Updated Incidence of STXBP1

In April, a team of researchers led by Dr. Dennis Lal at Cleveland Clinic published an updated incidence for rate for STXBP1 of 3.3 to 3.8 children per 100,000 births.[1] This is 1 in 26,000 to 1 in 30,000 births or over 10 STX’ers born a day.

Based on the numbers in our community Facebook groups, and other data points, we are nowhere near this incidence rate. Why? STXBP1 has traditionally been underdiagnosed due to diverse clinical presentation, phenotypic overlap with other neurodevelopmental disorders, and underutilization of genomic testing. My daughter, Juno, for example had a three year diagnostic odyssey to her diagnosis via whole exome testing. At the same time, Juno’s three year journey was short compared to many in our community. Katie from Danville, California, is one of our older STX’ers at 17, and was diagnosed 10 years ago after a six year diagnostic odyssey. And newly diagnosed adult patients are joining our community in increasing numbers.

This updated incidence rate aligns with and amplifies other papers that were recently published. In December 2019, Symonds and Mctague reported STXBP1 being the 5th most common diagnosis in patients referred for genetic testing.[2] And a study published in May by the Danish Epilepsy Center found STXBP1 was the 3rd most common diagnosed gene in adult patients with epilepsy.[3] In 2018, in a GeneDX study STXBP1 was the 7th most diagnosed gene for epilepsy and neurodevelopmental disorders, though this study only included genetic panel and not whole exome testing.[4]

It’s important to note that these numbers do not mean that STXBP1 is not rare. STXBP1 is still a rare disease, and our patients experience rare patient journeys. Indeed, even in these days where increasing STX’ers are being diagnosed, families are still often the only STXBP1 patient being seen by their neurologist, the only STXBP1 patient in their town, and one of a handful in their state or region. Contrast STXBP1’s incidence rate to that of another genetic condition, cystic fibrosis: cystic fibrosis impacts 1:3,000 births in people of Western European descent, and is a common disease in this population, even though many of us might not know anyone personally who has cystic fibrosis.

Why is incidence rate important?

As pointed out in the Cleveland Clinical Consult QD journal regarding the Lal lab study, “Accurate estimates of disease burden — previously unavailable for nearly all the disorders addressed in the study — are critically important to clinicians, researchers, patient advocacy groups, biopharmaceutical companies and policymakers as they make strategic decisions around care and investment priorities.”

More accurate information on the number of patients helps to ignite and expand research interest in STXBP1, which will accelerate our efforts to develop therapies for the STXBP1 community. Also this information should increase awareness of STXBP1 among clinicians, hopefully leading to better care across medical centers and practices. 

Methodology Deep Dive – watch out!

For those wanting to deep dive into the methodology used to calculate this incidence rate, here is the nerd out section of this post…

This paper did not look at STXBP1 incidence only. It analyzed the incidence of 101 neurodevelopmental genes, and 3100 additional other disorders caused by a single gene (monogenic). For each of these genes, first author Javier Lopez-Rivera and collaborators calculated estimated incidence using a model developed by Samocha and collaborators at the Broad Institute of Harvard and MIT.[5] The Samocha model was published in 2014, and is now widely used by clinical labs and research organizations when evaluating whether genetic variants are pathogenic, or disease causing. Because of the expansion of genomic sequencing, population-scale databases of genetic variation like ExAC and gnomAD now exist and can help us to understand genetics and their relationship with disease. The model developed by Samocha identifies genes that are “constrained”, meaning that there are fewer variants than would be expected by change. These constrained genes are “mutationally intolerant”, meaning that a mutation, or variant, in these genes is more likely to impact the gene’s function negatively. If the gene is important for health, individuals affected by those variants will be less likely to pass it on to future generations, resulting in a depletion of variants in the gene in the population at large. You can see the gene constraint scores for STXBP1 with the gnomAD data set here.

The authors point out that their STXBP1 calculation is much higher than the previous estimate published by Stanmberger et al in 2016.[6] They argue that the Stamberger study extrapolated from a patient cohort at an epilepsy study and therefore would not include STXBP1 patients without the epilepsy phenotype. The authors also comment that their incidence rate may be an overestimate as their calculations may not account for conditions where an embryo or fetus was not viable. But since other studies have demonstrated have shown that STXBP1 is not necessary for basic human cell viability (though very important functionally), it is unlikely this possibility impacts their incidence calculations for STXBP1.

For those of you who are still reading, thanks for nerding out with a deep dive on this important paper!

Summary

In closing, here are key takeaways from this post:

• STXBP1 is a rare disease with an updated incidence rate of 1 in 26,000 to 1 in 30,000 births

• Accurate incidence rate is important because it bolsters research interest in STXBP1, and should expedite development of therapies for the STXBP1 community

• Accurate incidence rate also spreads awareness among clinicians, hopefully leading to better patient care

• Genomic testing is expanding both in terms of reimbursement and standard of care, so our patient community will grow faster

-Charlene Son Rigby

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[1] López-Rivera, J.A., et al. A Catalogue of New Incidence Estimates of Monogenic Neurodevelopmental Disorders Caused by De Novo Variants. Brain 143, 1099–1105 (2020). https://pubmed.ncbi.nlm.nih.gov/32168371/

[2] Symonds, J.D., Mctague, A. Epilepsy and developmental disorders: Next generation sequencing in the clinic. European Journal of Paediatric Neurology. (2019). https://www.ncbi.nlm.nih.gov/pubmed/31882278

[3] Johannesen, K.M., et al. Utility of Genetic Testing for Therapeutic Decision‐Making in Adults with Epilepsy. Epilepsia 00, 1-6 (2020). https://doi.org/10.1111/epi.16533

[4] Lindy, A. S. et al. Diagnostic outcomes for genetic testing of 70 genes in 8565 patients with epilepsy and neurodevelopmental disorders. Epilepsia 59, 1062–1071 (2018). https://www.ncbi.nlm.nih.gov/pubmed/29655203

[5] Samocha KE et al. A framework for the interpretation of de novo mutation in human disease. Nat Genetics; 46: 944–50 (2014). https://pubmed.ncbi.nlm.nih.gov/25086666/

[6] Stamberger, H., et al. STXBP1 encephalopathy: A neurodevelopmental disorder including epilepsy. Neurology. 86, 954-62 (2016). https://www.ncbi.nlm.nih.gov/pubmed/26865513