomic medicine: trends in undergraduate medical genetics education. Genet Med 17, 927–934 (2015). https://doi.org/10.1038/gim.2014.208.

2.     Baars, M., Henneman, L. & ten Kate, L. Deficiency of knowledge of genetics and genetic tests among general practitioners, gynecologists, and pediatricians: A global problem. Genet Med 7, 605–610 (2005). https://doi.org/10.1097/01.gim.0000182895.28432.c7.

3.     Harvey, E., Fogel, C., Peyrot, M. et al. Providers' knowledge of genetics: A survey of 5915 individuals and families with genetic conditions. Genet Med 9, 259–267 (2007). https://doi.org/10.1097/GIM.0b013e31805002f2.

4.     White, S., Jacobs, C. & Phillips, J. Mainstreaming genetics and genomics: a systematic review of the barriers and facilitators for nurses and physicians in secondary and tertiary care. Genet Med 22, 1149–1155 (2020). https://doi.org/10.1038/s41436-020-0785-6.

5.     Wideroff L, Vadaparampil ST, Greene MH, et al. Hereditary breast/ovarian and colorectal cancer genetics knowledge in a national sample of US physicians. Journal of Medical Genetics 2005;42:749-755.

6.     https://medlineplus.gov/genetics/gene/nphs2/#synonyms

7.     Hereditary Nephrotic Syndrome, Stefanie Weber, in Comprehensive Pediatric Nephrology, 2008.

8.     Rood, IM, et al. Nephrotic Syndrome with Mutations in NPHS2: The Role of R229Q and Implications for Genetic Counseling. The Amer Journal of Kidney Diseases, September 18, 2018. DOI:https://doi.org/10.1053/j.ajkd.2018.06.034.

9.     Machuca, E, et al.  Clinical and epidemiological assessment of steroid-resistant nephrotic syndrome associated with the NPHS2 R229Q variant. Kidney International, Volume 75, Issue 7, 1 April 2009, Pages 727-735. https://doi.org/10.1038/ki.2008.650.

10.  Tory, K, et al. Mutation-dependent recessive inheritance of NPHS2-associated steroid-resistant nephrotic syndrome. Nat Genet. 2014 Mar;46(3):299-304. doi: 10.1038/ng.2898.

11.  Straner, P, et al. C-terminal oligomerization of podocin mediates interallelic interactions. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. Volume 1864, Issue 7, July 2018, Pages 2448-2457.

12.   https://cdn1.sema4.com/wp-content/uploads/Sema4-ECS-283-Residual-Risk-Table.pdf