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Ask the     Experts

Question: Has FOXP1 research evolved enough to illustrate differences in symptoms specific to the genetic diagnosis of deletion, frameshift mutation or pathogenic mutation? Stated another way, is it possible looking at the genetic report to anticipate specific symptoms?

Answer: We asked the SAB and developed the following response from 3 of our SAB advisors (Drs. Eichler, Schenck, and Rappold).  In short, this is a good but difficult question to fully address. The short answer is we do not yet have a full understanding of mutations and outcomes, but it is something that many of us are working towards.  There are 2 or 3 key issues facing scientists and our community:

1.       Scientists need to study lots of patients with standardized phenotyping to have the statistical power to be able to link different mutations with different outcomes.  These links are sometimes referred to as genotype-phenotype relationships.  It could take 100s of individuals with carefully collected data to understand these possible relationships.

2.       But, even beyond the FOXP1 gene change, we need to understand other possible genome variations that could have exacerbating or mitigating effects on how an individual’s FOXP1 change affects them.  These variations could be mutations in other genes, different “metagenomic” effects that affect how other genes are expressed even if not mutated, and many other phenomena.


3.       Finally, there are random events in every individual’s life that affect how the brain and other parts of the body develop and are “wired up.”  These can be extremely subtle and difficult to study, including environmental effects and even random events at the molecular level for normal proteins and systems – but they can be very influential on the final outcome/presentation.

Especially for issues #1 and #2, this is why it is so important to continue participating in research studies.  As Dr. Eichler put it, “It is important to … not stop the genetic odyssey at simply an exome or microarray result -- ie [it’s important to also be] building a biobank of material for subsequent DNA, RNA, methylation etc. analyses.”  There are at least 2 ways you and your family can contribute to research:


1.       Participate in the Foundation’s RareX data collection program and potentially other research efforts too.  These data will help build our understanding of FOXP1 syndrome, especially for individuals at different developmental stages (including following individuals over time to see how they develop – the natural history study)

2.       Provide samples for research (cells, genetic material, scans, etc.). Some of this can be biobanked in freezers, to use for possible future analyses as new insights and techniques emerge.  This is something the International FOXP1 Foundation is actively investigating.

Question: What are the differences between cross-sectional and longitudinal studies; how is a longitudinal study designed and what is it good for (eg, designing clinical study and its endpoints); and what are some "insight" exit ramps -- to help the community understand how often results can be collected and shared out from a longitudinal study?

Answer: (Answered by Dr. Paige Siper, Chief Psychologist at Seaver Autism Center)

Cross-sectional studies and longitudinal studies represent two different types of research design. Cross-sectional studies examine a cohort of individuals at one time point while longitudinal studies examine the same cohort across multiple time points. To date, the clinical characteristics of FOXP1 syndrome are described through cross-sectional studies, which provide a snapshot into the syndrome, including estimates of a variety of features. These initial cross-sectional studies offer important information to inform future studies. Longitudinal studies are now a critical next step to achieve larger goals including gaining a better understanding of FOXP1 syndrome trajectories and developing targeted treatments. Through an examination of individual changes over time, optimal outcome measures, also referred to as endpoints, can be identified. Longitudinal data is then used to determine appropriate clinical trial endpoints, which are necessary to assess the efficacy of a given therapy. Within other rare disease networks, longitudinal natural history studies are generally following participants annually over a given period of time (e.g., 3-5 years).  Depending on the specific research question, age of enrollment can be very broad (e.g., 12 months through adulthood) or narrower to capture specific periods of development. Given that natural history studies can be brief or last decades, a data analysis plan is made ahead of time to determine various points of data analysis.

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