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

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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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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239-kb Microdeletion Spanning KMT2E in a Child with Developmental Delay: Further Delineation of the Phenotype

Molecular Syndromology ◽

10.1159/000516635 ◽

2021 ◽

pp. 1-6

Author(s):

Konstantina Kosma ◽

Konstantinos Varvagiannis ◽

Anastasios Mitrakos ◽

Maria Tsipi ◽

Joanne Traeger-Synodinos ◽

...

Keyword(s):

Developmental Delay ◽

De Novo ◽

Neurodevelopmental Disorder ◽

Dominant Negative ◽

Dominant Negative Effect ◽

Chromosomal Microarray ◽

Global Developmental Delay ◽

Common Mechanism ◽

Facial Dysmorphism ◽

Gi Symptoms

Pathogenic KMT2E variants underly O'Donnell-Luria-Rodan syndrome, a recently described neurodevelopmental disorder characterized by global developmental delay, variable degrees of intellectual disability, and subtle facial dysmorphism. Less common findings include autism, seizures, gastrointestinal (GI) problems, and abnormal head circumference. Occurrence of mostly truncating variants as well as the similar phenotype observed in individuals with deletions spanning KMT2E suggest haploinsufficiency of this gene as a common mechanism for the disorder, while a gain-of-function or dominant-negative effect cannot be ruled out for some missense variants. Deletions reported in the literature encompass several additional known or presumed haploinsufficient genes, thus leading to more complex phenotypes. Here, we describe a male with antenatal onset hydronephrosis, hypotonia, global developmental delay, prominent GI symptoms as well as facial dysmorphism. Chromosomal microarray revealed a 239-kb de novo microdeletion spanning KMT2E and LHFPL3. Clinical presentation of our proband, harboring one of the smallest deletions of the region confirms the core features of this disorder, suggests GI symptoms as a prominent finding in affected individuals while expanding the phenotypic spectrum to abnormalities of the urinary tract.

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Ocular Manifestations of a Novel Proximal 19p13.3 Microdeletion

Case Reports in Genetics ◽

10.1155/2018/2492437 ◽

2018 ◽

Vol 2018 ◽

pp. 1-5

Author(s):

L. Swan ◽

D. Coman

Keyword(s):

Short Stature ◽

Developmental Delay ◽

Medical Literature ◽

De Novo ◽

Phenotypic Variability ◽

Clinical Manifestations ◽

Phenotypic Heterogeneity ◽

Facial Dysmorphism ◽

Ocular Manifestations

Microdeletions at 19p13.3 are rarely reported in the medical literature with significant phenotypic variability. Among the reported cases, common clinical manifestations have included developmental delay, facial dysmorphism, and hypotonia. Herein we described a child with a de novo 19p13.3 microdeletion, proximal to the reported cases of 19p13.3 microdeletion/duplication, with ocular manifestations of bilateral ocular colobomata complicated with microphthalmos and cataract, associated with short stature. This case highlights the phenotypic heterogeneity of deletions in the 19p13.3 region.

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A rare de novo interstitial duplication of 15q15.3q21.2 in a boy with severe short stature, hypogonadism, global developmental delay and intellectual disability

Molecular Cytogenetics ◽

10.1186/s13039-016-0214-3 ◽

2016 ◽

Vol 9 (1) ◽

Cited By ~ 4

Author(s):

Haiming Yuan ◽

Zhe Meng ◽

Lina Zhang ◽

Xiangyang Luo ◽

Liping Liu ◽

...

Keyword(s):

Intellectual Disability ◽

Short Stature ◽

Developmental Delay ◽

De Novo ◽

Global Developmental Delay ◽

Interstitial Duplication ◽

Severe Short Stature

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

Neuropediatrics ◽

10.1055/s-0038-1669926 ◽

2018 ◽

Vol 49 (06) ◽

pp. 401-404 ◽

Cited By ~ 6

Author(s):

Korbinian Riedhammer ◽

Reka Kovacs-Nagy ◽

Thomas Meitinger ◽

Julia Hoefele ◽

Matias Wagner ◽

...

Keyword(s):

Candidate Gene ◽

Developmental Delay ◽

Hormonal Regulation ◽

De Novo ◽

Missense Variant ◽

Global Developmental Delay ◽

Monogenic Disorders ◽

Strong Candidate ◽

The Brain ◽

Generation Sequencing

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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