De novo pathogenic variants inCHAMP1are associated with global developmental delay, intellectual disability, and dysmorphic facial features

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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Clinical and Genetic Characteristics and Prenatal Diagnosis of Rare Monogenic Global Developmental Delay and Intellectual Disability.

10.21203/rs.3.rs-38415/v1 ◽

2020 ◽

Author(s):

Liling Lin ◽

Ying Zhang ◽

Hong Pan ◽

Jingmin Wang ◽

Yu Qi ◽

...

Keyword(s):

Intellectual Disability ◽

Prenatal Diagnosis ◽

Developmental Delay ◽

Hot Spot ◽

Disease Onset ◽

Genetic Diagnosis ◽

Global Developmental Delay ◽

Genetic Characteristics ◽

Pathogenic Variants

Abstract Background: The estimated worldwide prevalence of global developmental delay (GDD) and intellectual disability (ID) is 1-3%. Rare monogenic GDD/ID is poorly characterized because its low prevalence limits research. In this study, we aimed to describe the diagnostic courses and clinical and genetic characteristics of a cohort with rare monogenic GDD/ID.Method:We retrospectively analyzed the diagnostic courses, clinical characteristics, and genetic spectra of rare monogenic GDD/ID patients. We also conducted a follow-up study on prenatal diagnosis in these families. Mutation pathogenicity was interpreted by molecular geneticists and clinicians according to the guidelines of the American College of Medical Genetics and Genomics. Results:Among 108 patients with rare monogenic GDD/ID, it often took 0.5-4 years and 3-5 referrals to obtain a genetic diagnosis after disease onset. Onset typically occurred before 6 years of age, and patients usually presented moderate to severe GDD/ID. The most common coexisting conditions were epilepsy (68%), facial dysmorphism (14%) and microcephaly (13%). In total, 149 different pathogenic variants were found in 81 different genes among the 108 pedigrees, and 71 variants were novel. The most common inheritance patterns in this outbred Chinese population were autosomal recessive (AR; 46.3%), autosomal dominant (AD; 37%), and X-linked (XL; 16.7%). GLB1, PLA2G6, SCN2A, SHANK3 and STXBP1 were important causal genes. Hot-spot mutations were rarely found. By the follow-up, 43 families, including 24 ARID, 13 ADID and 6 XLID families, had undergone prenatal diagnosis. The offspring of 6 ARID, 2 ADID and 2 XLID families had the same pathogenic variants as the probands.Conclusion:Rare monogenic GDD/ID is characterized by early onset, relatively severe symptoms, great clinical variability and genetic heterogeneity. Moreover, timely referrals to genetic counseling and prenatal diagnostic laboratories are important for affected families planning to have additional children.

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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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Spectrum of Movement Disorders in GNAO1 Encephalopathy: in-depth Phenotyping and Literature Review

10.21203/rs.3.rs-60924/v1 ◽

2020 ◽

Author(s):

Soo Yeon Kim ◽

YoungKyu Shim ◽

Young Joon Ko ◽

Soojin Park ◽

Se Song Jang ◽

...

Keyword(s):

Literature Review ◽

Exome Sequencing ◽

Developmental Delay ◽

Whole Exome Sequencing ◽

De Novo ◽

Neurodevelopmental Disorder ◽

Epileptic Encephalopathy ◽

Global Developmental Delay ◽

Pathogenic Variants ◽

Whole Exome

Abstract Background GNAO1 encephalopathy is a rare neurodevelopmental disorder characterized by distinct movement presentations and early onset epileptic encephalopathy. Here, we report the in-depth phenotyping of genetically confirmed patients with GNAO1 encephalopathy, focusing on movement presentations. Results Six patients who participated in Korean Undiagnosed Disease Program were diagnosed to have pathogenic or likely pathogenic variants in GNAO1 using whole exome sequencing. All medical records and personal video clips were analyzed with a literature review. Three of the 6 patients were male. Mean follow-up duration was 39 months (range, 7–78 months) and age at last examination was 8.0 years (range, 3.3–16.9 years). Initial complaints were hypotonia or developmental delay in 5 and right-hand clumsiness in 1 patient, which were noticed at 20 months of age on average (range, 0–75 months). All patients showed global developmental delay and 4 had severely retarded development. Five patients (5/6, 83.3%) had many different movement symptoms with various onset and progression. The symptoms included stereotyped hands movement, non-epileptic myoclonus, dyskinesia, dystonia and choreoathetosis. Whole exome sequencing identified 6 different variants in GNAO1. Three were novel de novo variants and atypical presentation was noted in a patient. One variant turned out to be inherited from patient’s mother who had mosaic variant. Distinct phenotypes in patients with variant p.Glu246Lys and p.Arg209His were elucidated by in-depth phenotyping and literature review. Conclusions We reported 6 patients with GNAO1 encephalopathy showing an extremely diverse clinical spectrum on video. Some characteristic movement features identified by careful inspection may also provide important diagnostic insight and practice guidelines.

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Spectrum of Movement Disorders in GNAO1 Encephalopathy: In-Depth Phenotyping and Case-by-Case Analysis

10.21203/rs.3.rs-60924/v2 ◽

2020 ◽

Author(s):

Soo Yeon Kim ◽

YoungKyu Shim ◽

Young Joon Ko ◽

Soojin Park ◽

Se Song Jang ◽

...

Keyword(s):

Literature Review ◽

Exome Sequencing ◽

Developmental Delay ◽

Whole Exome Sequencing ◽

De Novo ◽

Neurodevelopmental Disorder ◽

Epileptic Encephalopathy ◽

Global Developmental Delay ◽

Pathogenic Variants ◽

Whole Exome

Abstract Background: GNAO1 encephalopathy is a rare neurodevelopmental disorder characterized by distinct movement presentations and early onset epileptic encephalopathy. Here, we report the in-depth phenotyping of genetically confirmed patients with GNAO1 encephalopathy, focusing on movement presentations.Results: Six patients who participated in Korean Undiagnosed Disease Program were diagnosed to have pathogenic or likely pathogenic variants in GNAO1 using whole exome sequencing. All medical records and personal video clips were analyzed with a literature review. Three of the 6 patients were male. Median follow-up duration was 41 months (range, 7–78 months) and age at last examination was 7.4 years (range, 3.3–16.9 years). Initial complaints were hypotonia or developmental delay in 5 and right-hand clumsiness in 1 patient, which were noticed at median age of 3 months (range, 0–75 months). All patients showed global developmental delay and 4 had severely retarded development. Five patients (5/6, 83.3%) had many different movement symptoms with various onset and progression. The symptoms included stereotyped hands movement, non-epileptic myoclonus, dyskinesia, dystonia and choreoathetosis. Whole exome sequencing identified 6 different variants in GNAO1. Three were novel de novo variants and atypical presentation was noted in a patient. One variant turned out to be inherited from patient’s mother who had mosaic variant. Distinct and characteristics movement phenotypes in patients with variant p.Glu246Lys and p.Arg209His were elucidated by in-depth phenotyping and literature review. Conclusions: We reported 6 patients with GNAO1 encephalopathy showing an extremely diverse clinical spectrum on video. Some characteristic movement features identified by careful inspection may also provide important diagnostic insight and practice guidelines.

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Global developmental delay and intellectual disability associated with a de novo TOP2B mutation

Clinica Chimica Acta ◽

10.1016/j.cca.2017.03.022 ◽

2017 ◽

Vol 469 ◽

pp. 63-68 ◽

Cited By ~ 12

Author(s):

Ching-wan Lam ◽

Wai-lan Yeung ◽

Chun-yiu Law

Keyword(s):

Intellectual Disability ◽

Developmental Delay ◽

De Novo ◽

Global Developmental Delay

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Spectrum of movement disorders in GNAO1 encephalopathy: in-depth phenotyping and case-by-case analysis

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-020-01594-3 ◽

2020 ◽

Vol 15 (1) ◽

Author(s):

Soo Yeon Kim ◽

YoungKyu Shim ◽

Young Joon Ko ◽

Soojin Park ◽

Se Song Jang ◽

...

Keyword(s):

Literature Review ◽

Exome Sequencing ◽

Developmental Delay ◽

Whole Exome Sequencing ◽

De Novo ◽

Neurodevelopmental Disorder ◽

Epileptic Encephalopathy ◽

Global Developmental Delay ◽

Pathogenic Variants ◽

Whole Exome

Abstract Background GNAO1 encephalopathy is a rare neurodevelopmental disorder characterized by distinct movement presentations and early onset epileptic encephalopathy. Here, we report the in-depth phenotyping of genetically confirmed patients with GNAO1 encephalopathy, focusing on movement presentations. Results Six patients who participated in Korean Undiagnosed Disease Program were diagnosed to have pathogenic or likely pathogenic variants in GNAO1 using whole exome sequencing. All medical records and personal video clips were analyzed with a literature review. Three of the 6 patients were male. Median follow-up duration was 41 months (range 7–78 months) and age at last examination was 7.4 years (range 3.3–16.9 years). Initial complaints were hypotonia or developmental delay in 5 and right-hand clumsiness in 1 patient, which were noticed at median age of 3 months (range 0–75 months). All patients showed global developmental delay and 4 had severely retarded development. Five patients (5/6, 83.3%) had many different movement symptoms with various onset and progression. The symptoms included stereotyped hands movement, non-epileptic myoclonus, dyskinesia, dystonia and choreoathetosis. Whole exome sequencing identified 6 different variants in GNAO1. Three were novel de novo variants and atypical presentation was noted in a patient. One variant turned out to be inherited from patient’s mother who had mosaic variant. Distinct and characteristics movement phenotypes in patients with variant p.Glu246Lys and p.Arg209His were elucidated by in-depth phenotyping and literature review. Conclusions We reported 6 patients with GNAO1 encephalopathy showing an extremely diverse clinical spectrum on video. Some characteristic movement features identified by careful inspection may also provide important diagnostic insight and practice guidelines.

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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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De novo variant in the MAPK8IP3 gene in the differential diagnosis of global development delay. Case report.

10.5327/1516-3180.181 ◽

2021 ◽

Author(s):

Joseph Bruno Bidin Brooks

Keyword(s):

Case Report ◽

Developmental Delay ◽

De Novo ◽

Symptomatic Treatment ◽

Global Developmental Delay ◽

World Population ◽

Global Development ◽

Pathogenic Variants ◽

Development Delay ◽

Muscle Hypotonia

Context: The global development delay has a high prevalence and heterogeneity in the world population. With the advancement of technology and detection of pathogenic variants detected by sequencing the exome, genes related to global developmental delay could be identified and collaborate for further clinical clarification. Among the studied genes, the MAPK8IP3 gene, became an attractive candidate due to its performance in neuronal axonal transport in vertebrates and invertebrates. This case report was approved by the Ethics Committee of Universidade Metropolitana de Santos. Case Report: The present case refers to a 6-year-old male patient presenting with a clinical picture of global developmental delay without bodily dysmorphia. Cerebellar ataxia, muscle hypotonia and intellectual impairment are important clinical impairments. Skull MRI and complementary exams were normal. The genetic study showed a new and heterozygous pathogenic variant in the MAPK8IP3 gene. Conclusions: Symptomatic treatment with multiprofessional rehabilitation was instituted with partial improvement of symptoms.

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