Amy Blevins

Carolinas Healthcare System

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Bertrand Isidor

Centre Hospitalier Universitaire de Nantes

Marjon A. van Slegtenhorst

Erasmus MC

Benjamin Cogné

Centre Hospitalier Universitaire de Nantes

Jennifer B. Humberson

University of Virginia

Charlotte de Konink

Erasmus MC

Ingrid M.B.H. van de Laar

Erasmus MC

Grazia M.S. Mancini

Erasmus MC

Robert F. Stratton

Driscoll Children's Hospital

Sarah McKeown

Children's Hospital of Philadelphia

Deike Weiss

University Medical Center Hamburg-Eppendorf

Cooperative Institutions

Erasmus MC

Erasmus University Rotterdam

University of North Carolina at Chapel Hill

University College London

National Hospital for Neurology and Neurosurgery

University of Wisconsin–Madison

Inserm

Boston Children's Hospital

University of Melbourne

Heidelberg University

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Autosomal recessive MFN2‐related Charcot‐Marie‐Tooth disease with diaphragmatic weakness: Case report and literature review

American Journal of Medical Genetics Part A (2016)

Christopher Tan Marina Rabideau Amy Blevins M. Jody Westbrook Tali Ekstein

Pathogenic variants in the mitofusin 2 gene ( MFN2 ) are the most common cause of autosomal dominant Charcot‐Marie‐Tooth (CMT2) disease, which is typically characterized by axonal sensorimotor neuropathy. We report on a 7‐month‐old white female with hypotonia, motor delay, distal weakness, and motor/sensory axonal neuropathy in which next‐generation sequencing analysis identified compound heterozygous pathogenic variants (c.2054_2069_1170del and c.392A>G) in MFN2 . A review of the literature reveals that sporadic and familial cases of compound heterozygous or homozygous pathogenic MFN2 variants have been infrequently described, which indicates that MFN2 can also be inherited in a recessive manner. This case highlights several clinical findings not typically associated with MFN2 pathogenic variants, including young age of onset and rapidly progressing diaphragmatic paresis that necessitated tracheostomy and mechanical ventilation, and adds to the growing list of features identified in autosomal recessive MFN2 ‐related CMT2. Our patient with MFN2 ‐related CMT2 expands the clinical and mutational spectrum of individuals with autosomal recessive CMT2 and identifies a new clinical feature that warrants further observation. © 2016 Wiley Periodicals, Inc.

Tooth disease

MFN2

10.1002/ajmg.a.37611

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TAOK1 is associated with neurodevelopmental disorder and essential for neuronal maturation and cortical development

Human Mutation (2021)

Geeske M. van Woerden Melanie Bos Charlotte de Konink Ben Distel Rossella Avagliano Trezza

Thousand and one amino-acid kinase 1 (TAOK1) is a MAP3K protein kinase, regulating different mitogen-activated protein kinase pathways, thereby modulating a multitude of processes in the cell. Given the recent finding of TAOK1 involvement in neurodevelopmental disorders (NDDs), we investigated the role of TAOK1 in neuronal function and collected a cohort of 23 individuals with mostly de novo variants in TAOK1 to further define the associated NDD. Here, we provide evidence for an important role for TAOK1 in neuronal function, showing that altered TAOK1 expression levels in the embryonic mouse brain affect neural migration in vivo, as well as neuronal maturation in vitro. The molecular spectrum of the identified TAOK1 variants comprises largely truncating and nonsense variants, but also missense variants, for which we provide evidence that they can have a loss of function or dominant-negative effect on TAOK1, expanding the potential underlying causative mechanisms resulting in NDD. Taken together, our data indicate that TAOK1 activity needs to be properly controlled for normal neuronal function and that TAOK1 dysregulation leads to a neurodevelopmental disorder mainly comprising similar facial features, developmental delay/intellectual disability and/or variable learning or behavioral problems, muscular hypotonia, infant feeding difficulties, and growth problems.

Brain Development

Neurodevelopmental disorder

10.1002/humu.24176

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De novo KCNA6 variants with attenuated K_V1.6 channel deactivation in patients with epilepsy

Epilepsia (2022)

Vincenzo Salpietro Valentina Galassi Deforie Stéphanie Efthymiou Emer O’Connor Anna Marcé‐Grau

Abstract Objective Mutations in the genes encoding neuronal ion channels are a common cause of Mendelian neurological diseases. We sought to identify novel de novo sequence variants in cases with early infantile epileptic phenotypes and neurodevelopmental anomalies. Methods Following clinical diagnosis, we performed whole exome sequencing of the index cases and their parents. Identified channel variants were expressed in Xenopus oocytes and their functional properties assessed using two‐electrode voltage clamp. Results We identified novel de novo variants in KCNA6 in four unrelated individuals variably affected with neurodevelopmental disorders and seizures with onset in the first year of life. Three of the four identified mutations affect the pore‐lining S6 α‐helix of K V 1.6. A prominent finding of functional characterization in Xenopus oocytes was that the channel variants showed only minor effects on channel activation but slowed channel closure and shifted the voltage dependence of deactivation in a hyperpolarizing direction. Channels with a mutation affecting the S6 helix display dominant effects on channel deactivation when co‐expressed with wild‐type K V 1.6 or K V 1.1 subunits. Significance This is the first report of de novo nonsynonymous variants in KCNA6 associated with neurological or any clinical features. Channel variants showed a consistent effect on channel deactivation, slowing the rate of channel closure following normal activation. This specific gain‐of‐function feature is likely to underlie the neurological phenotype in our patients. Our data highlight KCNA6 as a novel channelopathy gene associated with early infantile epileptic phenotypes and neurodevelopmental anomalies.

10.1111/epi.17455

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Role of CAMK2D in neurodevelopment and associated conditions

The American Journal of Human Genetics (2024)

Pomme M.F. Rigter Charlotte de Konink Matthew J. Dunn Martina Proietti Onori Jennifer B. Humberson

Neurodevelopmental disorder

Loss function

Dilated Cardiomyopathy

10.1016/j.ajhg.2023.12.016

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Pathogenic SPTBN1 variants cause an autosomal dominant neurodevelopmental syndrome

Nature Genetics (2021)

Margot A. Cousin Blake A. Creighton Keith A. Breau Rebecca C. Spillmann Erin Torti

Haploinsufficiency

Neurodevelopmental disorder

10.1038/s41588-021-00886-z

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Citations (66)

Pathogenic SPTBN1 variants cause a novel autosomal dominant neurodevelopmental syndrome

medRxiv (Cold Spring Harbor Laboratory) (2020)

Margot A. Cousin Keith A. Breau Blake A. Creighton Rebecca C. Spillmann Erin Torti

Abstract SPTBN1 encodes βII-spectrin, the ubiquitously expressed member of the β-spectrin family that forms micrometer-scale networks associated with plasma membranes. βII-spectrin is abundantly expressed in the brain, where it is essential for neuronal development and connectivity. Mice deficient in neuronal βII-spectrin expression have defects in cortical organization, global developmental delay, dysmorphisms, and behavioral deficiencies of corresponding severity. These phenotypes, while less severe, are observed in haploinsufficient animals, suggesting that individuals carrying heterozygous variants in this gene may also present with measurable compromise of neural development and function. Here we report the identification of heterozygous SPTBN1 variants in 29 individuals who present with global developmental, language and motor delays, mild to severe intellectual disability, autistic features, seizures, behavioral and movement abnormalities, hypotonia, and variable dysmorphic facial features. We show that these SPTBN1 variants lead to loss-of-function, gain-of-function, and dominant negative effects that affect protein stability, disrupt binding to key protein partners, and disturb cytoskeleton organization and dynamics. Our studies define the genetic basis of this new neurodevelopmental syndrome, expand the set of spectrinopathies affecting the brain and neural development, and underscore the critical role of βII-spectrin in the central nervous system.

Haploinsufficiency

Neurodevelopmental disorder

Loss function

10.1101/2020.08.31.20184481

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Citations (3)