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:

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 hundreds of individuals with carefully collected data to understand these possible relationships.

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.

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 — i.e. [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:

• A) Participate in the Foundation’s RARE-X 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).
• B) 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.

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.

This article reports on a person who has FOXP1 syndrome for the same reason as many of our kids do — lack of complete and functional FOXP1 protein. The interesting twist in this case is that the lack of FOXP1 protein comes about in a different way than what has happened for many of our kids.

To step back a bit, the general rule for gene expression is that the final protein is produced when the cell machinery reads a messenger RNA (mRNA) from front to back to determine what amino acids to assemble into the protein, which is very important for its biological function. This mRNA is created from a specific portion of the DNA — a gene — and contains the genetic information that allows synthesis of the protein it codes for. However, it is not functional as it comes due to the presence of regions that must be removed (introns) before getting a mature mRNA. The resulting mRNA is basically a string of the remaining regions (exons) that are retained when the introns are removed, in a fundamental process known as splicing. This delicate process involves the recognition of specific genetic code in the mRNA that marks the beginning and end of each intron, and mutations in these sequences can alter the way that the cell machinery generates the mature mRNA.

This person’s mutation is in one of the splicing sites. With the mutation, the splicing machinery gets messed up and leads to an erroneous mRNA that entirely lacks Exon 18, generating a truncated protein sequence.

In the normal FOXP1 gene, there are 21 exons that encode the different functional parts of the protein; for example, exons 8–9 encode the gene-expression repressor region, exons 12–14 encode the dimerization region (for binding between two FOXP proteins), and exons 16–18 encode the region that binds to the DNA of many genes in the genome to later control their expression. Without that functional Exon 18, the mutant protein cannot do its job due to a truncated non-functional DNA-binding region.

Even when the mutation affects an intron — and therefore is different from many others that have been described, which result from deletion of a whole chunk of the genome around FOXP1 or point mutations within an exon that directly cause aberrant protein sequences — at the end of the day, all these mutations result in insufficient levels of functional FOXP1 protein, also known as haploinsufficiency.