The emerging face of FOXG1 Syndrome: a rare, genetically defined neurodevelopmental disorder coming of age in the genomics era.

doi:10.21203/rs.3.rs-4949811/v1

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Systematic Review

The emerging face of FOXG1 Syndrome: a rare, genetically defined neurodevelopmental disorder coming of age in the genomics era.

https://doi.org/10.21203/rs.3.rs-4949811/v1

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Background and Objectives

FOXG1 Syndrome was first identified in 2005 and has been closely associated with Rett Syndrome. However, with access to genetic testing an increasing number of patients have been identified that do not fulfill Rett Syndrome clinical criteria. Utilizing genetic surveys of large, severe neurodevelopmental disease (NDD) cohorts, we provide the first prevalence estimates of FOXG1 Syndrome independent of Rett Syndrome clinical criteria.

Methods

We performed a systematic review and meta-analysis of studies conducting extensive genetic testing on cohorts of severe neurodevelopmental patients within the last ten years. Fourteen studies were included, after exclusion of outliers biased for FOXG1 patients, providing analysis of over 36,000 severe neurodevelopmental disease pediatric patients in total.

Results

FOXG1 patients accounted for 0.20% [95% CI: 0.15–0.25%] of severe NDD pediatric patients. MECP2 and CDKL5 patients accounted for 0.54% [95% CI: 0.47–0.62%] and 0.35% [95% CI: 0.29–0.41%], respectively. This results in an estimated prevalence of 0.6–2.2 FOXG1 patients per 100,000 children or ~ 430–1600 patients in the United States. The estimated prevalence of CDLK5 patients was 2.1–7.7 cases per 100,000 female children, and the estimated prevalence of MECP2 patients was 3.2–11.9 cases per 100,000 female children.

Conclusions

Estimated prevalence of MECP2-driven severe NDD was comparable to estimates based on Rett Syndrome clinical criteria. Similarly, CDKL5-driven NDD were also comparable to an earlier study. However, prevalence estimates for FOXG1-associated severe NDD were ~ 10 times higher than expected if limited to reports based on Rett Syndrome clinical criteria. This data further supports that both FOXG1 Syndrome and CDKL5 deficiency represent distinct and sizable patient populations as compared to MECP2-associated Rett Syndrome. These findings have immediate implications for improved diagnosis of these patients and highlight the benefits of genetic testing in identifying them.

FOXG1

Rett Syndrome

MECP2

CDKL5 deficiency

genetic testing

rare disease prevalence

Approximately 6000 of the estimated 10000 total rare diseases are associated with genetic etiologies, and improved mapping of the genes responsible for many indications has led to an increase in the number of defined, specific rare diseases^1,2. Nevertheless, it remains very challenging to quantify these emerging patient populations and this can seriously hamper efforts to understand the underlying disease processes and to develop innovative therapies for these indications³.

FOXG1 Syndrome is one such example of a more recently characterized rare disease. It was first recognized in 2005 in a female patient presenting with microcephaly, cognitive impairment, and agenesis of the corpus callosum⁴. FOXG1 Syndrome is characterized by severe global developmental delay, microcephaly, speech/motor dysfunction, and is often associated with seizures; the disease is attributed to de novo autosomal dominant mutations in the Forkhead Box G1 (FOXG1) gene⁵ (ORPHA: 561854). FOXG1 belongs to the transcription factor family containing the Forkhead domain. Many FOX genes regulate developmental processes including the formation of cerebral neural patterns and stimulate neurogenesis, cell proliferation, and somatic differentiation. Specifically, FOXG1 plays a crucial role in Cajal-Retzius cell formation and forebrain development^6–10. In mice, deletion of the FOXG1 gene results in a marked reduction of the cerebral hemispheres partly due to reduced proliferation and precocious differentiation of FOXG1-deficient neural progenitors^7,11. Patients with a deleterious mutation in one allele of the FOXG1 gene have previously been diagnosed as a congenital variant of Rett Syndrome. Despite the potential overlap of clinical features in some cases, FOXG1 Syndrome patients are readily differentiated in recent years from Rett Syndrome by the increased application of genetic testing. To date, FOXG1 Syndrome has been reported in nearly one thousand patients worldwide, with a theoretical birth incidence based on mutational burden of 1 in ~ 30,000 live births¹². To help further disentangle FOXG1 Syndrome from Rett Syndrome, we conducted a systematic review and meta-analysis of severe neurodevelopment disease (NDD) patients undergoing genetic testing, and present the first estimates of FOXG1 Syndrome prevalence, independent of Rett Syndrome clinical criteria.

Systematic literature review.

Given the limited pool of literature available on FOXG1 patients, we utilized a deductive search strategy by searching for “FOXG1” or “forkhead G1” and excluding cancer, oncology and neoplasm (including expanded MESH terms) in PubMed. We further filtered human studies to generate our scoping pool of 291 papers for initial review (Fig. 1). Study abstracts were reviewed in duplicate by two independent assessors. Inclusion criteria for subsequent meta-analysis were human studies, including observational studies, patient registries and cohorts of patients diagnosed with severe neurodevelopmental disorders AND genetic testing for at least FOXG1, MECP2 and CDKL5. Case studies, reviews, randomized clinical trials, and animal studies were excluded, and potentially duplicating studies were identified to include only the most recent results (e.g. reports from the ongoing Deciphering Developmental Disorders Study). Studies with specific inclusion based on Rett Syndrome clinical features were also excluded from the meta-analysis for severe NDD but informed our estimates for populations based on Rett clinical criteria. Following an initial scoping review, iterative searching was also supported by artificial intelligence platform Semantic Scholar (www.semanticscholar.org) by submitting included papers from the initial scoping as a ‘look-a-like’ training set. See the summary of fourteen studies for neurodevelopmental disorders included in the meta-analysis in supplementary table 1^13–25.

Meta-analysis of genetic diagnosis in severe neurodevelopmental disease.

Determining prevalence rates for rare diseases has many challenges, not the least for recently recognized indications such as FOXG1 Syndrome. FOXG1 Syndrome diagnosis is confirmed by the identification of a de novo pathogenic mutation in the FOXG1 gene. Therefore, we performed a meta-analysis of primarily pediatric cohorts with severe neurodevelopmental disorders undergoing genetic testing for a broad panel of genes including, but not limited to, FOXG1, CDKL5, and MECP2 sequencing. Bias was assessed by Funnel Plot (Fig. 2A). The estimate of pooled prevalence with the 95% confidence interval was calculated by inverse variance with fixed effect weighting²⁶. Heterogeneity of studies was assessed by calculating I² as previously described²⁷ and was 73.2% (95% CI: 49.8–83%) for FOXG1 meta-analysis. This was unsurprising given the wide range of cohort sizes. Consequently, we also provided pooled prevalence calculations using random effects modelling²⁸ for comparison, as well as calculating pooled prevalence with only larger studies of 300 subjects or more (supplemental Fig. 1).

To determine a sufficient sample size required to reliably describe minority populations within the broader pool of severe neurodevelopmental disorders, we considered not more than 1% of children in the United States to have severe NDD. We also postulated our target population may be only 0.2% (± 0.1%) of the total population of severe NDD pediatric patients. Based on Gaussian distribution and applied as described²⁹, we determined that the minimum sample size required was approximately 7,600. All calculations described in this analysis were done in StatsDirect (v3.3.6).

Meta-analysis of patients with severe neurodevelopmental disorders, developmental and epileptic encephalopathies (DEE) and related phenotypes undergoing genetic testing, including FOXG1 sequencing.

To estimate the total number of FOXG1 patients independent of Rett clinical criteria, we conducted a systematic review of the literature to perform a meta-analysis of patients undergoing genetic testing as part of their diagnostic journey for severe neurodevelopmental disorders. Ultimately, we identified 14 publications sequencing FOXG1 as part of a larger cohort of neurodevelopmental disorders as described in the Methods. To minimize bias, we also included data from the international Epi25 Collaborative DEE subcohort, despite no FOXG1 patients reported in this cohort^30,31. We plotted the margin of error (half-length of the 95% CI) by the proportion of FOXG1 patients found per study in a funnel plot to identify potential outliers (Fig. 2A). We noted the international study of hyperkinetic movement disorders with neurodevelopmental delay was enriched for FOXG1 patients³² and was omitted from further analysis.

We expect ≤ 1% of children to experience severe neurodevelopmental delay or intellectual disability³³, and given the breadth of phenotypes encompassed in severe NDD we observe FOXG1 patients are only a small fraction of this group. To adequately represent FOXG1 patients, which may comprise as little as 0.2% (± 0.1%) of this broader severe NDD pediatric patient population, we require a survey size of at least 7,600 patients in the United States. In total, we compiled results from over 36,000 patients (primarily children) undergoing extensive genetic testing due to severe NDD (Fig. 2B), half of which were reported in the United States.

The pooled proportion of FOXG1 patients within the NDD meta-analysis was 0.20% [95% CI: 0.16–0.25%] (Fig. 2C). For comparison we also examined the proportion of MECP2 and CDKL5 patients identified within the largest cohorts (see supplemental Fig. 1) and calculated the pooled proportions of MECP2 and CDKL5 as 0.54% [95% CI: 0.47–0.62%] and 0.35% [95% CI: 0.29–0.41%], respectively.

Estimated total prevalence of FOXG1 pediatric patients within the United States as compared to MECP2 and CDKL5 deficiency pediatric patients.

Since the studies we compiled are primarily composed of pediatric patients, we restricted our patient estimates to children under the age of 18 years. Congenital abnormalities and developmental disorders are expected to occur in 2–5% of all children³⁴, or more when including autism spectrum disorder and ADHD³⁵. However, severe intellectual disability or neurodevelopmental delay is less common³³. According to the CDC, non-exclusive diagnosis of intellectual disability and/or epilepsy was reported in a parent/caregiver survey for 1.1% and 0.77% respectively in children aged 3–17 years of age in the United States³⁵. Similarly, only 1 in 340 children (or 0.3%) were reported with DEE or intellectual disabilities plus epilepsy in a recent study in New Zealand³⁶, and a study of severe to moderate intellectual disability across Europe reports prevalence estimates of 0.3–0.5% of children between the ages of 6 and 8³⁷. Consequently, we considered a conservative, lower bound estimate of severe NDD of 0.3% and an upper bound estimate of 1.1% of all children in the US to calculate FOXG1, MECP2 and CDKL5 patient prevalence.

Based on this approach, we estimate the prevalence of MECP2 pediatric patients in the United States is between 1,200–4,300 children under the age of 18 years (Fig. 3). These MECP2 + children are expected to be primarily female and presenting with Rett Syndrome but should also include patients with non-Rett severe intellectual disabilities³⁸. This is comparable to previous estimates of Rett Syndrome based on clinical criteria³⁹, of which approximately 90% are expected to be attributed to MECP2 mutations^40–48. In the same manner we estimated the number of CDKL5 and FOXG1 children in the United States. The estimated number of CDKL5 deficiency patients under the age of 18 in the United States is 750–2800 children (Fig. 3). The majority are also expected to be female. The estimated number of FOXG1 pediatric patients in the United States is between 430-1,600, and we expect a balanced female to male ratio for this autosomal dominant disease (Fig. 3).

Our approach to estimate the prevalence of FOXG1 Syndrome and CDKL5 deficiency independent of Rett Syndrome clinical criteria is only enabled by the extensive genetic testing of large cohorts of NDD patients primarily conducted in the last five years, thereby minimizing bias introduced by our search strategy focused on FOXG1. This also allows us to estimate the number of patients based on genetic etiology without defining strict phenotypic criteria a priori. This is particularly important as we continue to characterize these rare patient populations and understand the variability and overlap of clinical presentation within these patient groups. This also reflects the transition to genetics-led diagnostics.

This meta-analysis approach focused on genetic testing is also supported by the comparable estimates between MECP2 + NDD patients and Rett Syndrome patients due to MECP2 variants (Table 1). Not surprisingly, the patient estimates based on genetic etiology alone are slightly higher than the estimates of MECP2 driven Rett Syndrome specifically. This is likely due to the broader representation of phenotypes in the severe NDD cohorts, also including non-Rett/MECP2 + patients with NDD³⁸.

Table 1

Prevalence ratios and associated disorders for MECP2, CDKL5, and FOXG1 variants.
Gene	Prevalence ratio [estimate range]	Previously reported prevalence [95% CI]	Associated Disorders (ORPHA codes)
MECP2	3.2–11.9 per 100,000 female children	7.1 [4.8–10.5] per 100,000 female children³⁹	Rett Syndrome (778); Atypical Rett Syndrome (3095); Severe neonatal-onset encephalopathy with microcephaly (209370); Autism (106); X-linked intellectual disability-psychosis-macroorchidism syndrome (3077)
CDKL5	2.1–7.7 per 100,000 female children	4.4 [1.5–10.3] per 100,000 female children⁴⁹	CDKL5 deficiency (505652); Atypical Rett Syndrome (3095); Early infantile epileptic encephalopathy (1934)
FOXG1	0.6–2.2 per 100,000 children		FOXG1 Syndrome (561854); Atypical Rett Syndrome (3095); non-specific early-onset epileptic encephalopathy (442835)
Supplemental Table 1: Overview of studies of severe neurodevelopmental disorders included in the final meta-analysis for FOXG1

When we evaluate FOXG1 patients based on genetic etiology and independent of Rett Syndrome clinical criteria, we observe a significantly higher proportion of patients than may be otherwise expected. Prevalence estimates based on genetic testing show an approximate tenfold higher number of FOXG1 patients as compared to estimates limited to Rett Syndrome clinical criteria. We observe similar findings for CDKL5 patients and our analysis is also comparable to the previously published prevalence estimates of CDKL5 deficiency (Table 1)⁴⁹.

There are several limitations to our current analysis. One overarching challenge is the limited information concerning the overall prevalence of severe NDD in children on which to base the genetic distribution of patients. Better understanding of the burden of severe NDD in general would help us refine our specific patient number estimates. Another limitation of the genetics-lead approach is we have less information about the phenotypic characteristics of the patients as reported in the literature and therefore expect to capture a broader spectrum of disease under the severe NDD umbrella of symptoms. We rely on natural history studies to further characterize the spectrum of clinical presentation in FOXG1 Syndrome⁵. Furthermore, we are unable to estimate the subgroups of patients that may be the result of large insertion/deletions or copy number variants, which can also have overlapping features with FOXG1 Syndrome. While these were assessed in several of the studies, they were not specifically reported, and in some studies, they were expressly excluded (supplemental Table 1). Studies specifically focused on these types of large variants suggest that they may contribute as much as 16% to DEE populations⁵⁰. Additional technical limitations, such as challenges in determining if a variant is disease-causing, contribute to lack of diagnosis in many cases, and an underestimate of disease prevalence.

Nevertheless, this data shows both FOXG1 Syndrome and CDKL5 deficiency represent distinct and sizable patient populations as compared to MECP2-driven Rett Syndrome. This work further supports the observations that there is limited overlap for the majority of FOXG1 Syndrome patients or CDKL5 deficiency patients with Rett clinical criteria. This also has immediate implications for the diagnosis of these patients, as physicians should consider the increased possibilities for encountering them and the need to utilize more genetic testing to close the diagnosis gap for genetic etiologies of severe neurodevelopmental diseases. Better characterization of these patients will improve our understanding of the biological drivers of disease and accelerate the development of innovative therapies for these unique patient groups.

Acknowledgements:

We kindly thank David Lapidus for critical review of the analysis and informed feedback. This analysis was conducted on behalf of the FOXG1 Research Foundation.

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The authors declare potential competing interests as follows: Dr. Soo-Kyung Lee serves as Chief Scientific Officer for the FOXG1 Research Foundation. Dr. Jae Lee and Dr. Karen E. Malone belong to the scientific advisory board for the FOXG1 Research Foundation.

SupplementalFigure1.MetaanalysisforMECP2andCDKL5.gif
(A) Summary of estimated pooled prevalence results from meta-analysis for the indicated genes as calculated by fixed effects modeling or random effects modeling. (B) Heterogeneity of studies informed by I², including 95% confidence intervals, for each gene investigated. (C) Forest plot of meta-analysis for MECP2+ patients in severe neurodevelopmental disorder studies. (D) Forest plot of meta-analysis for CDKL5+ patients in severe neurodevelopmental disorder studies.
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The emerging face of FOXG1 Syndrome: a rare, genetically defined neurodevelopmental disorder coming of age in the genomics era.

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