DDX3X syndrome: from clinical phenotypes to biological insights

Abstract

DDX3X syndrome is a neurodevelopmental disorder accounting for up to 3% of cases of intellectual disability (ID) and affecting primarily females. Individuals diagnosed with DDX3X syndrome can also present with behavioral challenges, motor delays and movement disorders, epilepsy, and congenital malformations. DDX3X syndrome is caused by mutations in the X-linked gene DDX3X, which encodes a DEAD-box RNA helicase with critical roles in RNA metabolism, including mRNA translation. Emerging discoveries from animal models are unveiling a fundamental role of DDX3X in neuronal differentiation and development, especially in the neocortex. Here, we review the current knowledge on genetic and neurobiological mechanisms underlying DDX3X syndrome and their relationship with clinical phenotypes.

Graphical abstract:

DDX3X syndrome is a neurodevelopmental disorder caused by mutations in the X-linked RNA helicase DDX3X. The syndrome displays an X-linked semi-dominant pattern of inheritance and broad clinical presentations. Studies in mouse models have uncovered critical functions of DDX3X in the molecular and cellular processes that orchestrate the development of the cerebral cortex.

Intellectual disability (ID) is a prevalent neurodevelopmental disorder with no effective pharmacological treatments. Dozens of novel risk genes associated with ID have been identified (Martin et al. 2021; Kaplanis et al. 2020; Deciphering Developmental Disorders 2015; Deciphering Developmental Disorders Study 2017). Among these is the X-linked RNA helicase DDX3X, which was first associated with neurodevelopmental disorders in 2015 (DDX3X syndrome) (Snijders Blok et al. 2015; Deciphering Developmental Disorders 2015).

DDX3X mutations are now considered a leading cause of ID, accounting for up to 3% of cases in the female population (Snijders Blok et al. 2015; Deciphering Developmental Disorders 2015). DDX3X also meets genome-wide significant associations with autism spectrum disorder (ASD) (Ruzzo et al. 2019; Turner et al. 2019). Individuals with DDX3X mutations can present with an array of comorbidities, including epilepsy, congenital brain and cardiac malformations, behavioral alterations including ASD, motor delays, and movement disorders (Levy et al. 2023; Parra et al. 2024; Snijders Blok et al. 2015; Lennox et al. 2020; Wang et al. 2018; Tang et al. 2021).

Here we provide an overview of DDX3X syndrome, including its genetic underpinnings, the spectrum of associated clinical manifestations, and the biological mechanisms emerging from experimental models. The molecular functions of DDX3X, including insights from non-neural tissues, have been extensively covered elsewhere (Ryan & Schroder 2022; Gadek et al. 2023). In this review, we seek to illuminate the gaps in our knowledge of DDX3X role in neurodevelopment to advance our understanding of the mechanisms underlying the syndrome and chart future directions.

The genetic architecture of DDX3X syndrome

DDX3X is located on p11.4 of the X chromosome. In therian mammals, females have two X chromosomes (XX karyotype) and males have one X chromosome and one Y chromosome (XY karyotype). To ensure dosage compensation of X-linked genes between the sexes, an epigenetic mechanism known as X-chromosome inactivation (XCI) has evolved in eutherian mammals (Loda et al. 2022). Through XCI, one of the X chromosomes in female cells is randomly inactivated early during embryonic development (although with different timing and mechanisms between humans and mice) (Loda et al. 2022). This process leads to a form of tissue mosaicism in X-linked allelic expression between cells (Loda et al. 2022). As a result, despite having two X chromosomes, XX cells express genes from only one. However, ~23% of human genes on the X chromosome evade XCI, either constitutively or with a tissue-specific or developmental pattern (Tukiainen et al. 2017). Some of these escapees have a homologous gene on the Y chromosome, which can provide dosage compensation, but not necessarily in all tissues and/or developmental windows (Arnold 2022).

DDX3X belongs to this group of X-linked genes, as it escapes XCI in both human and mouse (Borensztein et al. 2017; Tukiainen et al. 2017; Boitnott et al. 2021) and has an homologous gene on the Y chromosome, DDX3Y. Although DDX3X and DDX3Y proteins share 92% amino acid sequence similarity, it is not clear how much their expression profiles and functions overlap (Shen et al. 2022; Venkataramanan et al. 2021). In humans, DDX3Y expression seems to be restricted in pre-meiotic male germ cells (Ditton et al. 2004; Vogt et al. 2022). In line with this male-specific expression, mutations or deletions in DDX3Y lead to infertility or subfertility (Foresta et al. 2000; Dicke et al. 2023), without reported cognitive impairments.

DDX3X is highly intolerant to detrimental genetic variation in the general population (Chen et al. 2024), indicating strong selective pressure on this gene. Germline mutations in DDX3X can cause DDX3X syndrome and can be detected when screening cohorts ascertained for ID/developmental delay (Deciphering Developmental Disorders 2015; Deciphering Developmental Disorders Study 2017; Martin et al. 2021; Wang et al. 2020), ASD (Ruzzo et al. 2019; Satterstrom et al. 2020; Fu et al. 2022; Turner et al. 2019; Iossifov et al. 2014; Yuen et al. 2017; Takata et al. 2018; Zhou et al. 2022), severe childhood speech disorder (Hildebrand et al. 2020), or cerebellar malformations (Aldinger et al. 2019).

DDX3X mutations follow a semi-dominant mode of inheritance (Martin et al. 2021), whereby heterozygous females are affected, and hemizygous males rarely survive because of lethality. In fact, most patients with DDX3X mutations are females with de novo nonsense/frameshift mutations causing haploinsufficiency or missense/in-frame mutations (Snijders Blok et al. 2015; Lennox et al. 2020; Levy et al. 2023). No male cases with loss-of-function mutations have been reported so far, and the few reported males with DDX3X syndrome typically inherit missense mutations from apparently asymptomatic mothers (Snijders Blok et al. 2015; Lennox et al. 2020; Levy et al. 2023; Kellaris et al. 2018). Mutations in males are seldomly tolerated, as exemplified by the clinical history of a mother of a boy with a maternally inherited DDX3X mutation reported by Snijders Blok et al. 2015. The woman had a history of recurrent miscarriages of unknown gender and a second pregnancy that was terminated because of sonographic detection of thickened nuchal fold and absent nasal bone, which had also been noted during the previous pregnancy with the son later diagnosed with DDX3X syndrome (Snijders Blok et al. 2015). Genetic testing after termination revealed that the male fetus had the same DDX3X missense mutation of his brother (Snijders Blok et al. 2015).

In line with the genetic evidence, functional analyses using an in vivo complementation essay in zebrafish suggest that DDX3X mutations found in males act as hypomorphic alleles (Snijders Blok et al. 2015; Kellaris et al. 2018). Expression of a human wild-type DDX3X worsens a ventralization phenotype induced by the expression of the canonical Wnt ligand WNT3A in zebrafish embryos. Expressing mutant DDX3X proteins carrying female-pathogenic mutations can obliterate this exacerbation. Male-pathogenic mutants have no effect, indicating that they do not lead to the complete loss of function of DDX3X (Snijders Blok et al. 2015; Kellaris et al. 2018).

Genotype-phenotype relationships have also begun to emerge (Gadek et al. 2023). One of the earliest hypotheses for the significant variability in the clinical manifestations (which we discuss below) is skewed XCI, namely preferential inactivation (>80%) of one of the two X chromosomes. Skewed XCI can protect female carriers of X-linked recessive variants (i.e., asymptomatic mothers of affected males) or, on the opposite, unmask these variants leading to variable penetrance (affected females). The latter has been reported in 7-12% of females with neurodevelopmental disorders (Fieremans et al. 2016; Giovenino et al. 2023). Skewed XCI can influence the penetrance of variants on genes escaping XCI, because of variability in escape (Tukiainen et al. 2017). A systematic assessment of XCI status in DDX3X syndrome has not been conducted. However, Snijders Blok and colleagues tested XCI in 15 females, and found extreme skewing (>95%) in 7/15 (Snijders Blok et al. 2015), which is significant given that skewing is rare in the general population (Fieremans et al. 2016; Giovenino et al. 2023). However, no conclusive correlations between XCI status and clinical phenotype could be drawn (Snijders Blok et al. 2015).

More robust genotype-phenotype correlations are delineated by the type of DDX3X mutation. In fact, patients with a subset of missense mutations are more likely to have polymicrogyria (PMG), which is characterized by abnormally dense or small gyri and is detected in 12% of individuals with DDX3X mutations (Lennox et al. 2020). PMG is also correlated with more severe clinical outcomes. For example, individuals with PMG are more likely to have microcephaly (70% in PMG vs 34% in non-PMG), partial agenesis of the corpus callosum (27% in PMG vs 1% in non-PMG) and cardiac findings (see discussion below) (Lennox et al. 2020). In line with these observations, Tang et al., 2021 also showed that patients with missense/in-frame mutations presented with more severe clinical phenotypes than those with nonsense/frameshift mutations (Tang et al. 2021). For example, when comparing full scale the Intelligence Quotient (IQ), non verbal IQ, verbal IQ and developmental quotient (DQ), Tang et al., found that the group of individuals with nonsense/frameshift mutations had significantly higher DQ scores compared to the missense/in-frame group (Tang et al. 2021). Similarly, the nonsense/frameshift carrier group had significantly higher scores in multiple areas, including communication, language, and motor domains. Experiments on exogenously expressed DDX3X mutant proteins suggest that the missense mutations associated with PMG and more severe clinical outcomes induce the formation of RNA granules (Lennox et al. 2020), potentially leading to a gain of function.

All together, the genotype-driven phenotypes alongside the experimental observations suggest that there might be more than one pathological mechanism at play, which will be critical to examine in future studies aiming at therapeutic developments.

Clinical manifestations associated with DDX3X syndrome

DDX3X syndrome is associated with a range of clinical manifestations, including neurodevelopmental challenges, behavioral issues, motor problems, sensory processing abnormalities, and congenital malformations (Levy et al. 2023; Parra et al. 2024; Lennox et al. 2020; Tang et al. 2021; Snijders Blok et al. 2015; Wang et al. 2018). The clinical profiling of DDX3X syndrome is largely based on data in female patients, given the bias in prevalence. Insights into the syndrome manifestation in male patients therefore are limited and require further investigation.

Neurodevelopmental challenges for affected patients often demand a multifaceted approach to care and intervention. ID/developmental delay range from mild to severe, and affected individuals can also have comorbid ASD and/or ADHD (Levy et al. 2023). In the largest retrospective study to date, 28 of 42 DDX3X patients (67%) were estimated to be above at-risk threshold for ASD (Lennox et al. 2020). In a prospective study, 9 of the 15 (60%) DDX3X patients tested by a trained clinician using gold-standard tools met diagnostic criteria for ASD and 8 (>50%) for ADHD (Tang et al. 2021). As mentioned, phenotypic variability is significant, as demonstrated by a case with monozygotic twins sharing the same DDX3X mutation but discordant symptoms (one twin nonverbal and with ASD, the other twin with verbal language and no diagnosis of ASD) (Levy et al. 2023). Girls and women with DDX3X syndrome have also been reported to have higher rates of anxiety and self-injurious behaviors, as shown by a study on 23 females with DDX3X syndrome compared with a group of females with ID due to other genetic conditions (Ng-Cordell et al. 2023). These observations indicate a pressing need for tailored interventions to address these specific challenges and their evolution during adolescence.

Patients with DDX3X syndrome often have delays in achieving motor milestones. The average age at which children with DDX3X syndrome achieve independent walking ranges from 25 months, with ~13% of them not achieving independent walking (Levy et al. 2023). Additionally, 70-80% of affected individuals have hypotonia and 34% experience hypertonia (Levy et al. 2023). The motor manifestations also differ based on the type of mutations and co-occurrence with PMG. For example, mixed hypotonia/hypertonia was observed in 29% of the non-PMG group but was significantly more common in the PMG group (64%) (Lennox et al. 2020).

Over 80% of individuals have at least one abnormal finding on a clinical brain MRI scan (Lennox et al. 2020; Parra et al. 2024). In the largest retrospective study, 87% presented with corpus callosum malformations visualized on MRI scans ranging from complete to mild agenesis (Lennox et al. 2020). Similarly, 56% of patients in the same cohort were noted to have globally diminished white matter volume (Lennox et al. 2020). As noted above, 12% of patients present with PMG (Lennox et al. 2020). 36% of patients had identifiable lateral “key-hole” shaped ventricles with characteristic enlargement of the temporal horns (Lennox et al. 2020).

Congenital malformations extend beyond the nervous system. Individuals with DDX3X mutations can receive a diagnosis of congenital heart defects (CHD), including atrial septal defects and ventricular septal defects (Wang et al. 2018; Lennox et al. 2020; Dikow et al. 2017; Tang et al. 2021). Based on the medical records of 90 individuals with DDX3X mutations, 13 (14%) had a CHD diagnosis, with five of them requiring surgical repair (Lennox et al. 2020). Within these 90, 10 had a more severe clinical outcome and PMG, and within this more severely affected group, 5 (50%) received a diagnosis of CHD (Lennox et al. 2020).

Other more rare phenotypic presentations include precocious puberty, auditory abnormalities, skin abnormalities, recurrent infections, and sleep disturbances (Levy et al. 2023). While the biological pathways underlying most of these manifestations have yet to be identified, the role of DDX3X in innate immune response, cytokine/chemokine production, and regulation of viral RNAs [e.g., (Samir et al. 2019; Yedavalli et al. 2004)] might contribute to the predisposition to recurrent infections.

Together, these varied phenotypic presentations underscore the broad biological implications of DDX3X mutations. Importantly, the trajectories of DDX3X syndrome have not been mapped, as there are no longitudinal studies to date and the information on adult cases is extremely sparse. The case of a 47-year-old woman who had a late-onset neurological decline, becoming nonverbal and losing the ability to walk or use her arms (Wang et al. 2018), illustrates the importance of capturing the symptomatology of DDX3X syndrome also in the adult population.

DDX3X functions during brain development: lessons from animal models

DDX3X encodes a RNA helicase that belongs to the DEAD/DEAH-box family of RNA helicases, which are multifunctional regulators of RNA metabolism, including splicing, mRNA stability, ribosome biogenesis, mRNA translation, and organization of RNA-containing phase-separated organelles (Bohnsack et al. 2023; Hondele et al. 2019). mRNA translation is finely regulated during brain development (Salamon et al. 2023; Harnett et al. 2022; Duffy et al. 2022), and deficits in these processes have been reported in mouse models of ASD and/or ID (De Rubeis et al. 2013; Santini et al. 2013; Gkogkas et al. 2013; Seo et al. 2022; Salamon et al. 2023). Therefore, it is not surprising that other DEAD/DEAH-box RNA helicases have also been implicated in ASD and ID (Paine et al. 2019; Balak et al. 2019; Lessel et al. 2017; Calame et al. 2023)

Functional studies using animal and cellular models are beginning to unveil the mechanisms underlying DDX3X syndrome. In mice, Ddx3x is necessary for placentation and embryonic development (Chen et al. 2016). Functional studies introducing germline mutations (crossing a Ddx3x^flox line with a Prm-Cre line) or epiblast-specific mutations (crossing a Ddx3x^flox line with a Sox2-Cre line) have illuminated distinct phenotypic consequences of Ddx3x deletion (Chen et al. 2016). Prm-Ddx3x^−/y or Sox2-Ddx3x^−/y null male mice die prenatally (Chen et al. 2016; Boitnott et al. 2021). In line with the permanent imprinted XCI on the paternal chromosome in extraembryonic tissues in mice (Borensztein et al. 2017; Loda et al. 2022), germline mutations on the maternal (but not paternal) X chromosome are embryonic lethal in Prm-Ddx3x^+/− females due to insufficient placental development (Chen et al. 2016). Whether DDX3X might contribute to human placentation is unexplored, but there is initial evidence that DDX3X affects gene expression in human placenta and intrauterine growth (Deyssenroth et al. 2017).

Sox2-Ddx3x^+/− females are viable and have been used as mouse model for DDX3X syndrome (Boitnott et al. 2021), as the recombination occurs early in gastrulation, restricting Ddx3x disruption only in the embryo proper and not in extraembryonic tissues necessary for placental development and function. Ddx3x haploinsufficient female mice show delays in meeting physical, sensory, and motor milestones (e.g. hypotonia), followed by hyperactivity, anxiety-like behaviors, memory deficits, and impaired motor function (Boitnott et al. 2021). Motor function shows a deterioration with aging, which however could be prevented by prior behavioral training (Boitnott et al. 2021). This comprehensive behavioral profile underscores the extensive impact of Ddx3x haploinsufficiency across multiple domains of neurodevelopment and behavior.

Ddx3x is also essential for the development of the hindbrain, in line with the observations that individuals with DDX3X mutations can have cerebellar malformations, e.g., cerebellar hypoplasia (Lennox et al. 2020; Aldinger et al. 2019; Parra et al. 2024). Patmore et al. created a conditional knockout Ddx3x mouse by crossing a Ddx3x^flox line with a Blbp-Cre deleter line, which activates Cre-dependent recombination from embryonic (E) day 9.5 onward in neural progenitor cells (Patmore et al. 2020). Blbp-Ddx3x^−/− female mice display normal cerebella until E16.5, but then show progressive cerebellar abnormalities, with failure in the formation of major brainstem nuclei and loss of normal cerebellar foliation and lamination (Patmore et al. 2020). Notably, Blbp-Ddx3x^+/− females and Blbp-Ddx3x^−/y males are largely indistinguishable from controls, and Blbp-Ddx3x^−/y males have upregulated Ddx3y expression, suggesting potential dosage compensation (Patmore et al. 2020). These findings corroborate an essential role of Ddx3x in cerebellar development.

Ddx3x is also critical for the development of the neocortex, in line with the cortical malformations often detected in patients with DDX3X syndrome, e.g., PMG (Lennox et al. 2020). Further, cortical development is a critical nexus of risk for ASD (Garcia-Forn et al. 2020). Corticogenesis begins with the proliferation of neural progenitor cells (NPCs) at embryonic day (E) 10 in mice, including radial glial cells (RGCs). A RGC can generate another RGC, thereby sustaining the population, or differentiate into either another type of progenitor, the intermediate progenitor cells (IPs), or into post-mitotic glutamatergic neurons. These neurons then migrate tangentially toward the cortical plate in an inside-out manner as deep layer neurons are born first (E11.5 - E13.5) while upper layer neurons are born later (E14.5 – E16.5) (Vanderhaeghen & Polleux 2023). This highly choreographed sequence of events is crucial for establishing the six-layered cytoarchitecture of the cortex, responsible for higher cognitive functions, sensory processing, and motor control.

Ddx3x is ubiquitously expressed in the mouse cortex (Lennox et al. 2020). In utero downregulation (~25%) of Ddx3x in E14.5 cortices resulted in increase of RGCs at the expense of neurons in the cortical plate (CP), indicating disrupted neuronal differentiation (Lennox et al. 2020). Orthogonal evidence in the genetic mouse models also support a role of Ddx3x in cortical development (Boitnott et al. 2021; Hoye et al. 2022).

Sox2-Ddx3x^+/− female pups show a reduction in brain volume reflective of a growth delay, with disproportionately thinner cortices (Boitnott et al. 2021). In this model, cortical layer distribution of glutamatergic neurons is altered, particularly affecting neurons expressing the transcription factor BCL11B/CTIP2. This population of neurons, primarily located in layer V and known to project subcerebrally, show altered laminar position, extending in deeper strata. Additionally, there is an increased number of CTIP2-positive neurons co-expressing the transcriptional factor BRN1 typically driving upper-layer fate, suggesting a disruption in neuron subtype specification (Boitnott et al. 2021). Importantly, these deficits displayed differences based on the cortical region (e.g., motor vs. somatosensory) (Boitnott et al. 2021).

The function of Ddx3x in cortical development has also been examined in a forebrain-conditional Ddx3x mouse line, generated by crossing a Ddx3x^flox line with an Emx1-Cre line (Hoye et al. 2022). Emx1-Ddx3x^−/− female null mice showed severe disruption of the cortex, likely resulting from increased cell death (Hoye et al. 2022). Emx1-Ddx3x^+/− and Emx1-Ddx3x^-/y showed substantial increase in RGCs and IPs, with a concomitant decrease in neurons (Hoye et al. 2022), confirming previous findings that Ddx3x is essential for neuronal differentiation (Lennox et al. 2020). Specifically, the depletion of Ddx3x resulted in longer cell cycle (Hoye et al. 2022). Hoye et al. also investigated potential compensatory effects from Ddx3y. First, they found upregulated Ddx3y mRNA in male cortices from Emx1-Ddx3x^-/y (Hoye et al. 2022), on par with previous findings in another conditional null male model (Patmore et al. 2020). This suggests that Ddx3y may upregulate in response to the loss of Ddx3x. Further, they knocked down Ddx3y at E14.5 via in utero electroporation and observed abnormal accumulation of progenitors in the VZ and decrease of neurons in the CP (Hoye et al. 2022), suggesting that in the mouse brain Ddx3x and Ddx3y might have redundant functions in neurogenesis.

Directly related to the role of Ddx3x in cortical progenitors’ proliferation and differentiation (Hoye et al. 2022; Lennox et al. 2020) is its function in regulating the synthesis of a specific subset of proteins. DDX3X promotes the translation of mRNAs with highly structured 5’UTRs (Calviello et al. 2021). In line with the proposed role of DDX3X as a translational activator for specific mRNAs, Emx1-Ddx3x mutant cortices at early phase of cortical neurogenesis (E11.5) show reduced translational efficiency for a subset of transcripts, including Rcor2, Setd3 and Topbp1 (Hoye et al. 2022). Interestingly, in utero downregulation of Setd3 in the cortex phenocopies, at least in part, the unbalance between progenitors and post-mitotic neurons observed in Ddx3x mutant brains (Hoye et al. 2022). How patient-specific mutations impact these aspects is not known.

The signaling cascades regulating DDX3X function during brain development are largely unknown. One of the potential pathways is the Wnt/β-catenin signaling pathway, as shown by evidence in zebrafish (Snijders Blok et al. 2015; Kellaris et al. 2018) and Xenopus tropicalis (Perfetto et al. 2021). For example, Ddx3 knockdown in Xenopus embryos distrupts the neural crest and reduces the activity of AKT, which in turn diminishes GSK3β phosphorylation, culminating in reduced β-catenin stabilization (Perfetto et al. 2021). The functionality of Ddx3 in these regulatory pathways appears to be dependent on its RNA helicase activity, as helicase-deficient Ddx3 mutant was unable to restore normal levels of neural crest markers, unlike its wild-type counterpart (Perfetto et al. 2021). Interestingly, the Wnt/β-catenin signaling pathway is critical for cortical development (Chenn & Walsh 2003; Zhang et al. 2020; Wrobel et al. 2007) and mutations in β-catenin (CTNNB1) have been associated with ASD and ID (Kuechler et al. 2015; Deciphering Developmental Disorders Study 2017; Satterstrom et al. 2020).

Conclusions and future directions

DDX3X syndrome epitomizes the intricate interplay between genetic mutations and neurodevelopmental outcomes, underscoring how mutations in a single gene can lead to a range of perturbations in brain development and function. As our understanding of the neurobiological mechanisms underlying DDX3X syndrome deepens, parallel efforts in a more comprehensive understanding of the clinical manifestations of DDX3X syndrome and complementary experimental modeling of patient-derived mutations will be needed. As mentioned, the natural history of DDX3X syndrome has yet to be mapped, and longitudinal studies will be critical to capture the evolution of symptoms during adolescence and in adult cohorts.

Further, the evidence of genotype-phenotype correlations in affected individuals raise the possibility of distinct pathological mechanisms – one loss-of-function associated with nonsense/frameshift and hypomorphic missense mutations and one gain-of-function resulting from a subset of missense mutations. The mouse models characterized so far only recapitulate loss of function mutations (Hoye et al. 2022; Patmore et al. 2020; Boitnott et al. 2021). In this context, it will be critical to contrast distinct groups of patient-derived mutations in experimental models. This includes models derived from human pluripotent stem cells (hiPSC), including brain organoids, whose development has made tremendous progress (Paulsen et al. 2022; Revah et al. 2022; Jourdon et al. 2023). There are currently no studies modeling DDX3X mutations in hiPSC-derived 2D or 3D neuronal models. Further, while research so far has mostly focused on the role of Ddx3x in cortical excitatory neurons (Boitnott et al. 2021; Hoye et al. 2022; Lennox et al. 2020), DDX3X has a broad expression pattern and it is likely that it plays a role in other neuronal cell types and in non-neuronal cells.

Insights gained from studying DDX3X syndrome will enhance our understanding of this specific condition while also offering valuable perspectives on the conditions resulting from mutations in DEAD/DEAH-box RNA helicases and the broader spectrum of neurodevelopmental disorders.

Glossary

ADHD

Attention-deficit/Hyperactivity Disorder

ASD

Autism Spectrum Disorder

CHD

Congenital Heart Defects

CP

Cortical Plate

DQ

Developmental Quotient

E

Embryonic Day

hiPSC

Human Induced Pluripotent Stem Cells

ID

Intellectual Disability

IPs

Intermediate Progenitor Cells

IQ

Intelligence Quotient

MRI

Magnetic Resonance Imaging

NPCs

Neural Progenitor Cells

PMG

Polymicrogyria

RGCs

Radial Glial Cells

VZ

Ventricular Zone

XCI

X-Chromosome Inactivation

Data availability statement

No new data were generated in this manuscript.