scholarly journals Homozygous missense WIPI2 variants cause a congenital disorder of autophagy with neurodevelopmental impairments of variable clinical severity and disease course

2021 ◽  
Author(s):  
Reza Maroofian ◽  
Andrea Gubas ◽  
Rauan Kaiyrzhanov ◽  
Marcello Scala ◽  
Khalid Hundallah ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Neurodevelopmental Disorder ◽  
Missense Variant ◽  
Clinical Severity ◽  
Global Developmental Delay ◽  
Disease Course ◽  
Single Family ◽  
Ataxic Gait ◽  
Related Disorder ◽  
Autophagy Pathway

Abstract WIPI2 is a member of the human WIPI protein family (seven-bladed b-propeller proteins binding phosphatidylinositols, PROPPINs), which play a pivotal role in autophagy and has been implicated in the pathogenesis of several neurological conditions. The homozygous WIPI2 variant c.745G>A; p.(Val249Met) (NM_015610.4) has recently been associated with a neurodevelopmental disorder in a single family. Using exome sequencing and Sanger segregation analysis, here two novel homozygous WIPI2 variants (c.551T>G; p.(Val184Gly) and c.724C>T; p.(Arg242Trp) (NM_015610.4)) were identified in four individuals of two consanguineous families. Additionally, follow-up clinical data were sought from the previously reported family. Three non-ambulant affected siblings of the first family harboring the p.(Val184Gly) missense variant presented with microcephaly, profound global developmental delay/intellectual disability, refractory infantile/childhood-onset epilepsy, progressive tetraplegia with joint contractures, and dyskinesia. In contrast, the proband of the second family carrying the p.(Arg242Trp) missense variant, similar to the initially reported WIPI2 cases, presented with a milder phenotype, encompassing moderate intellectual disability, speech and visual impairment, autistic features, and an ataxic gait. Brain MR imaging in five patients showed prominent white matter involvement with a global reduction in volume, posterior corpus callosum hypoplasia, abnormal dentate nuclei, and hypoplasia of the inferior cerebellar vermis. To investigate the functional impact of these novel WIPI2 variants, we overexpressed both in WIPI2-knockout HEK293A cells. In comparison to wildtype, expression of the Val166Gly WIPI2b mutant resulted in a deficient rescue of LC3 lipidation whereas Arg224Trp mutant increased LC3 lipidation, in line with the previously reported Val231Met variant. These findings support a dysregulation of the early steps of the autophagy pathway. Collectively, our findings provide evidence that biallelic WIPI2 variants cause a neurodevelopmental disorder of variable severity and disease course. Our report expands the clinical spectrum and establishes WIPI2-related disorder as a congenital disorders of autophagy.

scholarly journals A novel de novo KDM5C variant in a female with global developmental delay and ataxia: a case report

BMC Neurology ◽  
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.

scholarly journals Shukla-Vernon Syndrome: A Second Family with a Novel Variant in the BCORL1 Gene

Genes ◽  
2021 ◽  
Vol 12 (3) ◽  
pp. 452
Author(s):  
Babylakshmi Muthusamy ◽  
Anikha Bellad ◽  
Satish Chandra Girimaji ◽  
Akhilesh Pandey
Keyword(s):  
Intellectual Disability ◽  
Developmental Delay ◽  
Protein Complexes ◽  
Neurodevelopmental Disorder ◽  
Missense Variant ◽  
Global Developmental Delay ◽  
Dysmorphic Features ◽  
Pathogenic Variants ◽  
Behavioral Abnormalities ◽  
Novel Variant

Shukla-Vernon syndrome (SHUVER) is an extremely rare neurodevelopmental disorder characterized by global developmental delay, intellectual disability, behavioral anomalies, and dysmorphic features. Pathogenic variants in the BCORL1 gene have been identified as the molecular cause for this disorder. The BCORL1 gene encodes for BCL-6 corepressor-like protein 1, a transcriptional corepressor that is an integral component of protein complexes involved in transcription repression. In this study, we report an Indian family with two male siblings with features of Shukla-Vernon syndrome. The patients exhibited global developmental delay, intellectual disability, kyphosis, seizures, and dysmorphic features including bushy prominent eyebrows with synophrys, sharp beaked prominent nose, protuberant lower jaw, squint, and hypoplastic ears with fused ear lobes. No behavioral abnormalities were observed. Whole exome sequencing revealed a novel potentially pathogenic arginine to cysteine substitution (p.Arg1265Cys) in the BCORL1 protein. This is the second report of Shukla-Vernon syndrome with a novel missense variant in the BCORL1 gene. Our study confirms and expands the phenotypes and genotypes described previously for this syndrome and should aid in diagnosis and genetic counselling of patients and their families.

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.

scholarly journals A novel homozygous variant in TRAPPC2L results in a neurodevelopmental disorder and disrupts TRAPP complex function

2020 ◽  
pp. jmedgenet-2020-107016
Author(s):  
Noraldin Al-deri ◽  
Volkan Okur ◽  
Priyanka Ahimaz ◽  
Miroslav Milev ◽  
Zaheer Valivullah ◽  
...  
Keyword(s):  
Membrane Trafficking ◽  
Neurodevelopmental Disorder ◽  
Complex Function ◽  
Missense Variant ◽  
Clinical Findings ◽  
Size Exclusion ◽  
Global Developmental Delay ◽  
Functional Studies ◽  
Exclusion Chromatography

BackgroundNext-generation sequencing has facilitated the diagnosis of neurodevelopmental disorders with variable and non-specific clinical findings. Recently, a homozygous missense p.(Asp37Tyr) variant in TRAPPC2L, a core subunit of TRAPP complexes which function as tethering factors during membrane trafficking, was reported in two unrelated individuals with neurodevelopmental delay, post-infectious encephalopathy-associated developmental arrest, tetraplegia and accompanying rhabdomyolysis.MethodsWe performed whole genome sequencing on members of an Ashkenazi Jewish pedigree to identify the underlying genetic aetiology of global developmental delay/intellectual disability in three affected siblings. To assess the effect of the identified TRAPPC2L variant, we performed biochemical and cell biological functional studies on the TRAPPC2L protein.ResultsA rare homozygous predicted deleterious missense variant, p.(Ala2Gly), in TRAPPC2L was identified in the affected siblings and it segregated with the neurodevelopmental phenotype within the family. Using a yeast two-hybrid assay and in vitro binding, we demonstrate that the p.(Ala2Gly) variant, but not the p.(Asp37Tyr) variant, disrupted the interaction between TRAPPC2L and another core TRAPP protein, TRAPPC6a. Size exclusion chromatography suggested that this variant affects the assembly of TRAPP complexes. Employing two different membrane trafficking assays using fibroblasts from one of the affected siblings, we found a delay in traffic into and out of the Golgi. Similar to the p.(Asp37Tyr) variant, the p.(Ala2Gly) variant resulted in an increase in the levels of active RAB11.ConclusionOur data fill in a gap in the knowledge of TRAPP architecture with TRAPPC2L interacting with TRAPPC6a, positioning it as a putative adaptor for other TRAPP subunits. Collectively, our findings support the pathogenicity of the TRAPPC2L p.(Ala2Gly) variant.

scholarly journals Pathogenic variants in PIDD1 lead to an autosomal recessive neurodevelopmental disorder with pachygyria and psychiatric features

2021 ◽  
Author(s):  
Maha S. Zaki ◽  
Andrea Accogli ◽  
Ghayda Mirzaa ◽  
Fatima Rahman ◽  
Hiba Mohammed ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Autosomal Recessive ◽  
Neurodevelopmental Disorder ◽  
Death Domain ◽  
Multiprotein Complex ◽  
Related Disorder ◽  
Pathogenic Variants ◽  
Domain Protein ◽  
Caspase 2 ◽  
And Behavior

AbstractThe PIDDosome is a multiprotein complex, composed by the p53-induced death domain protein 1 (PIDD1), the bipartite linker protein CRADD (also known as RAIDD) and the proform of caspase-2 that induces apoptosis in response to DNA damage. In the recent years, biallelic pathogenic variants in CRADD have been associated with a neurodevelopmental disorder (MRT34; MIM 614499) characterized by pachygyria with a predominant anterior gradient, megalencephaly, epilepsy and intellectual disability. More recently, biallelic pathogenic variants in PIDD1 have been described in a few families with apparently nonsydnromic intellectual disability. Here, we aim to delineate the genetic and radio-clinical features of PIDD1-related disorder. Exome sequencing was carried out in six consanguineous families. Thorough clinical and neuroradiological evaluation was performed for all the affected individuals as well as reviewing all the data from previously reported cases. We identified five distinct novel homozygous variants (c.2584C>T p.(Arg862Trp), c.1340G>A p.(Trp447*), c.2116_2120del p.(Val706Hisfs*30), c.1564_1565delCA p.(Gln522fs*44), and c.1804_1805del p.(Gly602fs*26) in eleven subjects displaying intellectual disability, behaviorial and psychiatric features, and a typical anterior-predominant pachygyria, remarkably resembling the CRADD-related neuroimaging pattern. In summary, we outline the phenotypic and molecular spectrum of PIDD1 biallelic variants supporting the evidence that the PIDD1/CRADD/caspase-2 signaling is crucial for normal gyration of the developing human neocortex as well as cognition and behavior.

scholarly journals Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome

2021 ◽  
Author(s):  
Marjolein J. A. Weerts ◽  
Kristina Lanko ◽  
Francisco J. Guzmán-Vega ◽  
Adam Jackson ◽  
Reshmi Ramakrishnan ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Developmental Delay ◽  
Neurodevelopmental Disorder ◽  
Epileptic Activity ◽  
Language Delay ◽  
Global Developmental Delay ◽  
Sequence Variants ◽  
Loss Of Function ◽  
Phenotypic Spectrum

Abstract Purpose Pathogenic variants in SETD1B have been associated with a syndromic neurodevelopmental disorder including intellectual disability, language delay, and seizures. To date, clinical features have been described for 11 patients with (likely) pathogenic SETD1B sequence variants. This study aims to further delineate the spectrum of the SETD1B-related syndrome based on characterizing an expanded patient cohort. Methods We perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum. Selected variants were functionally tested using in vitro and genome-wide methylation assays. Results Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes. Developmental delay appeared to precede seizure onset, suggesting SETD1B dysfunction impacts physiological neurodevelopment even in the absence of epileptic activity. Males are significantly overrepresented and more severely affected, and we speculate that sex-linked traits could affect susceptibility to penetrance and the clinical spectrum of SETD1B variants. Conclusion Insights from this extensive cohort will facilitate the counseling regarding the molecular and phenotypic landscape of newly diagnosed patients with the SETD1B-related syndrome.

scholarly journals SETD1B-associated neurodevelopmental disorder

2020 ◽  
pp. jmedgenet-2019-106756
Author(s):  
Alexandra Roston ◽  
Dan Evans ◽  
Harinder Gill ◽  
Margaret McKinnon ◽  
Bertrand Isidor ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Exome Sequencing ◽  
Transcriptional Activation ◽  
Systemic Disease ◽  
Neurodevelopmental Disorder ◽  
Service Research ◽  
Global Developmental Delay ◽  
Supporting Evidence ◽  
Increased Risk ◽  
Coding Variants

BackgroundDysfunction of histone methyltransferases and chromatin modifiers has been implicated in complex neurodevelopmental syndromes and cancers. SETD1B encodes a lysine-specific methyltransferase that assists in transcriptional activation of genes by depositing H3K4 methyl marks. Previous reports of patients with rare variants in SETD1B describe a distinctive phenotype that includes seizures, global developmental delay and intellectual disability.MethodsTwo of the patients described herein were identified via genome-wide and exome-wide testing, with microarray and research-based exome, through the CAUSES (Clinical Assessment of the Utility of Sequencing and Evaluation as a Service) Research Clinic at the University of British Columbia. The third Vancouver patient had clinical trio exome sequencing through Blueprint Genetics. The fourth patient underwent singleton exome sequencing in Nantes, with subsequent recruitment to this cohort through GeneMatcher.ResultsHere we present clinical reports of four patients with rare coding variants in SETD1B that demonstrate a shared phenotype, including intellectual disability, language delay, conserved musculoskeletal findings and seizures that may be treatment-refractory. We include supporting evidence from next-generation sequencing among a cohort of paediatric patients with epilepsy.ConclusionRare coding variants in SETD1B can cause a diagnosable syndrome and could contribute as a risk factor for epilepsy, autism and other neurodevelopmental phenotypes. In the long term, some patients may also be at increased risk for cancers and other complex diseases. Thus, longitudinal studies are required to further elucidate the precise role of SETD1B in neurodevelopmental disorders and other systemic disease.

scholarly journals Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome

2021 ◽  
Author(s):  
Marjolein J.A. Weerts ◽  
Kristina Lanko ◽  
Francisco J. Guzmán-Vega ◽  
Adam Jackson ◽  
Reshmi Ramakrishnan ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Developmental Delay ◽  
Neurodevelopmental Disorder ◽  
Epileptic Activity ◽  
Language Delay ◽  
Global Developmental Delay ◽  
Sequence Variants ◽  
Loss Of Function ◽  
Phenotypic Spectrum

ABSTRACTPathogenic variants in SETD1B have been associated with a syndromic neurodevelopmental disorder including intellectual disability, language delay and seizures. To date, clinical features have been described for eleven patients with (likely) pathogenic SETD1B sequence variants. We perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum. Selected variants were functionally tested using in vitro and genome-wide methylation assays. Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes. Developmental delay appeared to precede seizure onset, suggesting SETD1B dysfunction impacts physiological neurodevelopment even in the absence of epileptic activity. Interestingly, males are significantly overrepresented and more severely affected, and we speculate that sex-linked traits could affect susceptibility to penetrance and the clinical spectrum of SETD1B variants. Finally, despite the possibility of non-redundant contributions of SETD1B and its paralogue SETD1A to epigenetic control, the clinical phenotypes of the related disorders share many similarities, indicating that elucidating shared and divergent downstream targets of both genes will help to understand the mechanism leading to the neurobehavioral phenotypes. Insights from this extensive cohort will facilitate the counseling regarding the molecular and phenotypic landscape of newly diagnosed patients with the SETD1B-related syndrome.

scholarly journals Highly clustered de novo frameshift variants in the neuronal splicing factor NOVA2 result in a specific abnormal C terminal part and cause a severe form of intellectual disability with autistic features

2019 ◽  
Author(s):  
Francesca Mattioli ◽  
Gaelle Hayot ◽  
Nathalie Drouot ◽  
Bertrand Isidor ◽  
Jérémie Courraud ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Rna Binding ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Brain Mri ◽  
Severe Form ◽  
Neural Cells ◽  
Loss Of Function ◽  
Ataxic Gait ◽  
Feeding Difficulties

ABSTRACTThe Neuro-Oncological Ventral Antigen 2 NOVA2 protein is a major factor regulating neuron specific alternative splicing, previously associated with an acquired neurologic condition, the paraneoplastic opsoclonus-myoclonus ataxia (POMA). We report here six individuals with de novo frameshift variants in the NOVA2 gene affected with a severe neurodevelopmental disorder characterized by intellectual disability (ID), motor and speech delay, autistic features, hypotonia, feeding difficulties, spasticity or ataxic gait and abnormal brain MRI. The six variants lead to the same reading frame, adding a common 133 aa long proline rich C-terminus part instead of the last KH RNA binding domain. We detected forty-one genes differentially spliced after NOVA2 inactivation in human neural cells. The mutant NOVA2 protein shows decreased ability to bind a target RNA, to regulate specific splicing events and to rescue the phenotype of altered retinotectal axonal pathfinding induced by loss of NOVA2 ortholog in zebrafish. Our results suggest a partial loss-of-function mechanism rather than a full heterozygous loss of function, although a specific contribution of the novel C terminal extension cannot be excluded on the basis of the genetic findings.

Biallelic variants in ZNF526 cause a severe neurodevelopmental disorder with microcephaly, bilateral cataract, epilepsy and simplified gyration

2021 ◽  
pp. jmedgenet-2020-107430
Author(s):  
Maria Lisa Dentici ◽  
Viola Alesi ◽  
Mathieu Quinodoz ◽  
Barbara Robens ◽  
Andrea Guerin ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Exome Sequencing ◽  
Zinc Finger Protein ◽  
Neurodevelopmental Disorder ◽  
Brain Mri ◽  
Missense Variant ◽  
Epileptic Encephalopathy ◽  
Gene Encoding ◽  
Psychomotor Delay ◽  
Severe Intellectual Disability

BackgroundNext-generation sequencing, combined with international pooling of cases, has impressively enhanced the discovery of genes responsible for Mendelian neurodevelopmental disorders, particularly in individuals affected by clinically undiagnosed diseases. To date, biallelic missense variants in ZNF526 gene, encoding a Krüppel-type zinc-finger protein, have been reported in three families with non-syndromic intellectual disability.MethodsHere, we describe five individuals from four unrelated families with an undiagnosed neurodevelopmental disorder in which we performed exome sequencing, on a combination of trio-based (4 subjects) or single probands (1 subject).ResultsWe identified five patients from four unrelated families with homozygous ZNF526 variants by whole exome sequencing. Four had variants resulting in truncation of ZNF526; they were affected by severe prenatal and postnatal microcephaly (ranging from −4 SD to −8 SD), profound psychomotor delay, hypertonic–dystonic movements, epilepsy and simplified gyral pattern on MRI. All of them also displayed bilateral progressive cataracts. A fifth patient had a homozygous missense variant and a slightly less severe disorder, with postnatal microcephaly (−2 SD), progressive bilateral cataracts, severe intellectual disability and unremarkable brain MRI.Mutant znf526 zebrafish larvae had notable malformations of the eye and central nervous system, resembling findings seen in the human holoprosencephaly spectrum.ConclusionOur findings support the role of ZNF526 biallelic variants in a complex neurodevelopmental disorder, primarily affecting brain and eyes, resulting in severe microcephaly, simplified gyral pattern, epileptic encephalopathy and bilateral cataracts.

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