De Novo and Inherited Pathogenic Variants in KDM3B Cause Intellectual Disability, Short Stature, and Facial Dysmorphism

Diets, Illja J.; Donk, Roos van der; Baltrunaite, Kristina; Waanders, Esmé; Reijnders, Margot R.F.; Dingemans, Alexander J.M.; Pfundt, Rolph; Silfhout, Anneke T. Vulto-van; Wiel, Laurens; Gilissen, Christian; Thévenon, Julien; Perrin, Laurence; Afenjar, Alexandra; Nava, Caroline; Keren, Boris; Bartz, Sarah; Peri, Bethany; Beunders, Gea; Verbeek, Nienke E.; Gassen, Koen van; Thiffault, Isabelle; Cadieux-Dion, Maxime; Huerta‐Saenz, Lina; Wagner, Matias; Konstantopoulou, Vassiliki; Vodopiutz, Julia; Griese, Matthias; Boel, Annekatrien; Callewaert, Bert; Brunner, Han G.; Kleefstra, Tjitske; Hoogerbrugge, Nicoline; Vries, Bert B.A. de; Hwa, Vivian; Dauber, Andrew; Hehir-Kwa, Jayne Y.; Kuiper, Roland P.; Jongmans, Marjolijn C.J.

doi:10.1016/j.ajhg.2019.02.023

Cited by 38 publications

(36 citation statements)

References 47 publications

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“…All nominated candidate genes were submitted to GeneMatcher. Six individuals were subsequently published within large collaborations connected through GeneMatcher and one individual was published as case report following two previous case descriptions, all together establishing six novel disease‐associated genes for NDDs, namely CYFIP2, KDM3B, IMPDH2, FITM2, RALGAPA1 , and VARS 28‐33 . Those seven individuals were considered as solved and assigned to the overall yield (Supplemental Figure 1A).…”

Section: Resultsmentioning

confidence: 99%

De novo variants in neurodevelopmental disorders—experiences from a tertiary care center

et al. 2021

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Up to 40% of neurodevelopmental disorders (NDDs) such as intellectual disability, developmental delay, autism spectrum disorder, and developmental motor abnormalities have a documented underlying monogenic defect, primarily due to de novo variants. Still, the overall burden of de novo variants as well as novel disease genes in NDDs await discovery. We performed parent‐offspring trio exome sequencing in 231 individuals with NDDs. Phenotypes were compiled using human phenotype ontology terms. The overall diagnostic yield was 49.8% (n = 115/231) with de novo variants contributing to more than 80% (n = 93/115) of all solved cases. De novo variants affected 72 different—mostly constrained—genes. In addition, we identified putative pathogenic variants in 16 genes not linked to NDDs to date. Reanalysis performed in 80 initially unsolved cases revealed a definitive diagnosis in two additional cases. Our study consolidates the contribution and genetic heterogeneity of de novo variants in NDDs highlighting trio exome sequencing as effective diagnostic tool for NDDs. Besides, we illustrate the potential of a trio‐approach for candidate gene discovery and the power of systematic reanalysis of unsolved cases.

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Section: Resultsmentioning

confidence: 99%

De novo variants in neurodevelopmental disorders—experiences from a tertiary care center

et al. 2021

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“…Clinical photographs of individuals' faces were analyzed according to the hybrid model reported previously. 26,27 This model combines two algorithms (OpenFace 28 and Clinical Face Phenotype Space 29 ) used for facial recognition to create a 468-dimensional vector of the facial features of a given individual. These vectors are used for calculating the clustering impact factor (CIF) of a patient group.…”

Section: Quantitative Facial Phenotypingmentioning

confidence: 99%

Opposite Modulation of RAC1 by Mutations in TRIO Is Associated with Distinct, Domain-Specific Neurodevelopmental Disorders

Barbosa

Greville‐Heygate

Bonnet

et al. 2020

The American Journal of Human Genetics

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The Rho-guanine nucleotide exchange factor (RhoGEF) TRIO acts as a key regulator of neuronal migration, axonal outgrowth, axon guidance, and synaptogenesis by activating the GTPase RAC1 and modulating actin cytoskeleton remodeling. Pathogenic variants in TRIO are associated with neurodevelopmental diseases, including intellectual disability (ID) and autism spectrum disorders (ASD). Here, we report the largest international cohort of 24 individuals with confirmed pathogenic missense or nonsense variants in TRIO. The nonsense mutations are spread along the TRIO sequence, and affected individuals show variable neurodevelopmental phenotypes. In contrast, missense variants cluster into two mutational hotspots in the TRIO sequence, one in the seventh spectrin repeat and one in the RAC1-activating GEFD1. Although all individuals in this cohort present with developmental delay and a neuro-behavioral phenotype, individuals with a pathogenic variant in the seventh spectrin repeat have a more severe ID associated with macrocephaly than do most individuals with GEFD1 variants, who display milder ID and microcephaly. Functional studies show that the spectrin and GEFD1 variants cause a TRIO-mediated hyper-or hypo-activation of RAC1, respectively, and we observe a striking correlation between RAC1 activation levels and the head size of the affected individuals. In addition, truncations in TRIO GEFD1 in the vertebrate model X. tropicalis induce defects that are concordant with the human phenotype. This work demonstrates distinct clinical and molecular disorders clustering in the GEFD1 and seventh spectrin repeat domains and highlights the importance of tight control of TRIO-RAC1 signaling in neuronal development.

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“…Individuals' faces were analyzed from provided frontal photos using the hybrid model reported previously. 45,46 This model combines two algorithms used for facial recognition (OpenFace 47 and Clinical Face Phenotype Space 48 ) to create a 468-dimensional vector of an individuals' facial features. These vectors are used to calculate the clustering impact factor (CIF) of an analyzed group, which is a measurement of how a group of individuals cluster within a group of control subjects.…”

Section: Quantitative Facial Phenotypingmentioning

confidence: 99%

Truncating SRCAP variants outside the Floating-Harbor syndrome locus cause a distinct neurodevelopmental disorder with a specific DNA methylation signature

Rots¹,

Chater‐Diehl²,

Dingemans³

et al. 2021

The American Journal of Human Genetics

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Summary Truncating variants in exons 33 and 34 of the SNF2-related CREBBP activator protein ( SRCAP ) gene cause the neurodevelopmental disorder (NDD) Floating-Harbor syndrome (FLHS), characterized by short stature, speech delay, and facial dysmorphism. Here, we present a cohort of 33 individuals with clinical features distinct from FLHS and truncating (mostly de novo ) SRCAP variants either proximal (n = 28) or distal (n = 5) to the FLHS locus. Detailed clinical characterization of the proximal SRCAP individuals identified shared characteristics: developmental delay with or without intellectual disability, behavioral and psychiatric problems, non-specific facial features, musculoskeletal issues, and hypotonia. Because FLHS is known to be associated with a unique set of DNA methylation (DNAm) changes in blood, a DNAm signature, we investigated whether there was a distinct signature associated with our affected individuals. A machine-learning model, based on the FLHS DNAm signature, negatively classified all our tested subjects. Comparing proximal variants with typically developing controls, we identified a DNAm signature distinct from the FLHS signature. Based on the DNAm and clinical data, we refer to the condition as “non-FLHS SRCAP -related NDD.” All five distal variants classified negatively using the FLHS DNAm model while two classified positively using the proximal model. This suggests divergent pathogenicity of these variants, though clinically the distal group presented with NDD, similar to the proximal SRCAP group. In summary, for SRCAP , there is a clear relationship between variant location, DNAm profile, and clinical phenotype. These results highlight the power of combined epigenetic, molecular, and clinical studies to identify and characterize genotype-epigenotype-phenotype correlations.

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De Novo and Inherited Pathogenic Variants in KDM3B Cause Intellectual Disability, Short Stature, and Facial Dysmorphism

Cited by 38 publications

References 47 publications

De novo variants in neurodevelopmental disorders—experiences from a tertiary care center

De novo variants in neurodevelopmental disorders—experiences from a tertiary care center

Opposite Modulation of RAC1 by Mutations in TRIO Is Associated with Distinct, Domain-Specific Neurodevelopmental Disorders

Truncating SRCAP variants outside the Floating-Harbor syndrome locus cause a distinct neurodevelopmental disorder with a specific DNA methylation signature

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