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.

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 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 Coffin-Lowry preprint 2018

2018 ◽  
Author(s):  
Paolo Moretti
Keyword(s):  
Family History ◽  
Clinical Features ◽  
De Novo ◽  
Severe Disease ◽  
Immunosuppressive Treatment ◽  
Pathogenic Variant ◽  
First Degree Relatives ◽  
Pathogenic Variants ◽  
History Of ◽  
Psychiatric Manifestations

Coffin-Lowry syndrome is an X-linked disease caused by pathogenic variants in RPS6KA3. The disease generally causes severe neurologic and non-neurologic abnormalities in males, and more variable phenotypes in females, including psychiatric manifestations. The majority of cases occur in the absence of known family history of the disease, and women carrying a de novo pathogenic variant may be undiagnosed due to the absence of severe disease manifestations or typically affected first-degree relatives. We describe the clinical features of a woman of normal intellect carrying a novel RPS6KA3 pathogenic variant in whom psychiatric manifestations and encephalopathy responded to immunosuppressive treatment.

scholarly journals Cell-based analysis of CAD variants identifies individuals likely to benefit from uridine therapy

2020 ◽  
Vol 22 (10) ◽  
pp. 1598-1605 ◽  
Author(s):  
Francisco del Caño-Ochoa ◽  
Bobby G. Ng ◽  
Malak Abedalthagafi ◽  
Mohammed Almannai ◽  
Ronald D. Cohn ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Clinical Presentation ◽  
De Novo ◽  
Clinical Phenotype ◽  
Transient Transfection ◽  
Missense Variants ◽  
De Novo Biosynthesis ◽  
Pathogenic Variants ◽  
Large Size ◽  
A Cell

Abstract Purpose Pathogenic autosomal recessive variants in CAD, encoding the multienzymatic protein initiating pyrimidine de novo biosynthesis, cause a severe inborn metabolic disorder treatable with a dietary supplement of uridine. This condition is difficult to diagnose given the large size of CAD with over 1000 missense variants and the nonspecific clinical presentation. We aimed to develop a reliable and discerning assay to assess the pathogenicity of CAD variants and to select affected individuals that might benefit from uridine therapy. Methods Using CRISPR/Cas9, we generated a human CAD-knockout cell line that requires uridine supplements for survival. Transient transfection of the knockout cells with recombinant CAD restores growth in absence of uridine. This system determines missense variants that inactivate CAD and do not rescue the growth phenotype. Results We identified 25 individuals with biallelic variants in CAD and a phenotype consistent with a CAD deficit. We used the CAD-knockout complementation assay to test a total of 34 variants, identifying 16 as deleterious for CAD activity. Combination of these pathogenic variants confirmed 11 subjects with a CAD deficit, for whom we describe the clinical phenotype. Conclusions We designed a cell-based assay to test the pathogenicity of CAD variants, identifying 11 CAD-deficient individuals who could benefit from uridine therapy.

scholarly journals Genomic diagnosis for children with intellectual disability and/or developmental delay

2016 ◽  
Author(s):  
Kevin M. Bowling ◽  
Michelle L. Thompson ◽  
Michelle D. Amaral ◽  
Candice R. Finnila ◽  
Susan M. Hiatt ◽  
...  
Keyword(s):  
Neurological Disease ◽  
Large Scale ◽  
De Novo ◽  
Pathogenic Variant ◽  
Research Progress ◽  
Degree Relative ◽  
Identification Rate ◽  
Pathogenic Variants ◽  
First Choice ◽  
Uncertain Significance

ABSTRACTBackgroundDevelopmental disabilities have diverse genetic causes that must be identified to facilitate precise diagnoses. We describe genomic data from 371 affected individuals, 309 of which were sequenced as proband-parent trios.MethodsWhole exome sequences (WES) were generated for 365 individuals (127 affected) and whole genome sequences (WGS) were generated for 612 individuals (244 affected).ResultsPathogenic or likely pathogenic variants were found in 100 individuals (27%), with variants of uncertain significance in an additional 42 (11.3%). We found that a family history of neurological disease, especially the presence of an affected 1st degree relative, reduces the pathogenic/likely pathogenic variant identification rate, reflecting both the disease relevance and ease of interpretation of de novo variants. We also found that improvements to genetic knowledge facilitated interpretation changes in many cases. Through systematic reanalyses we have thus far reclassified 15 variants, with 11.3% of families who initially were found to harbor a VUS, and 4.7% of families with a negative result, eventually found to harbor a pathogenic or likely pathogenic variant. To further such progress, the data described here are being shared through ClinVar, GeneMatcher, and dbGAP.ConclusionOur data strongly support the value of large-scale sequencing, especially WGS within proband-parent trios, as both an effective first-choice diagnostic tool and means to advance clinical and research progress related to pediatric neurological disease.

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 AB0727 STUDY OF MEFV GENE MUTATIONS IN A COHORT OF CHILDREN: A SINGLE CENTER

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 1394.2-1395
Author(s):  
T. Kriulina ◽  
E. Alexeeva ◽  
T. Dvoryakovskaya ◽  
I. Kriulin ◽  
K. Isaeva ◽  
...  
Keyword(s):  
Familial Mediterranean Fever ◽  
Clinical Presentation ◽  
Mefv Gene ◽  
Genetic Data ◽  
Hereditary Disease ◽  
Pathogenic Variant ◽  
Heterozygous Mutation ◽  
Clear Correlation ◽  
Pathogenic Variants ◽  
Mediterranean Fever

Background:Familial Mediterranean fever (FMF) is a monogenic autoinflammatory hereditary disease characterized by recurrent episodes of fever with sterile peritonitis, pleural inflammation, arthritis, and/or erysipelas-like rash. Among all variants of the MEFV gene, according to the literature, five pathogenic ones have been identified, which in 75% of cases lead to the development of a typical clinical presentation: V726A, M694V, M694I, M680I, and E148Q. Among them, the M694V variant is the most common and occurs in patients with FMF in 20-65% of cases. At the same time, approximately 10 to 20% of patients meeting the diagnostic criteria for FMF do not have pathogenic variants in the MEFV gene. Despite the fact that the molecular genetic, pathogenetic and clinical features of the disease have been studied detailed, the diagnosis remains difficult due to the lack of a clear correlation between the patient’s clinical and genetic data.Objectives:To analyze the obtained genetic data of patients with pathogenic variants in the MEFV gene.Methods:The study included 103 patients who are mainly observed at the rheumatology department of the National Medical Research Center of Children’s Health of Ministry of Health of the Russian Federation in Moscow. All patients underwent analysis of the MEFV gene using Sanger sequencing with further statistical processing of the data obtained.Results:Of 103 patients, the pathogenic variant of the MEFV gene was found in 93 patients (90.3%), in 10 patients (9.7%) - the pathogenicity of the revealed variant was contradictory. Of 93 patients with the pathogenic variant of MEFV, the clinical presentation of the disease fits to FMF in 37 patients (39.6%). 11 (29.7%) of them had a mutation in M694V. Out of 37 children who met the criteria for FMF diagnosis, 15 (40.5%) children had a homozygous pathogenic variant of MEVF, and 22 (59.5%) children had two mutations in a heterozygous state. 57 patients who do not have a typical clinical presentation, which is specifical for FMF are observed at the departments of rheumatology, cardiology and nephrology, 13 patients are on an outpatient observation, and 6 patients at the time of the study are over 18 years old. 8 (14%) of them had a mutation in M694V. Among 57 patients with pathogenic heterozygous variants in a, 22 patients (38.6%) are observed in the rheumatology department, among them:• Enthesitis-related arthritis - 2 patients (9%);• Systemic juvenile arthritis - 13 patients (59%);• Oligoarthritis - 5 patients (23%);• Polyarthritis- 2 patients (9%).Conclusion:Analysis of the obtained data showed that FMF is characterized by a combination of the clinical presentation and the pathogenic variant in the MEFV gene. However, the disease manifests itself not only in the homozygous pathogenic variant, but also in the combination of two mutations in heterozygous. The presence of one heterozygous mutation, generally, does not lead to the development of FMF.References:[1]Konstantopoulos, A. Kanta, C. Deltas, V. Atamian, D. Mavrogianni, A.G. Tzioufas, I. Kollainis, K. Ritis, H.M. Moutsopoulos, Familial Mediterranean fever associated pyrin mutations in Greece Ann. Rheum. Dis., 62 (2003), pp. 479-481, 10.1136/ard.62.5.479.[2]Gershoni-Baruch R, Brik R, Zacks N, Shinawi M, Lidar M, Livneh A: The contribution of genotypes at the MEFV and SAA1 loci to amyloidosis and disease severity in patients with Mediterranean Fever,Seminars in Arthritis and Rheumatism,Volume 43, Issue 3, 2013, Pages 387-391familial Mediterranean fever. Arthritis Rheum 2003; 48: 1149–1155.[3]Booty MG, Chae JJ, Masters SL, et al. Familial Mediterranean fever with a single MEFV mutation: where is the second hit? Arthritis Rheum 2009; 60:185.Disclosure of Interests:None declared

scholarly journals Spastic paraplegia type 73: expanding phenotype of the first two Brazilian families

2021 ◽  
Author(s):  
Vinícius Lopes Braga ◽  
Wladimir Bocca Vieira de Rezende Pinto ◽  
Bruno de Mattos Lombardi Badia ◽  
José Marcos Vieira de Albuquerque Filho ◽  
Igor Braga Farias ◽  
...  
Keyword(s):  
De Novo ◽  
Current Knowledge ◽  
Spastic Paraparesis ◽  
Pathogenic Variant ◽  
Lower Limbs ◽  
Spastic Paraplegia ◽  
Pathogenic Variants ◽  
Genetic Features ◽  
Age Range ◽  
Late Stages

Context: Hereditary spastic paraplegias (HSPs) represent an expanding group of neurodegenerative diseases characterized mainly by progressive spastic paraparesis of the lower limbs. More than 80 different genetic loci have been associated with HSPs. In 2015, heterozygous pathogenic variants in the CPT1C gene were first associated with SPG73, not yet described in Brazilian patients. Objective: We present clinical, neuroimaging and genetic features of three Brazilian patients with SPG73. Cases reports: We report one male and two female patients, age range 36 to 78 years old. Case 1 presented with a 4-year-history of spasticity, predominantly crural tetraplegia, bladder incontinence, dysphagia and dysphonia. Family history disclosed a sister with epilepsy. Whole-exome sequencing (WES) disclosed a heterozygosis variant c.863G>A (p.Arg288His) in exon 9 of the CPT1C. Cases 2 and 3 are first degree relatives (mother and son). Both presented with long-standing slowly progressive spastic paraplegia. Case 3 presented bladder incontinence, constipation, dysphagia and dysphonia at late stages. Cases 2 and 3 WES disclosed the heterozygosis variant c.196T>G (p.Phe66Val) in exon 4 of the CPT1C. Discussion: Previous literature described six patients from an Italian family with pure HSPs phenotype and the pathogenic variant c.109C>G (p.Arg3. 7Cys) in CPT1C gene. Another group described three patients associated with pure HSPs phenotype and the pathogenic variant (c.226C>T) in the CPT1C gene. All previous reported cases had benign clinical course and bulbar involvement was not described before. One of our cases presented with a de novo variant and rapidly progressive motor and bulbar compromise. Conclusion: our cases expand the current knowledge about SPG73, including a rapidly progressive phenotype with bulbar involvement and cognitive compromise at late stages of disease course.

scholarly journals Clinical Presentation and Novel Pathogenic Variants among 68 Chinese Neurofibromatosis 1 Children

Genes ◽  
2019 ◽  
Vol 10 (11) ◽  
pp. 847
Author(s):  
Ruen Yao ◽  
Tingting Yu ◽  
Yufei Xu ◽  
Li Yu ◽  
Jiwen Wang ◽  
...  
Keyword(s):  
Short Stature ◽  
Clinical Presentation ◽  
De Novo ◽  
Genetic Disorders ◽  
Phenotypic Expression ◽  
Neurofibromatosis 1 ◽  
Sequencing Analysis ◽  
Pathogenic Variants ◽  
Behavioral Features ◽  
Nf1 Gene

Background: Neurofibromatosis 1 (NF1) is one of the most common dominantly inherited genetic disorders worldwide, with an age-dependent phenotypic expression. Exploring the mutational spectrum and clinical presentation of NF1 patients at different ages from a diverse population will aid the understanding of genotype–phenotype correlations. Methods: In this study, 95 Chinese children with clinical suspicion of NF1 mainly due to the presence of multiple café-au-lait macules (CALMs) were subjected to medical exome-sequencing analysis and Sanger confirmation of pathogenic variants. Clinical presentations were evaluated regarding dermatological, ocular, neurological, and behavioral features. Results: Pathogenic or likely pathogenic NF1 variants were detected in 71.6% (68/95) of patients; 20 pathogenic variants were not previously reported, indicating that Chinese NF1 patients are still understudied. Parental Sanger sequencing confirmation revealed 77.9% of de novo variants, a percentage that was much higher than expected. The presence of a higher number of NF1-related features at young ages was correlated with positive diagnostic findings. In addition to CALMs, neurological and behavioral features had a high expression among Chinese NF1 children. We attempted to correlate short stature with the locations of the pathogenic variants across the NF1 gene. It is interesting to notice that variants detected in the C-terminal region of the NF1 gene were less likely to be associated with short stature among the NF1 patients, whereas variants at the N-terminal were highly penetrant for the short stature phenotype. Conclusion: Novel NF1 pathogenic variants are yet to be uncovered in under-studied NF1 patient populations; their identification will help to reveal novel genotype–phenotype correlations.

scholarly journals C-70 Neuropsychological Profiles of Patients With SCN8A-Related Epilepsy

2019 ◽  
Vol 34 (6) ◽  
pp. 1099-1099
Author(s):  
L Medlin ◽  
L Bello-Espinosa ◽  
N Desire ◽  
W MacAllister
Keyword(s):  
De Novo ◽  
Neuropsychological Functioning ◽  
Pathogenic Variant ◽  
Fine Motor ◽  
Motor Delay ◽  
Compulsive Disorder ◽  
Pathogenic Variants ◽  
Visual Spatial ◽  
Epileptiform Discharges ◽  
Oppositional Defiant

Abstract Objective Two cases of SCN8A-related epilepsy (a sodium-channelopathy) are presented. SCN8A-related epilepsy with encephalopathy (SCN8A-REE), the most common form, is typically characterized by refractory seizures, developmental delays, and intellectual disability (ID) but recently discovered variants have shown broadly normal cognition. Current cases highlight the heterogeneity seen with differing de-novo pathogenic variants. Method Case 1, a 6-year-old right-handed girl, presented with SCN8A-REE and a missense pathogenic variant (c.802A>C), not previously documented. History includes speech and motor delay, with focal motor seizures starting at 4-months. Early EEG showed bilateral centroparietal epileptiform discharges. Case 2, an 8-year-old right-handed girl, presented with SCN8A-related epilepsy with c.5630A>G pathogenic variant with seizure onset at 5-months. Initial EEG showed right occipital spikes. Results Case 1 currently shows motor and language delays and prominent motor tics. Testing documented ID with fairly global neuropsychological deficits (i.e., academics, attention/executive functions, memory, visual-spatial skills, fine motor, language). In contrast, Case 2 shows low average intellect and average academics, but evaluation documented attention deficits, fine motor delays, and behavioral issues in addition to tics; she was diagnosed with Attention-Deficit/Hyperactivity Disorder, Oppositional Defiant Disorder, Obsessive Compulsive Disorder, and Tourette’s. Conclusion These cases expand limited knowledge regarding neuropsychological functioning of children with SCN8A-related epilepsy with unique de-novo pathogenic variants. While SCN8A-REE is clearly associated with ID, other pathogenic variants may show better preserved intellect, despite other neuropsychological and behavioral concerns.

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