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Research Rookie – Edition 3

What are the odds? Chances of inheriting SDHB or SDHD mutation from a parent.

A lay summary of: Davidoff, Lim, Benn et al. (2023).  Distortion in transmission of pathogenic SDHB- and SDHD-mutated alleles from parent to offspring.  Endocrine-Related Cancer, 30, e220233.

Text in bold is defined in the glossary at the bottom of the page.

When one parent has a genetic mutation, the odds of their children inheriting that mutation is typically 50/50. These odds are “even” because each parent contributes one copy of that gene to the sperm or egg (the gamete) that will form a fertilized embryo.   There’s a 50/50 chance that this copy of the parent’s gene (and therefore the embryo) will have the specific mutation.  Thus, if one parent has an SDHB mutation, we normally would expect that, on average, half of that parent’s children would also carry the SDHB mutation and half would not.

(Note that we would not expect that half of the children would develop SDHB tumors, since having the mutation does not necessarily mean that the pheo/para tumor would grow. We know relatively little about the specific factors that determine if and/or when tumors will grow if an SDHx mutation is present in an individual’s DNA.)

Davidoff and colleagues began their study with a surprising observation.  A patient with an SDHB mutation had genetic diagnostic  testing prior to having a procedure to implant embryos for family planning.  The number of embryos with an SDHB mutation was higher than would be expected if the “transmission ratio” was 50/50.  Perhaps the assumption of a 50/50 ratio of inheritance for this the SDHB mutation was incorrect.

To test whether the SDHB transmission rate was indeed 0.50, the researchers examined the inheritance pattern of the SDHB mutation in a total of 82 families who had at least one family member with that mutation.  There were two groups of research participants – the first was a group of 41 Australian families and the second was 41 families from the UK.  The researchers found the probability of transmission for the SDHB mutation was 0.59 in the first group and 0.67 in the second.  In both samples, the transmission ratios were reliably greater than the expected 0.50 probability (50/50).  Similarly, an independent sample of 13 UK families also showed a higher-than-expected transmission ratio of 0.70.

The researchers suggested some reasons to be cautious in interpreting the results of their study.  For example, there may have been some potentially important factors (e.g., birth order, miscarriage rate) that could have affected the results but were not measured.  However, the higher transmission ratios did not seem to be related to factors such as age or gender of the parent with the SDHx mutation.

What might cause the relatively high transmission ratio?  The researchers suggested several possible mechanisms that might occur at different points in the development of embryos.  One explanation may be that there is an unequal division of genetic material at the time of the creation of the egg or sperm, resulting in more than 50% of eggs or sperm having the SDHx mutation.  Another possibility is that the mutation may be associated with a reproductive advantage.  This means, for example, the eggs and sperm that have this mutation may be more likely to produce a fertilized embryo than are the gametes without it.  Another possible example is that embryos that have an SDHx mutation may be more likely to survive than embryos without this mutation, particularly in low-oxygen environments that may be present in the uterus.  These are just speculations, however, and need to be explored in future research.

How may this affect people with an SDHx mutation?

As a result of this study, there should be a change in the way family genetic counseling is done.  The higher-than-predicted transmission ratios for the SDHB and SDHD should be explained to potential parents who have an SDHx mutation as part of a family genetic counselling program, so they can be fully informed in making decisions about childbearing.

Although this research may seem like bad news for patients with a genetic mutation who are planning to have a family, pre-implementation genetic testing can help prospective biological parents to implant only embryos that do not have the genetic mutation.  In addition, this research may help future generations of families with SDHB and SDHD.  A potentially protective role of the SDHx gene in embryonic development may be discovered, which may offer possibilities for future prevention or treatment pathways.  Finally, future research may uncover reasons for the high transmission ratio and some of these potential causes may be preventable.

Link to full article

Link to Genetics webpage

 

Glossary

gamete: A reproductive cell that carries only 1 copy of every gene.

pre-implantation genetic testing: An In Vitro fertilization procedure that includes genetic testing of embryos before they are placed in the uterus.

reproductive advantage: A mechanism of evolution that increases the frequency of heritable traits in a population over time.

SDHx mutation: A short-hand reference to the Succinate Dehydrogenase Genes (SDHA, SDHB, SDHC and SDHD) ) and the assembly factor (SDHAF2). Inherited mutations in the SDHx genes may increase the risk of tumors including sympathetic paragangliomas, head and neck paragangliomas, pheochromocytomas, renal cell carcinoma (RCC), and gastric gastrointestinal stromal tumors (GIST).

transmission ratio: the likelihood of a child inheriting a genetic mutation