Diagnostic testing, type of mutations
The diagnosis of a FOXP2-related condition is established by detection of one of the following:
- Large non-recurrent contiguous gene deletion that includes FOXP2 (~52% of affected individuals).
- Sequence variant within FOXP2 (~29%).
- Maternal uniparental disomy of chromosome 7 (UPD7) that reduces FOXP2 expression (~11%).
- Structural variant that disrupts FOXP2 (~8%).
Molecular genetic testing approaches can include gene-targeted testing (multigene panel or single-gene testing) or genomic testing (chromosomal microarray [CMA] and comprehensive genomic sequencing) depending on the phenotype. Gene-targeted testing requires determining which gene(s) are likely to be involved. Probands with distinctive findings (see the Professionals – Clinical characteristics section) are likely to be diagnosed using gene-targeted testing, whereas a more severe phenotype such as developmental delay (DD)/intellectual disability (ID) is more likely to be diagnosed using genomic testing, as it may be indistinguishable from other inherited disorders with this broader profile.
Genetic counseling
Genetic counseling for a FOXP2-related condition depends on the causative genetic alteration.
Large Non-Recurrent Contiguous Gene Deletion including FOXP2
- Parents: The majority of deletions are de novo, but evaluation of the parents by genomic testing is recommended.
- Siblings: If the deletion in the proband is not in one of the parents, the empiric recurrence risk to siblings is around 1%; due to the possibility of parental germline mosaicism. If one parent has the same deletion as the proband, the inheritance risk of the deletion for each sibling is 50%. The proband’s offspring have a 50% chance of inheriting the deletion.
Sequence Variant within FOXP2
- Parents: Based on a survey of current literature, 30% of individuals with a sequence variant within FOXP2 have an affected parent; 70% of have a de novo variant. Molecular genetic testing is recommended for the proband’s parents to identify whether the variant was inherited or de novo. If the proband’s FOXP2 pathogenic variant cannot be detected in leukocyte DNA of either parent, the proband may have a de novo FOXP2 pathogenic variant, or they may have inherited the variant due to germline mosaicism in a parent.
- Siblings: If a parent has the FOXP2 pathogenic variant, the risk to siblings of inheriting the variant is 50%. If the FOXP2 pathogenic variant cannot be detected in either parent, the risk to siblings is approximately 1%, due to the possibility of parental germline mosaicism. When parents are clinically unaffected, the risk to the proband’s siblings is low. Offspring of a proband have a 50% chance of inheriting the FOXP2 sequence variant.
Structural Variant
- Parents: Evaluation of the parents by karyotyping will detect the structural variant present. The proportion of parents carrying a structural variant is currently unknown.
- Siblings: The risk to the siblings of the proband depends on the genetic status of the parents. If one parent has the structural variant seen in the proband, the risk to siblings is increased and depends on the specific structural variant.
- Offspring: Risk to offspring depends on the specific structural variant.
- Other: If a proband’s parent has the FOXP2 genetic alteration, the parent’s family members may be at risk.