A De Novo Missense Variant in POU3F2 Identified in a Child with Global Developmental Delay

Many genetic and nongenetic causes for developmental delay in childhood could be identified. Often, however, the molecular basis cannot be elucidated. As next-generation sequencing is becoming more frequently available in a diagnostic context, an increasing number of genetic variations are found as causative in children with developmental delay.We performed trio exome sequencing in a girl with developmental delay and minor dysmorphological features. Using a filter for de novo variants, the heterozygous missense variant c.812A>T, p.(Glu217Val) was found in the candidate gene POU3F2 in our patient. POU3F2 plays an important role in neuronal differentiation and hormonal regulation. To date, it has not been associated with monogenic disorders. Studies on Pou3f2 knockout mice highlighted the importance of this protein in the development of the brain. Furthermore, microdeletions with an overlapping region including only POU3F2 and FBXL4 were linked to developmental delay in six unrelated families. Therefore, POU3F2 is a strong candidate gene for developmental delay, although functional assays proving this assumption still have to be done.

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A de novo missense variant in MED13 in a patient with global developmental delay, marked facial dysmorphism, macroglossia, short stature, and macrocephaly

American Journal of Medical Genetics Part A ◽

10.1002/ajmg.a.62238 ◽

2021 ◽

Author(s):

Alice P. Rogers ◽

Kathryn Friend ◽

Lesley Rawlings ◽

Christopher P. Barnett

Keyword(s):

Short Stature ◽

Developmental Delay ◽

De Novo ◽

Missense Variant ◽

Global Developmental Delay ◽

Facial Dysmorphism

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KCNQ2 mutations: genotype-phenotype association beyond epilepsy

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/cjn.2015.66 ◽

2015 ◽

Vol 42 (S1) ◽

pp. S8-S8

Author(s):

SE Buerki ◽

GA Horwath ◽

MI Van Allen ◽

A Datta ◽

C Boelman ◽

...

Keyword(s):

Developmental Delay ◽

Autonomic Dysfunction ◽

De Novo ◽

Focal Epilepsy ◽

Missense Variant ◽

Epileptic Encephalopathy ◽

Global Developmental Delay ◽

High Signal ◽

Brain Volume Loss ◽

Hyperkinetic Movement Disorder

Background: KCNQ2 abnormalities were described in infants with benign familial neonatal seizures (BFNS) and epileptic encephalopathy (EE). Associated features possibly include abnormal neuroimaging findings such as hypomyelination and/or T2 high signal of basal ganglia. Methods: This report describes 4 infants carrying different heterozygous KCNQ2 variants and 2 infants with 20q13.33 deletions encompassing KCNQ2 gene. Results: The different KCNQ2 mutations led to EE in 3 patients and included a novel de novo missense variant, p.Arg201Cys/c.601C>T, in an infant with severe EE and global developmental delay, hyperkinetic movement disorder, autonomic dysfunction with chronic hypoventilation, apnea, low GABA levels in CSF, and hypomyelination. She died at age 3 years of respiratory failure. One patient with BFNS and normal MRI has a previously reported c.508delG frame shift mutation in KCNQ2. Of the two de novo 22q13.33 deletions (1.2Mb versus 254.1 Kb) the larger caused a more severe phenotype, including focal epilepsy from infancy until 4 years, moderate developmental delay and diffuse brain volume loss. Conclusions: Along with varied epilepsy phenotypes and neuroimaging findings KCNQ abnormalities were associated with severe autonomic dysfunction and reduced CSF GABA levels. This might have further treatment implications, besides that the altered potassium channel function itself presents a therapeutic target.

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X-linked neonatal-onset epileptic encephalopathy associated with a gain-of-function variant p.R660T in GRIA3

PLoS Genetics ◽

10.1371/journal.pgen.1009608 ◽

2021 ◽

Vol 17 (6) ◽

pp. e1009608

Author(s):

Jia-Hui Sun ◽

Jiang Chen ◽

Fernando Eduardo Ayala Valenzuela ◽

Carolyn Brown ◽

Diane Masser-Frye ◽

...

Keyword(s):

Developmental Delay ◽

Prolonged Exposure ◽

De Novo ◽

Missense Variant ◽

Epileptic Encephalopathy ◽

Global Developmental Delay ◽

Decay Kinetics ◽

Gain Of Function ◽

Ca1 Neurons ◽

Pathogenic Variants

The X-linked GRIA3 gene encodes the GLUA3 subunit of AMPA-type glutamate receptors. Pathogenic variants in this gene were previously reported in neurodevelopmental diseases, mostly in male patients but rarely in females. Here we report a de novo pathogenic missense variant in GRIA3 (c.1979G>C; p. R660T) identified in a 1-year-old female patient with severe epilepsy and global developmental delay. When exogenously expressed in human embryonic kidney (HEK) cells, GLUA3_R660T showed slower desensitization and deactivation kinetics compared to wildtype (wt) GLUA3 receptors. Substantial non-desensitized currents were observed with the mutant but not for wt GLUA3 with prolonged exposure to glutamate. When co-expressed with GLUA2, the decay kinetics were similarly slowed in GLUA2/A3_R660T with non-desensitized steady state currents. In cultured cerebellar granule neurons, miniature excitatory postsynaptic currents (mEPSCs) were significantly slower in R660T transfected cells than those expressing wt GLUA3. When overexpressed in hippocampal CA1 neurons by in utero electroporation, the evoked EPSCs and mEPSCs were slower in neurons expressing R660T mutant compared to those expressing wt GLUA3. Therefore our study provides functional evidence that a gain of function (GoF) variant in GRIA3 may cause epileptic encephalopathy and global developmental delay in a female subject by enhancing synaptic transmission.

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A novel de novo KDM5C variant in a female with global developmental delay and ataxia: a case report

BMC Neurology ◽

10.1186/s12883-021-02380-9 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Natalie C. Lippa ◽

Subit Barua ◽

Vimla Aggarwal ◽

Elaine Pereira ◽

Jennifer M. Bain

Keyword(s):

Case Report ◽

Intellectual Disability ◽

Short Stature ◽

Developmental Delay ◽

De Novo ◽

Phenotypic Variability ◽

Missense Variant ◽

Global Developmental Delay ◽

Related Disorder ◽

Patient Reported

Abstract Background Pathogenic variants in KDM5C are a cause of X-linked intellectual disability in males. Other features in males include short stature, dysmorphic features, seizures and spasticity. In some instances, female relatives were noted to have learning difficulties and mild intellectual disabilities, but full phenotypic descriptions were often incomplete. Recently, detailed phenotypic features of five affected females with de novo variants were described. (Clin Genet 98:43–55, 2020) Four individuals had a protein truncating variant and 1 individual had a missense variant. All five individuals had developmental delay/intellectual disability and three neurological features. Case presentation Here we report a three-year-old female with global developmental delay, hypotonia and ataxia. Through whole exome sequencing, a de novo c.1516A > G (p.Met506Val) variant in KDM5C was identified. This missense variant is in the jumonji-C domain of this multi domain protein where other missense variants have been previously reported in KDM5C related disorder. The KDM5C gene is highly intolerant to functional variation which suggests its pathogenicity. The probands motor delays and language impairment is consistent with other reported female patients with de novo variants in KDM5C. However, other features reported in females (distinctive facial features, skeletal abnormalities, short stature and endocrine features) were absent. To the best of our knowledge, our proband is the first female patient reported with a diagnosis of ataxia. Conclusions This case report provides evidence for an emerging and phenotypic variability that adds to the literature of the role of KDM5C in females with neurodevelopmental disorders as well as movement disorders.

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A novel de novo TMEM63A variant in a patient with severe hypomyelination and global developmental delay

Brain and Development ◽

10.1016/j.braindev.2021.09.006 ◽

2021 ◽

Author(s):

Shinobu Fukumura ◽

Takuya Hiraide ◽

Akiyo Yamamoto ◽

Kousuke Tsuchida ◽

Kazushi Aoto ◽

...

Keyword(s):

Developmental Delay ◽

De Novo ◽

Global Developmental Delay

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A de novo 1.6Mb microdeletion at 19q13.2 in a boy with Diamond-Blackfan anemia, global developmental delay and multiple congenital anomalies

Molecular Cytogenetics ◽

10.1186/s13039-016-0268-2 ◽

2016 ◽

Vol 9 (1) ◽

Cited By ~ 2

Author(s):

Haiming Yuan ◽

Zhe Meng ◽

Liping Liu ◽

Xiaoyan Deng ◽

Xizi Hu ◽

...

Keyword(s):

Developmental Delay ◽

Congenital Anomalies ◽

De Novo ◽

Global Developmental Delay ◽

Multiple Congenital Anomalies ◽

Diamond Blackfan Anemia

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EIF2AK2-related Neurodevelopmental Disorder With Leukoencephalopathy, Developmental Delay, and Episodic Neurologic Regression Mimics Pelizaeus-Merzbacher Disease

Neurology Genetics ◽

10.1212/nxg.0000000000000539 ◽

2020 ◽

Vol 7 (1) ◽

pp. e539

Author(s):

Daniel G. Calame ◽

Meagan Hainlen ◽

Danielle Takacs ◽

Leah Ferrante ◽

Kayla Pence ◽

...

Keyword(s):

Developmental Delay ◽

De Novo ◽

Neurodevelopmental Disorder ◽

Copy Number Variants ◽

Retrospective Chart Review ◽

Missense Variant ◽

Chromosomal Microarray ◽

Single Nucleotide Variants ◽

Pelizaeus Merzbacher Disease ◽

Delayed Myelination

ObjectiveTo demonstrate that de novo missense single nucleotide variants (SNVs) in EIF2AK2 cause a neurodevelopmental disorder with leukoencephalopathy resembling Pelizaeus-Merzbacher disease (PMD).MethodsA retrospective chart review was performed of 2 unrelated males evaluated at a single institution with de novo EIF2AK2 SNVs identified by clinical exome sequencing (ES). Clinical and radiographic data were reviewed and summarized.ResultsBoth individuals presented in the first year of life with concern for seizures and developmental delay. Common clinical findings included horizontal and/or pendular nystagmus during infancy, axial hypotonia, appendicular hypertonia, spasticity, and episodic neurologic regression with febrile viral illnesses. MRI of the brain demonstrated severely delayed myelination in infancy. A hypomyelinating pattern was confirmed on serial imaging at age 4 years for proband 1. In proband 2, repeat imaging at age 13 months confirmed persistent delayed myelination. These clinical and radiographic features led to a strong suspicion of PMD. However, neither PLP1 copy number variants nor pathogenic SNVs were detected by chromosomal microarray and trio ES, respectively. Reanalysis of trio ES identified heterozygous de novo EIF2AK2 missense variant c.290C>T (p.Ser97Phe) in proband 1 and c.326C>T (p.Ala109Val) in proband 2.ConclusionsThe autosomal dominant EIF2AK2-related leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome should be considered in the differential diagnosis for PMD and other hypomyelinating leukodystrophies (HLDs). A characteristic history of developmental regression with febrile illnesses may help distinguish it from other HLDs.

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PRUNE1 Deficiency: Expanding the Clinical and Genetic Spectrum

Neuropediatrics ◽

10.1055/s-0038-1661396 ◽

2018 ◽

Vol 49 (05) ◽

pp. 330-338 ◽

Cited By ~ 4

Author(s):

Anna Schossig ◽

Tobias Haack ◽

Reka Kovács-Nagy ◽

Matthias Braunisch ◽

Christine Makowski ◽

...

Keyword(s):

Developmental Delay ◽

Early Onset ◽

Brain Mri ◽

Missense Variant ◽

Global Developmental Delay ◽

Multiplex Family ◽

Consistent Finding ◽

Whole Exome ◽

Severe Developmental Disabilities ◽

Stem Lesions

Background Primary microcephaly and profound global developmental delay have been considered the core clinical phenotype in patients with bi-allelic PRUNE1 mutations. Methods Linkage analysis and whole-exome sequencing (WES) in a multiplex family and extraction of further cases from a WES repository containing 571 children with severe developmental disabilities and neurologic symptoms. Results We identified bi-allelic PRUNE1 mutations in twelve children from six unrelated families. All patients who survived beyond the first 6 months of life had early-onset global developmental delay, bilateral spastic paresis, dysphagia and difficult-to-treat seizures, while congenital or later-evolving microcephaly was not a consistent finding. Brain MRI showed variable anomalies with progressive cerebral and cerebellar atrophies and T2-hyperintense brain stem lesions. Peripheral neuropathy was documented in five cases. Disease course was progressive in all patients and eight children died in the first or early second decade of life. In addition to the previously reported missense mutation p.(Asp106Asn), we observed a novel homozygous missense variant p.(Leu172Pro) and a homozygous contiguous gene deletion encompassing most of the PRUNE1 gene and part of the neighboring BNIPL gene. Conclusions PRUNE1 deficiency causes severe early-onset disease affecting the central and peripheral nervous systems. Microcephaly is probably not a universal feature.

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De novo variants in MPP5 cause global developmental delay and behavioral changes

Human Molecular Genetics ◽

10.1093/hmg/ddaa224 ◽

2020 ◽

Vol 29 (20) ◽

pp. 3388-3401 ◽

Cited By ~ 1

Author(s):

Noelle Sterling ◽

Anna R Duncan ◽

Raehee Park ◽

David A Koolen ◽

Jiahai Shi ◽

...

Keyword(s):

Cell Death ◽

Developmental Delay ◽

Cell Polarity ◽

De Novo ◽

Apoptotic Cell ◽

Ventricular Zone ◽

Behavioral Changes ◽

Ependymal Cells ◽

Global Developmental Delay ◽

Apical Surface

Abstract Membrane Protein Palmitoylated 5 (MPP5) is a highly conserved apical complex protein essential for cell polarity, fate and survival. Defects in cell polarity are associated with neurologic disorders including autism and microcephaly. MPP5 is essential for neurogenesis in animal models, but human variants leading to neurologic impairment have not been described. We identified three patients with heterozygous MPP5 de novo variants (DNV) and global developmental delay (GDD) and compared their phenotypes and magnetic resonance imaging (MRI) to ascertain how MPP5 DNV leads to GDD. All three patients with MPP5 DNV experienced GDD with language delay/regression and behavioral changes. MRI ranged from normal to decreased gyral folding and microcephaly. The effects of MPP5 depletion on the developing brain were assessed by creating a heterozygous conditional knock out (het CKO) murine model with central nervous system (CNS)-specific Nestin-Cre drivers. In the het CKO model, Mpp5 depletion led to microcephaly, decreased cerebellar volume and cortical thickness. Het CKO mice had decreased ependymal cells and Mpp5 at the apical surface of cortical ventricular zone compared with wild type. Het CKO mice also failed to maintain progenitor pools essential for neurogenesis. The proportion of cortical cells undergoing apoptotic cell death increased, suggesting that cell death reduces progenitor population and neuron number. Het CKO mice also showed behavioral changes, similar to our patients. To our knowledge, this is the first report to show that variants in MPP5 are associated with GDD, behavioral abnormalities and language regression/delay. Murine modeling shows that neurogenesis is likely altered in these individuals, with cell death and skewed cellular composition playing significant roles.

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