scholarly journals A de novo frameshift pathogenic variant in TBR1 identified in autism without intellectual disability

2020 ◽  
Vol 14 (1) ◽  
Author(s):  
Laurie-Anne Sapey-Triomphe ◽  
Julie Reversat ◽  
Gaëtan Lesca ◽  
Nicolas Chatron ◽  
Marina Bussa ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Magnetic Resonance ◽  
Brain Development ◽  
Language Impairment ◽  
De Novo ◽  
Genetic Alterations ◽  
Autism Spectrum ◽  
Pathogenic Variant ◽  
Pathogenic Variants ◽  
Patient Reported

Abstract Background In order to be able to provide accurate genetic counseling to patients with Autism Spectrum Disorder (ASD), it is crucial to identify correlations between heterogeneous phenotypes and genetic alterations. Among the hundreds of de novo pathogenic variants reported in ASD, single-nucleotide variations and small insertions/deletions were reported in TBR1. This gene encodes a transcription factor that plays a key role in brain development. Pathogenic variants in TBR1 are often associated with severe forms of ASD, including intellectual disability and language impairment. Methods Adults diagnosed with ASD but without intellectual disability (diagnosis of Asperger syndrome, according to the DSM-IV) took part in a genetic consultation encompassing metabolic assessments, a molecular karyotype and the screening of a panel of 268 genes involved in intellectual disability, ASD and epilepsy. In addition, the patient reported here went through a neuropsychological assessment, structural magnetic resonance imaging and magnetic resonance spectroscopy measurements. Results Here, we report the case of a young adult male who presents with a typical form of ASD. Importantly, this patient presents with no intellectual disability or language impairment, despite a de novo heterozygous frameshift pathogenic variant in TBR1, leading to an early premature termination codon (c.26del, p.(Pro9Leufs*12)). Conclusion Based on this case report, we discuss the role of TBR1 in general brain development, language development, intellectual disability and other symptoms of ASD. Providing a detailed clinical description of the individuals with such pathogenic variants should help to understand the genotype-phenotype relationships in ASD.

scholarly journals Detailed Clinical and Psychological Phenotype of the X-linked HNRNPH2-Related Neurodevelopmental Disorder

2021 ◽  
Vol 7 (1) ◽  
pp. e551
Author(s):  
Jennifer M. Bain ◽  
Olivia Thornburg ◽  
Cheryl Pan ◽  
Donnielle Rome-Martin ◽  
Lia Boyle ◽  
...  
Keyword(s):  
Language Impairment ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Retrospective Chart Review ◽  
Premature Death ◽  
Parent Report ◽  
Autism Spectrum ◽  
Pathogenic Variants ◽  
Motor Problems ◽  
Cortical Visual Impairment

ObjectiveTo expand the clinical phenotype of the X-linked HNRNPH2-related neurodevelopmental disorder in 33 individuals.MethodsParticipants were diagnosed with pathogenic or likely pathogenic variants in HNRNPH2 using American College of Medical Genetics and Genomics/Association of Molecular Pathology criteria, largely identified via clinical exome sequencing. Genetic reports were reviewed. Clinical data were collected by retrospective chart review and caregiver report including standardized parent report measures.ResultsWe expand our clinical characterization of HNRNPH2-related disorders to include 33 individuals, aged 2–38 years, both females and males, with 11 different de novo missense variants, most within the nuclear localization signal. The major features of the phenotype include developmental delay/intellectual disability, severe language impairment, motor problems, growth, and musculoskeletal disturbances. Minor features include dysmorphic features, epilepsy, neuropsychiatric diagnoses such as autism spectrum disorder, and cortical visual impairment. Although rare, we report early stroke and premature death with this condition.ConclusionsThe spectrum of X-linked HNRNPH2-related disorders continues to expand as the allelic spectrum and identification of affected males increases.

scholarly journals Case Report: Clinical Features of a Chinese Boy With Epileptic Seizures and Intellectual Disabilities Who Carries a Truncated NUS1 Variant

2021 ◽  
Vol 9 ◽  
Author(s):  
Pingli Zhang ◽  
Di Cui ◽  
Peiyuan Liao ◽  
Xiang Yuan ◽  
Nuan Yang ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Clinical Features ◽  
De Novo ◽  
Epileptic Seizures ◽  
Epileptic Encephalopathy ◽  
Chinese Patient ◽  
Pathogenic Variant ◽  
Phenotype Correlation ◽  
Congenital Disorder Of Glycosylation ◽  
Pathogenic Variants

The mental retardation-55 with seizures (MRD55) is a rare genetic disease characterized by developmental delay, intellectual disability, language delay and multiple types of epileptic seizures. It is caused by pathogenic variants of the NUS1 gene, which encodes Nogo-B receptor (NgBR), a necessary subunit for the glycosylation reactions in mammals. To date, 25 disease-causing mutations of NUS1 have been reported, which are responsible for various diseases, including dystonia, Parkinson's disease, developmental and epileptic encephalopathy as well as congenital disorder of glycosylation. In addition, only 9 of these mutations were reported with detailed clinical features. There are no reports about Chinese cases with MRD55. In this study, a novel, de novo pathogenic variant of NUS1 (c.51_54delTCTG, p.L18Tfs*31) was identified in a Chinese patient with intellectual disability and epileptic seizures. This pathogenic variant resulted in truncated NgBR proteins, which might be the cause of the clinical features of the patient. Oxcarbazepine was an effective treatment for improving speech and movement of the patient, who consequently presented with no seizure. With this novel pathogenic variant found in NUS1, we expand the genotype spectrum of MRD55 and provide valuable insights into the potential genotype-phenotype correlation.

scholarly journals De novo variants in CACNA1E found in patients with intellectual disability, developmental regression and social cognition deficit but no seizures

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Beryl Royer-Bertrand ◽  
Marine Jequier Gygax ◽  
Katarina Cisarova ◽  
Jill A. Rosenfeld ◽  
Jennifer A. Bassetti ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Calcium Channel ◽  
Developmental Disorders ◽  
De Novo ◽  
Autism Spectrum ◽  
Small Sample ◽  
Control Population ◽  
Pathogenic Variants ◽  
Developmental Regression ◽  
Short Period

Abstract Background De novo variants in the voltage-gated calcium channel subunit α1 E gene (CACNA1E) have been described as causative of epileptic encephalopathy with contractures, macrocephaly and dyskinesias. Methods Following the observation of an index patient with developmental delay and autism spectrum disorder (ASD) without seizures who had a de novo deleterious CACNA1E variant, we screened GeneMatcher for other individuals with CACNA1E variants and neurodevelopmental phenotypes without epilepsy. The spectrum of pathogenic CACNA1E variants was compared to the mutational landscape of variants in the gnomAD control population database. Results We identified seven unrelated individuals with intellectual disability, developmental regression and ASD-like behavioral profile, and notably without epilepsy, who had de novo heterozygous putatively pathogenic variants in CACNA1E. Age of onset of clinical manifestation, presence or absence of regression and degree of severity were variable, and no clear-cut genotype–phenotype association could be recognized. The analysis of disease-associated variants and their comparison to benign variants from the control population allowed for the identification of regions in the CACNA1E protein that seem to be intolerant to substitutions and thus more likely to harbor pathogenic variants. As in a few reported cases with CACNA1E variants and epilepsy, one patient showed a positive clinical behavioral response to topiramate, a specific calcium channel modulator. Limitations The significance of our study is limited by the absence of functional experiments of the effect of identified variants, the small sample size and the lack of systematic ASD assessment in all participants. Moreover, topiramate was given to one patient only and for a short period of time. Conclusions Our results indicate that CACNA1E variants may result in neurodevelopmental disorders without epilepsy and expand the mutational and phenotypic spectrum of this gene. CACNA1E deserves to be included in gene panels for non-specific developmental disorders, including ASD, and not limited to patients with seizures, to improve diagnostic recognition and explore the possible efficacy of topiramate.

scholarly journals New Candidates for Autism/Intellectual Disability Identified by Whole-Exome Sequencing

2021 ◽  
Vol 22 (24) ◽  
pp. 13439
Author(s):  
Lucia Pia Bruno ◽  
Gabriella Doddato ◽  
Floriana Valentino ◽  
Margherita Baldassarri ◽  
Rossella Tita ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Molecular Diagnosis ◽  
De Novo ◽  
Genetic Locus ◽  
Autism Spectrum ◽  
Bioinformatic Tools ◽  
Pathogenic Variants ◽  
Whole Exome

Intellectual disability (ID) is characterized by impairments in the cognitive processes and in the tasks of daily life. It encompasses a clinically and genetically heterogeneous group of neurodevelopmental disorders often associated with autism spectrum disorder (ASD). Social and communication abilities are strongly compromised in ASD. The prevalence of ID/ASD is 1–3%, and approximately 30% of the patients remain without a molecular diagnosis. Considering the extreme genetic locus heterogeneity, next-generation sequencing approaches have provided powerful tools for candidate gene identification. Molecular diagnosis is crucial to improve outcome, prevent complications, and hopefully start a therapeutic approach. Here, we performed parent–offspring trio whole-exome sequencing (WES) in a cohort of 60 mostly syndromic ID/ASD patients and we detected 8 pathogenic variants in genes already known to be associated with ID/ASD (SYNGAP1, SMAD6, PACS1, SHANK3, KMT2A, KCNQ2, ACTB, and POGZ). We found four de novo disruptive variants of four novel candidate ASD/ID genes: MBP, PCDHA1, PCDH15, PDPR. We additionally selected via bioinformatic tools many variants in unknown genes that alone or in combination can contribute to the phenotype. In conclusion, our data confirm the efficacy of WES in detecting pathogenic variants of known and novel ID/ASD genes.

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.

IL1RAPL1 Gene Deletion in a Female Patient with Developmental Delay and Continuous Spike-Wave during Sleep

2021 ◽  
Author(s):  
Evan Jiang ◽  
Mark P. Fitzgerald ◽  
Katherine L. Helbig ◽  
Ethan M. Goldberg
Keyword(s):  
Intellectual Disability ◽  
Developmental Delay ◽  
Synapse Formation ◽  
De Novo ◽  
Interleukin 1 ◽  
Autism Spectrum ◽  
Neurological Dysfunction ◽  
Behavioral Disorder ◽  
Clinical Genetic ◽  
Severe Intellectual Disability

AbstractInterleukin-1 receptor accessory protein-like 1 (IL1RAPL1) encodes a protein that is highly expressed in neurons and has been shown to regulate neurite outgrowth as well as synapse formation and synaptic transmission. Clinically, mutations in or deletions of IL1RAPL1 have been associated with a spectrum of neurological dysfunction including autism spectrum disorder and nonsyndromic X-linked developmental delay/intellectual disability of varying severity. Nearly all reported cases are in males; in the few reported cases involving females, the clinical presentation was mild or the deletion was identified in phenotypically normal carriers in accordance with X-linked inheritance. Using genome-wide microarray analysis, we identified a novel de novo 373 kb interstitial deletion of the X chromosome (Xp21.1-p21.2) that includes exons 4 to 6 of the IL1RAPL1 gene in an 8-year-old girl with severe intellectual disability and behavioral disorder with a history of developmental regression. Overnight continuous video electroencephalography revealed electrical status epilepticus in sleep (ESES). This case expands the clinical genetic spectrum of IL1RAPL1-related neurodevelopmental disorders and highlights a new genetic association of ESES.

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 Pathogenic WDFY3 variants cause neurodevelopmental disorders and opposing effects on brain size

Brain ◽  
2019 ◽  
Vol 142 (9) ◽  
pp. 2617-2630 ◽  
Author(s):  
Diana Le Duc ◽  
Cecilia Giulivi ◽  
Susan M Hiatt ◽  
Eleonora Napoli ◽  
Alexios Panoutsopoulos ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Wnt Pathway ◽  
De Novo ◽  
Autism Spectrum ◽  
Neural Progenitors ◽  
Scaffolding Protein ◽  
Published Data ◽  
Ph Domain ◽  
Human Phenotype ◽  
Neurodevelopmental Delay

Abstract The underpinnings of mild to moderate neurodevelopmental delay remain elusive, often leading to late diagnosis and interventions. Here, we present data on exome and genome sequencing as well as array analysis of 13 individuals that point to pathogenic, heterozygous, mostly de novo variants in WDFY3 (significant de novo enrichment P = 0.003) as a monogenic cause of mild and non-specific neurodevelopmental delay. Nine variants were protein-truncating and four missense. Overlapping symptoms included neurodevelopmental delay, intellectual disability, macrocephaly, and psychiatric disorders (autism spectrum disorders/attention deficit hyperactivity disorder). One proband presented with an opposing phenotype of microcephaly and the only missense-variant located in the PH-domain of WDFY3. Findings of this case are supported by previously published data, demonstrating that pathogenic PH-domain variants can lead to microcephaly via canonical Wnt-pathway upregulation. In a separate study, we reported that the autophagy scaffolding protein WDFY3 is required for cerebral cortical size regulation in mice, by controlling proper division of neural progenitors. Here, we show that proliferating cortical neural progenitors of human embryonic brains highly express WDFY3, further supporting a role for this molecule in the regulation of prenatal neurogenesis. We present data on Wnt-pathway dysregulation in Wdfy3-haploinsufficient mice, which display macrocephaly and deficits in motor coordination and associative learning, recapitulating the human phenotype. Consequently, we propose that in humans WDFY3 loss-of-function variants lead to macrocephaly via downregulation of the Wnt pathway. In summary, we present WDFY3 as a novel gene linked to mild to moderate neurodevelopmental delay and intellectual disability and conclude that variants putatively causing haploinsufficiency lead to macrocephaly, while an opposing pathomechanism due to variants in the PH-domain of WDFY3 leads to microcephaly.

scholarly journals Gene discoveries in autism are biased towards comorbidity with intellectual disability

2020 ◽  
Vol 57 (9) ◽  
pp. 647-652
Author(s):  
Matthew Jensen ◽  
Corrine Smolen ◽  
Santhosh Girirajan
Keyword(s):  
Intellectual Disability ◽  
Genetic Factors ◽  
De Novo ◽  
High Functioning Autism ◽  
Copy Number Variants ◽  
Social Responsiveness ◽  
High Functioning ◽  
Pathogenic Variants ◽  
Increased Risk ◽  
Normal Cognitive Function

BackgroundAutism typically presents with highly heterogeneous features, including frequent comorbidity with intellectual disability (ID). The overlap between these phenotypes has confounded the diagnosis and discovery of genetic factors associated with autism. We analysed pathogenic de novo genetic variants in individuals with autism who had either ID or normal cognitive function to determine whether genes associated with autism also contribute towards ID comorbidity.MethodsWe analysed 2290 individuals from the Simons Simplex Collection for de novo likely gene-disruptive (LGD) variants and copy-number variants (CNVs), and determined their relevance towards IQ and Social Responsiveness Scale (SRS) measures.ResultsIndividuals who carried de novo variants in a set of 173 autism-associated genes showed an average 12.8-point decrease in IQ scores (p=5.49×10−6) and 2.8-point increase in SRS scores (p=0.013) compared with individuals without such variants. Furthermore, individuals with high-functioning autism (IQ >100) had lower frequencies of de novo LGD variants (42 of 397 vs 86 of 562, p=0.021) and CNVs (9 of 397 vs 24 of 562, p=0.065) compared with individuals who manifested both autism and ID (IQ <70). Pathogenic variants disrupting autism-associated genes conferred a 4.85-fold increased risk (p=0.011) for comorbid ID, while de novo variants observed in individuals with high-functioning autism disrupted genes with little functional relevance towards neurodevelopment.ConclusionsPathogenic de novo variants disrupting autism-associated genes contribute towards autism and ID comorbidity, while other genetic factors are likely to be causal for high-functioning autism.

Rapidly Progressive Multisutural Craniosynostosis in a Patient With Jackson-Weiss Syndrome and a De Novo FGFR2 Pathogenic Variant

2019 ◽  
Vol 56 (10) ◽  
pp. 1386-1392
Author(s):  
Karel-Bart Celie ◽  
Melissa Yuan ◽  
Christopher Cunniff ◽  
Jarrod Bogue ◽  
Caitlin Hoffman ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Early Treatment ◽  
Clinical Presentation ◽  
De Novo ◽  
Pathogenic Variant ◽  
Medical Complications ◽  
3 Dimensional ◽  
Constitutive Activation ◽  
Pathogenic Variants ◽  
Dimensional Modeling

Little is currently known about the mechanisms by which pathogenic variants of FGFR2 produce changes in the FGFR protein and influence the clinical presentation of affected individuals. We report on a patient with a de novo pathogenic variant of FGFR2 and a phenotype consistent with Jackson-Weiss syndrome who presented with delayed, rapidly progressive multisutural craniosynostosis and associated medical complications. Using 3-dimensional modeling of the FGFR protein, we provide evidence that this variant resulted in abnormal dimerization and constitutive activation of FGFR, leading to the Jackson-Weiss phenotype. Knowledge regarding the correlation between genotype and phenotype of persons with FGFR2-related craniosynostosis has the potential to allow for anticipation of medical complications, institution of early treatment, and improved clinical outcomes.

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