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 A Founder Pathogenic Variant of PPIB Unique to Chinese Population Causes Osteogenesis Imperfecta IX

2021 ◽  
Vol 12 ◽  
Author(s):  
Wenting Zhu ◽  
Kai Yan ◽  
Xijing Chen ◽  
Wei Zhao ◽  
Yiqing Wu ◽  
...  
Keyword(s):  
Osteogenesis Imperfecta ◽  
Founder Effect ◽  
Chinese Population ◽  
Disease Incidence ◽  
Genetic Disorder ◽  
Missense Variant ◽  
Bone Fragility ◽  
Pathogenic Variant ◽  
Pathogenic Variants ◽  
Specific Allele

Background: Osteogenesis imperfecta (OI) is a heterogeneous genetic disorder characterized by bone fragility. PPIB pathogenic variants cause a perinatal lethal form of OI type IX. A limited number of pathogenic variants have been reported so far worldwide.Methods: We identified a rare pedigree whose phenotype was highly consistent with OI-IX. Exome sequencing was performed to uncover the causal variants. The variant pathogenicity was classified following the ACMG/AMP guidelines. The founder effect and the age of the variant were assessed.Results: We identified a homozygous missense variant c.509G > A/p.G170D in PPIB in an affected fetus. This variant is a Chinese-specific allele and can now be classified as pathogenic. We estimated the allele frequency (AF) of this variant to be 0.0000427 in a Chinese cohort involving 128,781 individuals. All patients and carriers shared a common haplotype, indicative of a founder effect. The estimated age of variant was 65,160 years. We further identified pathogenic variants of PPIB in gnomAD and ClinVar databases, the conserved estimation of OI type IX incidence to be 1/1,000,000 in Chinese population.Conclusion: We reported a founder pathogenic variant in PPIB specific to the Chinese population. We further provided our initial estimation of OI-IX disease incidence in China.

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

2020 ◽  
Author(s):  
Ilaria Mannucci ◽  
Nan Cher Yeo ◽  
Hannes Huber ◽  
Jaclyn Murry ◽  
Jeff Abramson ◽  
...  
Keyword(s):  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Missense Variant ◽  
Stress Granule ◽  
Helicase Activity ◽  
Speech Impairment ◽  
Granule Formation ◽  
Missense Variants ◽  
Functional Analyses ◽  
Global Translation

Background We aimed to define the clinical and mutational spectrum, and to provide novel molecular insights into DHX30-associated neurodevelopmental disorder. Methods Clinical and genetic data from affected individuals were collected through family support group, GeneMatcher and our network of collaborators. Novel missense variants were investigated by in-vitro and in-vivo assays. These analyses included investigation of stress granule formation, global translation, ATPase and helicase activity, as well as the effect of selected variants on embryonal development in Zebrafish. Results We identified altogether 25 previously unreported individuals. 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 and global translation, trigger stress granule formation, and cause developmental defects in a zebrafish model. Notably, 4 individuals harboring heterozygous variants resulting either in haploinsufficiency or truncated proteins presented a milder clinical course, similar to an individual bearing a de novo mosaic missense variant within HCM. Late-onset severe ataxia was observed in an individual with a de novo missense variant within the ratchet-like domain, and early-onset lethal epileptic encephalopathy in an individual with a homozygous missense variant within the helicase core region but not within a HCM. We report ten novel variants, two of which are recurrent, and provide evidence of gonadal mosaicism in one family. Functional analyses confirmed pathogenicity of all missense variants, and suggest the existence of clinically distinct subtypes that correlate with their location and nature. Moreover, we established here DHX30 as an ATP-dependent RNA helicase. Conclusions Our study highlights the usefulness of social media in order 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, clinicians, molecular genetics diagnostic laboratories and research laboratories.

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 De novo coding variants in the AGO1 gene cause a neurodevelopmental disorder with intellectual disability

2020 ◽  
Author(s):  
Audrey Schalk ◽  
Margot A. Cousin ◽  
Thomas D. Challman ◽  
Karen E. Wain ◽  
Zöe Powis ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Amino Acid ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Three Dimensional ◽  
Amino Acid Residues ◽  
Protein Coding ◽  
Motor Delay ◽  
Pathogenic Variants ◽  
Coding Variants

ABSTRACTHigh-impact pathogenic variants in more than 1,000 protein-coding genes cause Mendelian forms of neurodevelopmental disorders (NDD), including the newly reported AGO2 gene. This study describes the molecular and clinical characterization of 28 probands with NDD harboring heterozygous AGO1 coding variants. De novo status was always confirmed when parents were available (26/28). A total of 15 unique variants leading to amino acid changes or deletions were identified: 12 missense variants, two in-frame deletions of one codon, and one canonical splice variant leading to a deletion of two amino acid residues. Some variants were recurrently identified in several unrelated individuals: p.(Phe180del), p.(Leu190Pro), p.(Leu190Arg), p.(Gly199Ser), p.(Val254Ile) and p.(Glu376del). AGO1 encodes the Argonaute 1 protein, which functions in gene-silencing pathways mediated by small non-coding RNAs. Three-dimensional protein structure predictions suggest that these variants might alter the flexibility of the AGO1 linkers domains, which likely would impair its function in mRNA processing. Affected individuals present with intellectual disability of varying severity, as well as speech and motor delay, autistic behavior and additional behavioral manifestations. Our study establishes that de novo coding variants in AGO1 are involved in a novel monogenic form of NDD, highly similar to AGO2 phenotype.

De novo SCAMP5 mutation causes a neurodevelopmental disorder with autistic features and seizures

2019 ◽  
Vol 57 (2) ◽  
pp. 138-144 ◽  
Author(s):  
Laurence Hubert ◽  
Magda Cannata Serio ◽  
Laure Villoing-Gaudé ◽  
Nathalie Boddaert ◽  
Anna Kaminska ◽  
...  
Keyword(s):  
Protein Function ◽  
De Novo ◽  
Fat Body ◽  
Neurodevelopmental Disorder ◽  
Missense Variant ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
Functional Studies ◽  
Pathogenic Variants

BackgroundAutistic spectrum disorders (ASDs) with developmental delay and seizures are a genetically heterogeneous group of diseases caused by at least 700 different genes. Still, a number of cases remain genetically undiagnosed.ObjectiveThe objective of this study was to identify and characterise pathogenic variants in two individuals from unrelated families, both of whom presented a similar clinical phenotype that included an ASD, intellectual disability (ID) and seizures.MethodsWhole-exome sequencing was used to identify pathogenic variants in the two individuals. Functional studies performed in the Drosophila melanogaster model was used to assess the protein function in vivo.ResultsProbands shared a heterozygous de novo secretory carrier membrane protein (SCAMP5) variant (NM_001178111.1:c.538G>T) resulting in a p.Gly180Trp missense variant. SCAMP5 belongs to a family of tetraspanin membrane proteins found in secretory and endocytic compartments of neuronal synapses. In the fly SCAMP orthologue, the p.Gly302Trp genotype corresponds to human p.Gly180Trp. Western blot analysis of proteins overexpressed in the Drosophila fat body showed strongly reduced levels of the SCAMP p.Gly302Trp protein compared with the wild-type protein, indicating that the mutant either reduced expression or increased turnover of the protein. The expression of the fly homologue of the human SCAMP5 p.Gly180Trp mutation caused similar eye and neuronal phenotypes as the expression of SCAMP RNAi, suggesting a dominant-negative effect.ConclusionOur study identifies SCAMP5 deficiency as a cause for ASD and ID and underscores the importance of synaptic vesicular trafficking in neurodevelopmental disorders.

scholarly journals De novo coding variants in the AGO1 gene cause a neurodevelopmental disorder with intellectual disability

2021 ◽  
pp. jmedgenet-2021-107751
Author(s):  
Audrey Schalk ◽  
Margot A Cousin ◽  
Nikita R Dsouza ◽  
Thomas D Challman ◽  
Karen E Wain ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Amino Acid ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Three Dimensional ◽  
Amino Acid Residues ◽  
Motor Delay ◽  
Pathogenic Variants ◽  
Silencing Pathways ◽  
Coding Variants

BackgroundHigh-impact pathogenic variants in more than a thousand genes are involved in Mendelian forms of neurodevelopmental disorders (NDD).MethodsThis study describes the molecular and clinical characterisation of 28 probands with NDD harbouring heterozygous AGO1 coding variants, occurring de novo for all those whose transmission could have been verified (26/28).ResultsA total of 15 unique variants leading to amino acid changes or deletions were identified: 12 missense variants, two in-frame deletions of one codon, and one canonical splice variant leading to a deletion of two amino acid residues. Recurrently identified variants were present in several unrelated individuals: p.(Phe180del), p.(Leu190Pro), p.(Leu190Arg), p.(Gly199Ser), p.(Val254Ile) and p.(Glu376del). AGO1 encodes the Argonaute 1 protein, which functions in gene-silencing pathways mediated by small non-coding RNAs. Three-dimensional protein structure predictions suggest that these variants might alter the flexibility of the AGO1 linker domains, which likely would impair its function in mRNA processing. Affected individuals present with intellectual disability of varying severity, as well as speech and motor delay, autistic behaviour and additional behavioural manifestations.ConclusionOur study establishes that de novo coding variants in AGO1 are involved in a novel monogenic form of NDD, highly similar to the recently reported AGO2-related NDD.

scholarly journals A novel de novo DDX3X missense variant in a female with brachycephaly and intellectual disability: a case report

2021 ◽  
Vol 47 (1) ◽  
Author(s):  
Giada Moresco ◽  
Jole Costanza ◽  
Carlo Santaniello ◽  
Ornella Rondinone ◽  
Federico Grilli ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Clinical Presentation ◽  
De Novo ◽  
Clinical Signs ◽  
Missense Variant ◽  
Psychomotor Development ◽  
Helicase Domain ◽  
Protein Activity ◽  
Mrna Metabolism ◽  
Pathogenic Variants

Abstract Background De novo pathogenic variants in the DDX3X gene are reported to account for 1–3% of unexplained intellectual disability (ID) in females, leading to the rare disease known as DDX3X syndrome (MRXSSB, OMIM #300958). Besides ID, these patients manifest a variable clinical presentation, which includes neurological and behavioral defects, and abnormal brain MRIs. Case presentation We report a 10-year-old girl affected by delayed psychomotor development, delayed myelination, and polymicrogyria (PMG). We identified a novel de novo missense mutation in the DDX3X gene (c.625C > G) by whole exome sequencing (WES). The DDX3X gene encodes a DEAD-box ATP-dependent RNA-helicase broadly implicated in gene expression through regulation of mRNA metabolism. The identified mutation is located just upstream the helicase domain and is suggested to impair the protein activity, thus resulting in the altered translation of DDX3X-dependent mRNAs. The proband, presenting with the typical PMG phenotype related to the syndrome, does not show other clinical signs frequently reported in presence of missense DDX3X mutations that are associated with a most severe clinical presentation. In addition, she has brachycephaly, never described in female DDX3X patients, and macroglossia, that has never been associated with the syndrome. Conclusions This case expands the knowledge of DDX3X pathogenic variants and the associated DDX3X syndrome phenotypic spectrum.

scholarly journals First report of X-linked hypohidrotic ectodermal dysplasia with a hemizygous c.1142G > C in the EDA gene: variant of uncertain significance or new pathogenic variant?

2021 ◽  
Vol 47 (1) ◽  
Author(s):  
Mario Tumminello ◽  
Antonella Gangemi ◽  
Federico Matina ◽  
Melania Guardino ◽  
Bianca Lea Giuffrè ◽  
...  
Keyword(s):  
Ectodermal Dysplasia ◽  
Genetic Disorder ◽  
Missense Variant ◽  
Pathogenic Variant ◽  
Hypohidrotic Ectodermal Dysplasia ◽  
Variant Of Uncertain Significance ◽  
Uncertain Significance ◽  
Clinical Potential ◽  
Genomic Variant ◽  
Eda Gene

Abstract Background Hypohidrotic Ectodermal Dysplasia (HED) is a genetic disorder which affects structures of ectodermal origin. X-linked hypohidrotic ectodermal dysplasia (XLHED) is the most common form of disease. XLHED is characterized by hypotrichosis, hypohydrosis and hypodontia. The cardinal features of classic HED become obvious during childhood. Identification of a hemizygous EDA pathogenic variant in an affected male confirms the diagnosis. Case presentation We report on a male newborn with the main clinical characteristics of the X-linked HED including hypotrichosis, hypodontia and hypohidrosis. Gene panel sequencing identified a new hemizygous missense variant of uncertain significance (VUS) c.1142G > C (p.Gly381Ala) in the EDA gene, located on the X chromosome and inherited from the healthy mother. Conclusion Despite the potential functional impact of VUS remains uncharacterized, our goal is to evaluate the clinical potential consequences of missense VUS on EDA gene. Even if the proband’s phenotype is characteristic for classic HED, further reports of patients with same clinical phenotype and the same genomic variant are needed to consider this novel VUS as responsible for the development of HED.

scholarly journals A novel nonsense variant of the AGXT identified in a Chinese family: special variant research in the Chinese reference genome

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Chang Bao Xu ◽  
Xu Dong Zhou ◽  
Hong En Xu ◽  
Yong Li Zhao ◽  
Xing Hua Zhao ◽  
...  
Keyword(s):  
High Throughput Sequencing ◽  
Reference Genome ◽  
Genetic Diagnosis ◽  
Primary Hyperoxaluria ◽  
Missense Variant ◽  
Population Heterogeneity ◽  
Chinese Family ◽  
Pathogenic Variants ◽  
Variation Database ◽  
Genetic Level

Abstract Background Primary hyperoxaluria(PH)is a rare autosomal recessive genetic disease that contains three subtypes (PH1, PH2 and PH3). Approximately 80% of PH patients has been reported as subtype PH1, this subtype of PH has been related to a higher risk of renal failure at any age. Several genetic studies indicate that the variants in gene AGXT are responsible for the occurrence of PH1. However, the population heterogeneity of the variants in AGXT makes the genetic diagnosis of PH1 more challenging as it is hard to locate each specific variant. It is valuable to have a complete spectrum of AGXT variants from different population for early diagnosis and clinical treatments of PH1. Case presentation In this study, We performed high-throughput sequencing and genetic analysis of a 6-year-old male PH1 patient from a Chinese family. Two variants (c.346G > A: p.Gly116Arg; c.864G > A: p.Trp288X) of the gene AGXT were identified. We found a nonsense variant (c.864G > A: p.Trp288X) that comes from the proband’s mother and has never been reported previously. The other missense variant (c.346G > A: p.Gly116Arg) was inherited from his father and has been found previously in a domain of aminotransferase, which plays an important role in the function of AGT protein. Furthermore, we searched 110 pathogenic variants of AGXT that have been reported worldwide in healthy local Chinese population, none of these pathogenic variants was detected in the local genomes. Conclusions Our research provides an important diagnosis basis for PH1 on the genetic level by updating the genotype of PH1 and also develops a better understanding of the variants in AGXT by broadening the variation database of AGXT according to the Chinese reference genome.

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.

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