Delineation of a novel neurodevelopmental syndrome associated with
            <i>PAX5</i>
            haploinsufficiency

Gofin, Yoel; Wang, Tianyun; Gillentine, Madelyn A.; Scott, Tiana M.; Berry, Aliska M.; Azamian, Mahshid S.; Genetti, Casie A.; Agrawal, Pankaj B.; Picker, Jonathan; Wojcik, Monica H.; Delgado, Mauricio R.; Lynch, Sally Ann; Scherer, Stephen W.; Howe, Jennifer; Bacino, Carlos A.; VanNoy, Grace E.; O’Donnell-Luria, Anne H.; Lalani, Seema R.; Graf, William D.; Rosenfeld, Jill A.; Eichler, Evan E.; Earl, Rachel K.; Scott, Daryl A.

doi:10.1002/humu.24332

Cited by 6 publications

(10 citation statements)

References 31 publications

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“…While previous genetic studies have suggested PAX5 haploinsufficiency as a risk factor for ASD (Gofin et al, 2022;Iossifov et al, 2012;O'Roak et al, 2014;Stessman et al, 2017), our results provide causal evidence for the role of PAX5 in the etiology of ASD. The social phenotype of known ASD mouse models can range from asocial behavior (Tsai et al, 2012;Won et al, 2012) to hypersociability (Fountain et al, 2017;Katayama et al, 2016;Stoppel and Anderson, 2017).…”

Section: Discussionsupporting

confidence: 47%

“…PAX5 deficiency leads to aberrant motor control and motor learning Next, we hypothesized that the neurological and psychiatric phenotype of the patient is caused by the underlying PAX5 mutations, particularly as PAX5 haploinsufficiency has been associated with ASD (Gofin et al, 2022;Iossifov et al, 2012;O'Roak et al, 2014;Stessman et al, 2017). Furthermore, the patient presented with sufficient sensorimotor symptoms in daily life to consider the diagnosis of developmental coordination disorder (see patient description in Materials and methods; Table S2).…”

Section: Resultsmentioning

confidence: 99%

“…Based on phenotypic heterogeneity and genetic complexity, ASD is considered to be primarily a multifactorial disorder. PAX5 has been identified as a candidate ASD risk gene by the discovery of heterozygous PAX5 mutations in individuals with ASD ( Gofin et al, 2022 ; Iossifov et al, 2012 ; O’Roak et al, 2014 ; Stessman et al, 2017 ). Here, we demonstrate that PAX5 mutations can cause a monogenic form of ASD.…”

Section: Introductionmentioning

confidence: 99%

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Biallelic PAX5 mutations cause hypogammaglobulinemia, sensorimotor deficits, and autism spectrum disorder

Kaiser

Gruenbacher

Oyaga

et al. 2022

Journal of Experimental Medicine

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The genetic causes of primary antibody deficiencies and autism spectrum disorder (ASD) are largely unknown. Here, we report a patient with hypogammaglobulinemia and ASD who carries biallelic mutations in the transcription factor PAX5. A patient-specific Pax5 mutant mouse revealed an early B cell developmental block and impaired immune responses as the cause of hypogammaglobulinemia. Pax5 mutant mice displayed behavioral deficits in all ASD domains. The patient and the mouse model showed aberrant cerebellar foliation and severely impaired sensorimotor learning. PAX5 deficiency also caused profound hypoplasia of the substantia nigra and ventral tegmental area due to loss of GABAergic neurons, thus affecting two midbrain hubs, controlling motor function and reward processing, respectively. Heterozygous Pax5 mutant mice exhibited similar anatomic and behavioral abnormalities. Lineage tracing identified Pax5 as a crucial regulator of cerebellar morphogenesis and midbrain GABAergic neurogenesis. These findings reveal new roles of Pax5 in brain development and unravel the underlying mechanism of a novel immunological and neurodevelopmental syndrome.

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Section: Discussionsupporting

confidence: 47%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Biallelic PAX5 mutations cause hypogammaglobulinemia, sensorimotor deficits, and autism spectrum disorder

Kaiser

Gruenbacher

Oyaga

et al. 2022

Journal of Experimental Medicine

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“…These included transcript factors like UTF1, SP8, SATB2, SIX6/3 and PAX5 and PAX3 (Figures S1E). PAX5, associated with brain development and autism spectrum disorder (ASD) [37], and UTF1, which controls pluripotency and self‐renewal in ESCs [38], are significantly decreased in H9 (NSC/PSC) but not in KOLF2.1J. SP8, which promotes the premature differentiation of NSC is increased in KOLF2.1J (NSC/PSC) [39].…”

Section: Resultsmentioning

confidence: 99%

“…As previously reported for iNeuron differentiation [13], while the abundance of most of the transcriptional regulators quantified was largely unchanged in both cell lines, a cohort of factors linked with maintenance of pluripotency (e.g., OCT4, NANOG) was dramatically downregulated (log 2 (NSC/PSC) < -2.0) to similar levels in both cell lines (Figures 1D,F). On the other hand, the hPSC-to-hNSC transition in both cell lines is associated with a strong increase (log 2 (NSC/PSC) > 2.0) in the abundance of numerous proteins linked to nervous system development (e.g., MAP2, ZEB1/2, POU3F2) (Figures 1D,F and autism spectrum disorder (ASD) [37], and UTF1, which controls pluripotency and self-renewal in ESCs [38], are significantly decreased in H9 (NSC/PSC) but not in KOLF2.1J. SP8, which promotes the premature differentiation of NSC is increased in KOLF2.1J (NSC/PSC) [39].…”

Section: Quantifying Proteome Remodeling During Conversion Of Hpscs T...mentioning

confidence: 99%

Quantitative proteome remodeling characterization of two human reference pluripotent stem cell lines during neurogenesis and cardiomyogenesis

Nam

Ordureau

2022

Proteomics

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Human pluripotent stem cells (PSCs) have become popular tools within the research community to study developmental and model diseases. While many induced-PSCs (iPSCs) from various genetic background sources are currently available, scientific advancement has been hampered by the considerable phenotypic variations observed between different iPSC lines. A recent collaborative effort selected a novel iPSC line to address this and encourage the adoption of a standardized iPSC line termed KOLF2.1J. Here, leveraging the multiplexing power of isobaric labeling, we systematically investigate, at the 10k proteome level, the relative protein abundance profiles of the KOLF2.1J reference iPSC line upon two distinct cell state differentiation trajectories. In addition, we side-by-side systematically compare this line with the H9 line, an established embryonically derived PSC line that we previously characterized. We noticed differences in the basal proteome of the two cell lines and highlighted the differentially expressed proteins. While the difference between the cell line's proteome subsisted upon differentiation, the global proteome remodeling trajectory was highly similar during the tested differentiation routes. We thus conclude that the KOLF2.1J line performs well at the proteome level upon the neuro and cardiomyogenesis differentiation protocol used. We believe this dataset will serve as a resource of value for the research community.

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Genome and RNA sequencing boost neuromuscular diagnoses to 62% from 34% with exome sequencing alone

Marchant,

Bryen,

Bahlo

et al. 2024

Ann Clin Transl Neurol

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ObjectiveMost families with heritable neuromuscular disorders do not receive a molecular diagnosis. Here we evaluate diagnostic utility of exome, genome, RNA sequencing, and protein studies and provide evidence‐based recommendations for their integration into practice.MethodsIn total, 247 families with suspected monogenic neuromuscular disorders who remained without a genetic diagnosis after standard diagnostic investigations underwent research‐led massively parallel sequencing: neuromuscular disorder gene panel, exome, genome, and/or RNA sequencing to identify causal variants. Protein and RNA studies were also deployed when required.ResultsIntegration of exome sequencing and auxiliary genome, RNA and/or protein studies identified causal or likely causal variants in 62% (152 out of 247) of families. Exome sequencing alone informed 55% (83 out of 152) of diagnoses, with remaining diagnoses (45%; 69 out of 152) requiring genome sequencing, RNA and/or protein studies to identify variants and/or support pathogenicity. Arrestingly, novel disease genes accounted for <4% (6 out of 152) of diagnoses while 36.2% of solved families (55 out of 152) harbored at least one splice‐altering or structural variant in a known neuromuscular disorder gene. We posit that contemporary neuromuscular disorder gene‐panel sequencing could likely provide 66% (100 out of 152) of our diagnoses today.InterpretationOur results emphasize thorough clinical phenotyping to enable deep scrutiny of all rare genetic variation in phenotypically consistent genes. Post‐exome auxiliary investigations extended our diagnostic yield by 81% overall (34–62%). We present a diagnostic algorithm that details deployment of genomic and auxiliary investigations to obtain these diagnoses today most effectively. We hope this provides a practical guide for clinicians as they gain greater access to clinical genome and transcriptome sequencing.

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Delineation of a novel neurodevelopmental syndrome associated with PAX5 haploinsufficiency

Abstract: PAX5 is a transcription factor associated with abnormal posterior midbrain and cerebellum development in mice. PAX5 is highly loss-of-function intolerant and

Cited by 6 publications

References 31 publications

Biallelic PAX5 mutations cause hypogammaglobulinemia, sensorimotor deficits, and autism spectrum disorder

Biallelic PAX5 mutations cause hypogammaglobulinemia, sensorimotor deficits, and autism spectrum disorder

Quantitative proteome remodeling characterization of two human reference pluripotent stem cell lines during neurogenesis and cardiomyogenesis

Genome and RNA sequencing boost neuromuscular diagnoses to 62% from 34% with exome sequencing alone

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