Autism Spectrum Disorders via the FOXP1 Gene

Autism Spectrum Disorders (ASD) encompass several neurodevelopmental disorders characterized by varying degrees of social impairment, communication ability, and propensity for restricted interests and repetitive behavior(s) which usually present by age 3. Diagnosis is based on the degree and severity of symptoms and behaviors (Diagnostic and Statistical Manual of Mental Disorders (DSM-5); Levy et al. 2009; McPartland et al. 2016). Comorbidities occur in more than 70% of cases and include intellectual disability (ID), epilepsy, language deficits, and gastrointestinal problems (Sztainberg and Zoghbi 2016). ID specifically refers to significant impairment of cognitive and adaptive development (intelligence quotient, IQ<70) due to abnormalities of brain structure and/or function (American Association of Intellectual and Developmental Disabilities, AAIDD). ID is not a single entity, but rather a general symptom of neurologic dysfunction that is diagnosed before age 18 in ~1-3% of the population (Kaufman et al. 2010; Vissers et al. 2016).

The FOXP1 gene has been implicated in sporadic ASD and ID cases and is associated with global developmental delay with moderate to severe language impairment. Specifically, expressive speech impairment and consonant expression is a hallmark trait of individuals with FOXP1-associated ASD and ID (Le Fevre et al. 2013). Facial features include broad forehead, down-slanting or narrow palpebral fissures, short nose with a broad tip, macrocephaly (variable), frontal upsweep of hair, and prominent fingertip pads. Less common features include widely spaced eyes, ptosis of eyelids, smooth philtrum, sparse lateral eyebrows, and epicanthus (Lozano et al. 2015; Le Fevre et al. 2013; Hamdan et al. 2010).

FOXP1 is a member of the human FOX gene family defined by a DNA binding forkhead box (FOX) domain and involvement in immunological, hematological, and embryological development. FOXP1 is enriched within the brain, including the neocortex, hippocampus, and striatum (Ferland et al. 2003; Teramitsu et al. 2004) and is expressed ubiquitously throughout the central nervous system (Teramitsu et al. 2004). Mouse studies have shown a potential role of FOXP1 in control of motor neuron migration and axon trajectory choice (Palmesino et al. 2010). Members of the FOXP subfamily bind DNA as a homo- or heterodimer. For example, FOXP1 has been shown to work cooperatively in mice with FOXP2, which is also implicated in ASD and ID phenotypes (Le Fevre et al. 2013; Shu et al. 2007). Numerous isoforms of FOXP1 have been described, with the most inclusive transcript encompassing 21 exons, of which exons 6-21 are protein coding (Brown et al. 2008).

FOXP1 pathogenic variants are almost exclusively de novo and include whole and partial gene deletions, translocations, missense, nonsense, and frameshift variants. FOXP1-associated ASD and ID features are inherited in an autosomal dominant manner, likely through haploinsufficiency. At least one study has reported dominant negative effects of abnormal FOXP1 protein product impacting both wild type FOXP1 and FOXP2 protein translocation into the nucleus (Lozano et al. 2015).

Currently, the contribution of de novo and inherited factors to Autism Spectrum Disorders (ASD) risk is estimated to be approximately 50-60% (Krumm et al. 2015) and 25-50% for intellectual disability (ID), with the percentage increasing proportionately with phenotypic severity (McLaren and Bryson 1987). FOXP1 is classified in the Simons Foundation Autism Research Initiative (SFARI) Database as a ‘strong candidate’ gene regarding ASD risk (https://gene.sfari.org/database/human-gene/FOXP1). However, more than 700 genes total have been associated with ASD features (Bourgeron 2016). One comprehensive study investigating shared clinical features of individuals with FOXP1 putative causative variants from multiple studies described 10 individuals (Le Fevre et al. 2013), however the SFARI gene database indicates there have been as many as 24 reports of affected individuals, half of which were also diagnosed with ASD (https://gene.sfari.org/database/human-gene/FOXP1).

Overall, de novo copy number variants (CNVs) are estimated to account for approximately 6% of ASD risk (Lim et al. 2013). The contribution of FOXP1 CNVs specifically is unclear; however, 3p interstitial deletions that encompass either solely FOXP1 or additional genes within this region have been reported by multiple sources (Le Fevre et al. 2013; Palumbo et al. 2013; Horn et al. 2010; Carr et al. 2010; Pariani et al. 2009). Individuals with large deletions affecting FOXP1 and additional genes share broad forehead, short, broad nose, and macrocephaly phenotypes with those having deletions affecting FOXP1 exclusively, suggesting these features may be specific to FOXP1 disruption (Le Fevre et al. 2013).

This test provides full coverage of all coding exons of the FOXP1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).