scholarly journals NMIHBA results from hypomorphic PRUNE1 variants that lack short-chain exopolyphosphatase activity

2020 ◽  
Author(s):  
Harikiran Nistala ◽  
John Dronzek ◽  
Claudia Gonzaga-Jauregui ◽  
Shek Man Chim ◽  
Saathyaki Rajamani ◽  
...  
Keyword(s):  
Neurodegenerative Disorder ◽  
Neurodevelopmental Disorder ◽  
Cortical Atrophy ◽  
Global Developmental Delay ◽  
Compound Heterozygous ◽  
Genetic Ablation ◽  
Severe Intellectual Disability ◽  
Disease Biology ◽  
Variant Alleles ◽  
Clinical Description

Abstract Neurodevelopmental disorder with microcephaly, hypotonia and variable brain anomalies (NMIHBA) is an autosomal recessive neurodevelopmental and neurodegenerative disorder characterized by global developmental delay and severe intellectual disability. Microcephaly, progressive cortical atrophy, cerebellar hypoplasia and delayed myelination are neurological hallmarks in affected individuals. NMIHBA is caused by biallelic variants in PRUNE1 encoding prune exopolyphosphatase 1. We provide in-depth clinical description of two affected siblings harboring compound heterozygous variant alleles, c.383G > A (p.Arg128Gln), c.520G > T (p.Gly174*) in PRUNE1. To gain insights into disease biology, we biochemically characterized missense variants within the conserved N-terminal aspartic acid-histidine-histidine (DHH) motif and provide evidence that they result in the destabilization of protein structure and/or loss of exopolyphosphatase activity. Genetic ablation of Prune1 results in midgestational lethality in mice, associated with perturbations to embryonic growth and vascular development. Our findings suggest that NMIHBA results from hypomorphic variant alleles in humans and underscore the potential key role of PRUNE1 exopolyphoshatase activity in neurodevelopment.

scholarly journals Functional modeling of NMIHBA-causing PRUNE1 variants reveals a requirement for its exopolyphosphatase activity

2020 ◽  
Author(s):  
Harikiran Nistala ◽  
John Dronzek ◽  
Claudia Gonzaga-Jauregui ◽  
Shek Man Chim ◽  
Saathyaki Rajamani ◽  
...  
Keyword(s):  
Neurodegenerative Disorder ◽  
Neurodevelopmental Disorder ◽  
Cortical Atrophy ◽  
Global Developmental Delay ◽  
Compound Heterozygous ◽  
Genetic Ablation ◽  
Severe Intellectual Disability ◽  
Disease Biology ◽  
Variant Alleles ◽  
Clinical Description

AbstractNeurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies (NMIHBA) is an autosomal recessive neurodevelopmental and neurodegenerative disorder characterized by global developmental delay and severe intellectual disability. Microcephaly, progressive cortical atrophy, cerebellar hypoplasia and delayed myelination are neurological hallmarks in affected individuals. NMIHBA is caused by biallelic variants in PRUNE1 encoding prune exopolyphosphatase 1. We provide in-depth clinical description of two affected siblings harboring compound heterozygous variant alleles, c.383G>A (p.Arg128Gln), c.520G>T (p.Gly174*) in PRUNE1. To gain insights into disease biology, we biochemically characterized missense variants within the conserved N-terminal aspartic acid-histidine-histidine (DHH) motif and provide evidence that they result in the destabilization of protein structure and/or loss of exopolyphosphatase activity. Genetic ablation of Prune1 results in midgestational lethality in mice, associated with perturbations to embryonic growth and vascular development. Our findings suggest that NMIHBA results from hypomorphic variant alleles in humans and underscore the potential key role of PRUNE1 exopolyphoshatase activity in neurodevelopment.

scholarly journals A Neurodevelopmental Disorder Caused by Mutations in the VPS51 Subunit of the GARP and EARP Complexes

2018 ◽  
Author(s):  
David C. Gershlick ◽  
Morié Ishida ◽  
Julie R. Jones ◽  
Allison Bellomo ◽  
Juan S. Bonifacino ◽  
...  
Keyword(s):  
Protein Complexes ◽  
Genetic Locus ◽  
Neurodevelopmental Disorder ◽  
Failure To Thrive ◽  
The Other ◽  
Single Amino Acid ◽  
Global Developmental Delay ◽  
Compound Heterozygous ◽  
Acid Hydrolases ◽  
Gene Encoding

AbstractGARP and EARP are related heterotetrameric protein complexes that associate with the cytosolic face of the trans-Golgi network and recycling endosomes, respectively. At these locations, GARP and EARP function to promote the fusion of endosome-derived transport carriers with their corresponding compartments. GARP and EARP share three subunits, VPS51, VPS52 and VPS53, and each has an additional complex-specific subunit, VPS54 or VPS50, respectively. The role of these complexes in human physiology, however, remains poorly understood. By exome sequencing, we have identified compound heterozygous mutations in the gene encoding the shared GARP/EARP subunit VPS51 in a six-year-old patient with severe global developmental delay, microcephaly, hypotonia, epilepsy, cortical vision impairment, pontocerebellar abnormalities, failure to thrive, liver dysfunction, lower extremity edema and dysmorphic features. The mutation in one allele causes a frameshift that produces a longer but highly unstable protein that is degraded by the proteasome. In contrast, the other mutant allele produces a protein with a single amino-acid substitution that is stable but assembles less efficiently with the other GARP/EARP subunits. Consequently, skin fibroblasts from the patient have reduced levels of fully-assembled GARP and EARP complexes. Likely because of this deficiency, the patient’s fibroblasts display altered distribution of the cation-independent mannose 6-phosphate receptor, which normally sorts acid hydrolases to lysosomes. Furthermore, a fraction of the patient’s fibroblasts exhibit swelling of lysosomes. These findings thus identify a novel genetic locus for a neurodevelopmental disorder and highlight the critical importance of GARP/EARP function in cellular and organismal physiology.

scholarly journals Unusual phenotypes in patients with a pathogenic germline variant in DICER1

2021 ◽  
Author(s):  
Kateryna Venger ◽  
Miriam Elbracht ◽  
Julia Carlens ◽  
Peter Deutz ◽  
Felix Zeppernick ◽  
...  
Keyword(s):  
Wilms Tumor ◽  
Pleuropulmonary Blastoma ◽  
Global Developmental Delay ◽  
Facial Dysmorphism ◽  
Compound Heterozygous ◽  
Incomplete Penetrance ◽  
Developmental Abnormalities ◽  
Lung Cysts ◽  
Developmental Features ◽  
Skeletal Findings

AbstractPathogenic germline DICER1 variants are associated with pleuropulmonary blastoma, multinodular goiter, embryonal rhabdomyosarcoma and other tumour types, while mosaic missense DICER1 variants in the RNase IIIb domain are linked to cause GLOW (global developmental delay, lung cysts, overgrowth, and Wilms’ tumor) syndrome. Here, we report four families with germline DICER1 pathogenic variants in which one member in each family had a more complex phenotype, including skeletal findings, facial dysmorphism and developmental abnormalities. The developmental features occur with a variable expressivity and incomplete penetrance as also described for the neoplastic and dysplastic lesions associated with DICER1 variants. Whole exome sequencing (WES) was performed on all four cases and revealed no further pathogenic or likely pathogenic dominant, homozygous or compound heterozygous variants in three of them. Notably, a frameshift variant in ARID1B was detected in one patient explaining part of her phenotype. This series of patients shows that pathogenic DICER1 variants may be associated with a broader phenotypic spectrum than initially assumed, including predisposition to different tumours, skeletal findings, dysmorphism and developmental abnormalities, but genetic work up in syndromic patients should be comprehensive in order not to miss additional underlying /modifying causes.

scholarly journals Contribution of Multiple Inherited Variants to Autism Spectrum Disorder (ASD) in a Family with 3 Affected Siblings

Genes ◽  
2021 ◽  
Vol 12 (7) ◽  
pp. 1053
Author(s):  
Jasleen Dhaliwal ◽  
Ying Qiao ◽  
Kristina Calli ◽  
Sally Martell ◽  
Simone Race ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Rare Variants ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Compound Heterozygous ◽  
Variable Effect ◽  
Gabaergic Neurotransmission ◽  
High Heritability ◽  
Compound Heterozygous Variants

Autism Spectrum Disorder (ASD) is the most common neurodevelopmental disorder in children and shows high heritability. However, how inherited variants contribute to ASD in multiplex families remains unclear. Using whole-genome sequencing (WGS) in a family with three affected children, we identified multiple inherited DNA variants in ASD-associated genes and pathways (RELN, SHANK2, DLG1, SCN10A, KMT2C and ASH1L). All are shared among the three children, except ASH1L, which is only present in the most severely affected child. The compound heterozygous variants in RELN, and the maternally inherited variant in SHANK2, are considered to be major risk factors for ASD in this family. Both genes are involved in neuron activities, including synaptic functions and the GABAergic neurotransmission system, which are highly associated with ASD pathogenesis. DLG1 is also involved in synapse functions, and KMT2C and ASH1L are involved in chromatin organization. Our data suggest that multiple inherited rare variants, each with a subthreshold and/or variable effect, may converge to certain pathways and contribute quantitatively and additively, or alternatively act via a 2nd-hit or multiple-hits to render pathogenicity of ASD in this family. Additionally, this multiple-hits model further supports the quantitative trait hypothesis of a complex genetic, multifactorial etiology for the development of ASDs.

scholarly journals Genotype–phenotype correlations and novel molecular insights into the DHX30-associated neurodevelopmental disorders

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Ilaria Mannucci ◽  
Nghi D. P. Dang ◽  
Hannes Huber ◽  
Jaclyn B. Murry ◽  
Jeff Abramson ◽  
...  
Keyword(s):  
De Novo ◽  
Clinical Course ◽  
Neurodevelopmental Disorder ◽  
Global Developmental Delay ◽  
Helicase Activity ◽  
Speech Impairment ◽  
Human Phenotype ◽  
Missense Variants ◽  
The Impact ◽  
Global Translation

Abstract Background We aimed to define the clinical and variant spectrum and to provide novel molecular insights into the DHX30-associated neurodevelopmental disorder. Methods Clinical and genetic data from affected individuals were collected through Facebook-based family support group, GeneMatcher, and our network of collaborators. We investigated the impact of novel missense variants with respect to ATPase and helicase activity, stress granule (SG) formation, global translation, and their effect on embryonic development in zebrafish. SG formation was additionally analyzed in CRISPR/Cas9-mediated DHX30-deficient HEK293T and zebrafish models, along with in vivo behavioral assays. Results We identified 25 previously unreported individuals, ten of whom carry novel variants, two of which are recurrent, and provide evidence of gonadal mosaicism in one family. All 19 individuals harboring heterozygous missense variants within helicase core motifs (HCMs) have global developmental delay, intellectual disability, severe speech impairment, and gait abnormalities. These variants impair the ATPase and helicase activity of DHX30, trigger SG formation, interfere with global translation, and cause developmental defects in a zebrafish model. Notably, 4 individuals harboring heterozygous variants resulting either in haploinsufficiency or truncated proteins presented with a milder clinical course, similar to an individual harboring a de novo mosaic HCM missense variant. Functionally, we established DHX30 as an ATP-dependent RNA helicase and as an evolutionary conserved factor in SG assembly. Based on the clinical course, the variant location, and type we establish two distinct clinical subtypes. DHX30 loss-of-function variants cause a milder phenotype whereas a severe phenotype is caused by HCM missense variants that, in addition to the loss of ATPase and helicase activity, lead to a detrimental gain-of-function with respect to SG formation. Behavioral characterization of dhx30-deficient zebrafish revealed altered sleep-wake activity and social interaction, partially resembling the human phenotype. Conclusions Our study highlights the usefulness of social media to define novel Mendelian disorders and exemplifies how functional analyses accompanied by clinical and genetic findings can define clinically distinct subtypes for ultra-rare disorders. Such approaches require close interdisciplinary collaboration between families/legal representatives of the affected individuals, clinicians, molecular genetics diagnostic laboratories, and research laboratories.

Two new cases of nonepileptic neurodevelopmental disorder due to GRIN2B variants and detailed clinical description of the behavioral phenotype

2021 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Paola Sabrina Buonuomo ◽  
Gerarda Mastrogiorgio ◽  
Paolo Alfieri ◽  
Alessandra Terracciano ◽  
Claudia Cesario ◽  
...  
Keyword(s):  
Neurodevelopmental Disorder ◽  
Behavioral Phenotype ◽  
Clinical Description

scholarly journals Compound heterozygous PLA2G6 loss-of-function variants in Swaledale sheep with neuroaxonal dystrophy

2020 ◽  
Author(s):  
Anna Letko ◽  
Ben Strugnell ◽  
Irene M. Häfliger ◽  
Julia M. Paris ◽  
Katie Waine ◽  
...  
Keyword(s):  
Neurodegenerative Disorder ◽  
Neuronal Degeneration ◽  
Neuroaxonal Dystrophy ◽  
Histopathological Analysis ◽  
Compound Heterozygous ◽  
Loss Of Function ◽  
Genome Region ◽  
Pathogenic Variants ◽  
Progressive Ataxia ◽  
Intron 2

Abstract Sporadic occurrences of neurodegenerative disorders including neuroaxonal dystrophy (NAD) have been previously reported in sheep. However, so far no causative genetic variant has been found for ovine NAD. The aim of this study was to characterize the phenotype and the genetic aetiology of an early-onset neurodegenerative disorder observed in several lambs of purebred Swaledale sheep, a native English breed. Affected lambs showed progressive ataxia and stiff gait and subsequent histopathological analysis revealed the widespread presence of axonal spheroid indicating neuronal degeneration. Thus, the observed clinical phenotype could be explained by a novel form of NAD. After SNP genotyping and subsequent linkage mapping within a paternal half-sib pedigree with a total of five NAD-affected lambs, we identified two loss-of-function variants by whole-genome sequencing in the ovine PLA2G6 gene situated in a NAD-linked genome region on chromosome 3. All cases were carriers of a compound heterozygous splice site variant in intron 2 and a nonsense variant in exon 8. Herein we present evidence for the occurrence of a familial novel form of recessively inherited NAD in sheep due to allelic heterogeneity at PLA2G6. This study reports two pathogenic variants in PLA2G6 causing a novel form of NAD in Swaledale sheep which enables selection against this fatal disorder.

scholarly journals A Novel ELP2 Compound Heterozygous Mutation in a Boy with Severe Intellectual Disability, Spastic Diplegia, Stereotypic Behavior and Review of the Current Literature

2020 ◽  
Vol 11 (5-6) ◽  
pp. 315-319
Author(s):  
Ayberk Turkyilmaz ◽  
Gunes Sager
Keyword(s):  
Intellectual Disability ◽  
Current Literature ◽  
Stereotypic Behavior ◽  
Compound Heterozygous Mutation ◽  
Heterozygous Mutation ◽  
Spastic Diplegia ◽  
Compound Heterozygous ◽  
Sequencing Analysis ◽  
Severe Intellectual Disability ◽  
Elongator Complex

The elongator complex consists of 6 highly conserved subunit proteins and is indispensable for various cellular functions, such as transcription elongation, histone acetylation, and tRNA modification. The elongator complex contains 2 subunits, each of which consists of 3 different proteins (encoded by the <i>ELP1–3</i> and <i>ELP4–6</i> genes). According to the OMIM database, <i>ELP2</i> gene variations have been reported to be associated with autosomal recessive mental retardation type 58. Here, we report a male patient with severe intellectual disability, spastic diplegia, and stereotypic behavior; in addition, we also provide a review of the current literature. Using whole-exome sequencing analysis, we detected a novel compound heterozygous variation in the <i>ELP2</i> gene. We present this case report to clarify the clinical findings of a very rare neurodevelopmental phenotype and to contribute new information to the current literature on genotype-phenotype correlations.

scholarly journals Site-specific abnormalities in the visual system of a mouse model of CDKL5 deficiency disorder

2019 ◽  
Vol 28 (17) ◽  
pp. 2851-2861 ◽  
Author(s):  
Leonardo Lupori ◽  
Giulia Sagona ◽  
Claudia Fuchs ◽  
Raffaele Mazziotti ◽  
Antonia Stefanov ◽  
...  
Keyword(s):  
Neurodevelopmental Disorder ◽  
Normal Function ◽  
Dorsal Lateral Geniculate Nucleus ◽  
Global Developmental Delay ◽  
Visual Responses ◽  
Preclinical Research ◽  
Morphological Alterations ◽  
Visual Deficits ◽  
Visual Cortical ◽  
And Function

Abstract CDKL5 deficiency disorder (CDD) is a neurodevelopmental disorder characterized by a severe global developmental delay and early-onset seizures. Notably, patients show distinctive visual abnormalities often clinically diagnosed as cortical visual impairment. However, the involvement of cerebral cortical dysfunctions in the origin of the symptoms is poorly understood. CDD mouse models also display visual deficits, and cortical visual responses can be used as a robust biomarker in CDKL5 mutant mice. A deeper understanding of the circuits underlying the described visual deficits is essential for directing preclinical research and translational approaches. Here, we addressed this question in two ways: first, we performed an in-depth morphological analysis of the visual pathway, from the retina to the primary visual cortex (V1), of CDKL5 null mice. We found that the lack of CDKL5 produced no alteration in the organization of retinal circuits. Conversely, CDKL5 mutants showed reduced density and altered morphology of spines and decreased excitatory synapse marker PSD95 in the dorsal lateral geniculate nucleus and in V1. An increase in the inhibitory marker VGAT was selectively present in V1. Second, using a conditional CDKL5 knockout model, we showed that selective cortical deletion of CDKL5 from excitatory cells is sufficient to produce abnormalities of visual cortical responses, demonstrating that the normal function of cortical circuits is dependent on CDKL5. Intriguingly, these deficits were associated with morphological alterations of V1 excitatory and inhibitory synaptic contacts. In summary, this work proposes cortical circuit structure and function as a critically important target for studying CDD.

Clinical Characteristics and Genotype–Phenotype Correlation in Children with KMT2E Gene-Related Neurodevelopmental Disorders: Report of Two New Cases and Review of Published Literature

2020 ◽  
Author(s):  
Indar Kumar Sharawat ◽  
Prateek Kumar Panda ◽  
Lesa Dawman
Keyword(s):  
Developmental Delay ◽  
Neurodevelopmental Disorder ◽  
Copy Number Variants ◽  
Cerebral White Matter ◽  
Global Developmental Delay ◽  
Missense Mutations ◽  
Search Terms ◽  
Pathogenic Factors ◽  
The Common ◽  
Variable Combination

Abstract Background In recent years, many new candidate genes are being identified as putative pathogenic factors in children with developmental delay and autism. Recently, heterozygous mutations in the KMT2E gene have been identified as a cause of a unique neurodevelopmental disorder with variable combination of global developmental delay or isolated speech delay, intellectual disability, autistic features, and seizures. Methods Here, we present two new cases of KMT2E mutation-associated neurodevelopmental disorder in a 4-year-old girl and 5-year-old boy. We also performed a pooled review of the previously published cases of KMT2E-related neurodevelopmental disorder. Articles were identified through search engines using appropriate search terms. Results Along with the presented 2 cases, 40 cases were analyzed. Out of them, 30, 6, and 4 children had protein-truncating mutations, missense mutations, and copy number variants, respectively. The common features were global developmental delay (97%) followed by macrocephaly (35%), seizures (30%), and autism (25%). Children with missense variants had severe phenotype, with microcephaly, profound developmental delay, and increased frequency of seizures. Neuroimaging revealed nonspecific changes, including cerebral white matter signal abnormalities. Conclusion KMT2E-related neurodevelopmental disorder remains one of the clinical differentials in children with global developmental delay and/or autistic features/seizure. With the reporting of more cases in the future, the already heterogeneous clinical spectrum of this disease is likely to be widened.

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