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

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.

scholarly journals Chromosomal Microarray Analysis in Children with Unexplained Developmental Delay/Intellectual Disability

2018 ◽  
Vol 08 (01) ◽  
pp. 001-009
Author(s):  
Pinar Arican ◽  
Berk Ozyilmaz ◽  
Dilek Cavusoglu ◽  
Pinar Gencpinar ◽  
Kadri Erdogan ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Developmental Delay ◽  
De Novo ◽  
Copy Number Variants ◽  
Autism Spectrum ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Genetic Syndromes ◽  
Pathogenic Cnvs ◽  
Spectrum Disorders

AbstractChromosomal microarray (CMA) analysis for discovery of copy number variants (CNVs) is now recommended as a first-line diagnostic tool in patients with unexplained developmental delay/intellectual disability (DD/ID) and autism spectrum disorders. In this study, we present the results of CMA analysis in patients with DD/ID. Of 210 patients, pathogenic CNVs were detected in 26 (12%) and variants of uncertain clinical significance in 36 (17%) children. The diagnosis of well-recognized genetic syndromes was achieved in 12 patients. CMA analysis revealed pathogenic de novo CNVs, such as 11p13 duplication with new clinical features. Our results support the utility of CMA as a routine diagnostic test for unexplained DD/ID.

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

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 <i>KMT2E</i> variants underly O&apos;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 <i>KMT2E</i> 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 <i>KMT2E</i> and <i>LHFPL3</i>. 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.

scholarly journals Pathogenic DNM1 Gene Variant Presenting With Unusually Nonsevere Neurodevelopmental Phenotype: A Case Report

2021 ◽  
Vol 7 (5) ◽  
pp. e618
Author(s):  
Elaine Choi ◽  
Breanne Dale ◽  
Rajesh RamachandranNair ◽  
Resham Ejaz
Keyword(s):  
Developmental Delays ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Brain Mri ◽  
Intractable Epilepsy ◽  
Missense Variant ◽  
Chromosomal Microarray ◽  
Gtpase Domain ◽  
Pathogenic Variants ◽  
Neurodevelopmental Phenotype

Background and ObjectivesTo date, all reports of pathogenic variants affecting the GTPase domain of the DNM1 gene have a clinically severe neurodevelopmental phenotype, including severe delays or intractable epilepsy. We describe a case with moderate developmental delays and self-resolved epilepsy.MethodsThe patient was followed by our neurology and genetics teams. After clinical examination and EEG to characterize the patient's presentation, we conducted etiologic workup including brain MRI, chromosomal microarray, genetic and metabolic investigations, and nerve conduction studies. Subsequently, we arranged an Intellectual Disability Plus Trio Panel.ResultsOur patient presented with seizures at 2 days old, requiring phenobarbital. She also had hypotonia, mild dysmorphic features, and mild ataxia. Although initial workup returned unremarkable, the trio gene panel identified a de novo heterozygous pathogenic missense variant in the DNM1 GTPase domain. Now 4 years old, she has been seizure-free for 3 years without ongoing treatment and has nonsevere developmental delays (e.g., ambulates independently and speaks 2-word phrases).DiscussionOur case confirms that not all individuals with DNM1 pathogenic variants, even affecting the GTPase domain, will present with intractable epilepsy or severe delays. Expanding the known clinical spectrum of dynamin-related neurodevelopmental disorder is crucial for patient prognostication and counseling.

scholarly journals An integrative approach to investigate the respective roles of single-nucleotide variants and copy-number variants in Attention-Deficit/Hyperactivity Disorder

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Leandro de Araújo Lima ◽  
Ana Cecília Feio-dos-Santos ◽  
Sintia Iole Belangero ◽  
Ary Gadelha ◽  
Rodrigo Affonseca Bressan ◽  
...  
Keyword(s):  
Attention Deficit Hyperactivity Disorder ◽  
Attention Deficit ◽  
Copy Number ◽  
De Novo ◽  
Copy Number Variants ◽  
Integrative Approach ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Hyperactivity Disorder ◽  
New Genes

Abstract Many studies have attempted to investigate the genetic susceptibility of Attention-Deficit/Hyperactivity Disorder (ADHD), but without much success. The present study aimed to analyze both single-nucleotide and copy-number variants contributing to the genetic architecture of ADHD. We generated exome data from 30 Brazilian trios with sporadic ADHD. We also analyzed a Brazilian sample of 503 children/adolescent controls from a High Risk Cohort Study for the Development of Childhood Psychiatric Disorders, and also previously published results of five CNV studies and one GWAS meta-analysis of ADHD involving children/adolescents. The results from the Brazilian trios showed that cases with de novo SNVs tend not to have de novo CNVs and vice-versa. Although the sample size is small, we could also see that various comorbidities are more frequent in cases with only inherited variants. Moreover, using only genes expressed in brain, we constructed two “in silico” protein-protein interaction networks, one with genes from any analysis, and other with genes with hits in two analyses. Topological and functional analyses of genes in this network uncovered genes related to synapse, cell adhesion, glutamatergic and serotoninergic pathways, both confirming findings of previous studies and capturing new genes and genetic variants in these pathways.

scholarly journals A Novel Missense Variant in the Gene PPP2R5D Causes a Rare Neurodevelopmental Disorder with Increased Phenotype

2021 ◽  
Vol 2021 ◽  
pp. 1-7
Author(s):  
Lulu Yan ◽  
Ru Shen ◽  
Zongfu Cao ◽  
Chunxiao Han ◽  
Yuxin Zhang ◽  
...  
Keyword(s):  
De Novo ◽  
Genetic Disorder ◽  
Neurodevelopmental Disorder ◽  
Three Dimensional ◽  
Missense Variant ◽  
Pathogenic Variant ◽  
Dimensional Structure ◽  
Chinese Family ◽  
Speech Impairment ◽  
Pathogenic Variants

PPP2R5D-related neurodevelopmental disorder, which is mainly caused by de novo missense variants in the PPP2R5D gene, is a rare autosomal dominant genetic disorder with about 100 patients and a total of thirteen pathogenic variants known to exist globally so far. Here, we present a 24-month-old Chinese boy with developmental delay and other common clinical characteristics of PPP2R5D-related neurodevelopmental disorder including hypotonia, macrocephaly, intellectual disability, speech impairment, and behavioral abnormality. Trio-whole exome sequencing (WES) and Sanger sequencing were performed to identify the causal gene variant. The pathogenicity of the variant was evaluated using bioinformatics tools. We identified a novel pathogenic variant in the PPP2R5D gene (c.620G>T, p.Trp207Leu). The variant is located in the variant hotspot region of this gene and is predicted to cause PPP2R5D protein dysfunction due to an increase in local hydrophobicity and unstable three-dimensional structure. We report a novel pathogenic variant of PPP2R5D associated with PPP2R5D-related neurodevelopmental disorder from a Chinese family. Our findings expanded the phenotypic and mutational spectrum of PPP2R5D-related neurodevelopmental disorder.

scholarly journals The prenatal diagnosis and clinical outcomes of fetuses with 15q11.2 copy number variants: a case series of 36 patients

2021 ◽  
Author(s):  
Jessica Kang ◽  
Chien Nan Lee ◽  
Yi-Ning Su ◽  
Ming-Wei Lin ◽  
Yi-Yun Tai ◽  
...  
Keyword(s):  
Pregnant Women ◽  
Developmental Delay ◽  
Copy Number ◽  
De Novo ◽  
Copy Number Variants ◽  
Case Series ◽  
Copy Number Variant ◽  
University Hospital ◽  
Limited Information ◽  
Ultrasound Findings

Objective: The prenatal genetic counseling of fetus diagnosed with the 15q11.2 copy number variant (CNV) involving the BP1-BP2 region has been difficult due to limited information and controversial opinion on prognosis. Design: Case series. Setting: This study uses data from National Taiwan University Hospital. Sample: Data of 36 pregnant women who underwent prenatal microarray analysis from 2012 to 2017 and were assessed at National Taiwan University Hospital. Methods: Data were collected by reviewing patients’ medical record. Comparison of patient characteristics, prenatal ultrasound findings and postnatal outcomes between different cases involving the 15q11.2 BP1-BP2 region were presented. Main outcome measured: Postnatal prognosis. Results: Out of the 36 patients diagnosed with CNVs involving the BP1-BP2 region, 5 were diagnosed with microduplication and 31 with microdeletion. Abnormal ultrasound findings were recorded in 12 cases prenatally. De novo microduplications were observed in 25% of the cases and microdeletions were found in 14%. Amongst the cases, 10 pregnant women received termination of pregnancy and 26 gave birth to healthy individuals (27 babies in total). Conclusion: The prognoses of 15q11.2 CNVs were controversial and recent studies have revealed its connection with developmental delay and autism. In our study, no obvious developmental delay or neurological disorders were detected postnatally in the 1 case of 15q11.2 microduplication and 25 cases of microdeletion.

Gray Matter Heterotopia, Mental Retardation, Developmental Delay, Microcephaly, and Facial Dysmorphisms in a Boy with Ring Chromosome 6: A 10-Year Follow-Up and Literature Review

2018 ◽  
Vol 154 (4) ◽  
pp. 201-208 ◽  
Author(s):  
Shu Liu ◽  
Zhiqing Wang ◽  
Sisi Wei ◽  
Jinqun Liang ◽  
Nuan Chen ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Gray Matter ◽  
De Novo ◽  
Ring Chromosome ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Chromosome 6 ◽  
Material Loss ◽  
Ring Chromosome 6

Ring chromosome 6, r(6), is an extremely rare cytogenetic abnormality with clinical heterogeneity which arises typically de novo. The phenotypes of r(6) can be highly variable, ranging from almost normal to severe malformations and neurological defects. Up to now, only 33 cases have been reported in the literature. In this 10-year follow-up study, we report a case presenting distinctive facial features, severe developmental delay, and gray matter heterotopia with r(6) and terminal deletions of 6p25.3 (115426-384174, 268 kb) and 6q26-27 (168697778-170732033, 2.03 Mb) encompassing 2 and 15 candidate genes, respectively, which were detected using G-banding karyotyping, FISH, and chromosomal microarray analysis. We also analyzed the available information on the clinical features of the reported r(6) cases in order to provide more valuable information on genotype-phenotype correlations. To the best of our knowledge, this is the first report of gray matter heterotopia manifested in a patient with r(6) in China, and the deletions of 6p and 6q in our case are the smallest with the precise size of euchromatic material loss currently known.

A case of deletion 8q22.2q22.3 in a child with de novo balanced translocation t(1;6)

2021 ◽  
pp. 49-56
Author(s):  
М.Е. Миньженкова ◽  
Ж.Г. Маркова ◽  
И.В. Анисимова ◽  
И.В. Канивец ◽  
Н.В. Шилова
Keyword(s):  
Developmental Delay ◽  
De Novo ◽  
Current Trend ◽  
Chromosomal Microarray ◽  
Congenital Defects ◽  
Chromosomal Microarray Analysis ◽  
Balanced Translocation ◽  
Genomic Imbalance ◽  
Abnormal Phenotype ◽  
Balanced Translocations

Выяснение этиопатогенеза аномального фенотипа у пациентов со сбалансированными транслокациями является актуальным аспектом в современной клинической цитогенетике. Формирование аномалий развития может быть ассоциировано с наличием скрытого геномного дисбаланса как в точках разрывов, так и на хромосомах, не задействованных в перестройке. Целью данного исследования явилась этиологическая диагностика геномного дисбаланса у пациента со сбалансированной транслокацией и аномалиями развития. Для детекции геномного дисбаланса у пациента со сбалансированной транслокацией использовали хромосомный микроматричный анализ (ХМА) и FISH-исследование. У пациента со сбалансированной транслокацией при ХМА была выявлена делеция на хромосоме 8, не задействованной в транслокации. Таким образом, в статье представлен новый случай делеции 8q22.2q22.3 у пациента со сбалансированной транслокацией t(1;6) и аномалиями развития вследствие делеции. Identification of the etiopathogenesis of the abnormal phenotype in patients with balanced translocations is current trend in cytogenetic laboratories. The formation of developmental anomalies can be associated with the presence of a cryptic genomic imbalance both at breakpoints and on chromosomes not involved in rearrangements.The aim of this study is diagnostics of genomic imbalance in a patient with balanced translocation and abnormal phenotype. The case was characterized by GTG-banding, chromosomal microarray analysis and FISH diagnosis. We present a new case of deletion 8q22.2-q22.3 in child with balanced translocation t(1;6) and developmental delay/congenital defects due to deletion.

Recurrent de novo missense variants in GNB2 can cause syndromic intellectual disability

2021 ◽  
pp. jmedgenet-2020-107462
Author(s):  
Natalie B Tan ◽  
Alistair T Pagnamenta ◽  
Matteo P Ferla ◽  
Jonathan Gadian ◽  
Brian HY Chung ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
G Proteins ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Missense Variant ◽  
Cellular Functions ◽  
Missense Variants ◽  
Neurodevelopmental Disease ◽  
Genes Encoding ◽  
International Data

PurposeBinding proteins (G-proteins) mediate signalling pathways involved in diverse cellular functions and comprise Gα and Gβγ units. Human diseases have been reported for all five Gβ proteins. A de novo missense variant in GNB2 was recently reported in one individual with developmental delay/intellectual disability (DD/ID) and dysmorphism. We aim to confirm GNB2 as a neurodevelopmental disease gene, and elucidate the GNB2-associated neurodevelopmental phenotype in a patient cohort.MethodsWe discovered a GNB2 variant in the index case via exome sequencing and sought individuals with GNB2 variants via international data-sharing initiatives. In silico modelling of the variants was assessed, along with multiple lines of evidence in keeping with American College of Medical Genetics and Genomics guidelines for interpretation of sequence variants.ResultsWe identified 12 unrelated individuals with five de novo missense variants in GNB2, four of which are recurrent: p.(Ala73Thr), p.(Gly77Arg), p.(Lys89Glu) and p.(Lys89Thr). All individuals have DD/ID with variable dysmorphism and extraneurologic features. The variants are located at the universally conserved shared interface with the Gα subunit, which modelling suggests weaken this interaction.ConclusionMissense variants in GNB2 cause a congenital neurodevelopmental disorder with variable syndromic features, broadening the spectrum of multisystem phenotypes associated with variants in genes encoding G-proteins.

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