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 Whole-exome sequencing with targeted analysis and epilepsy after acute symptomatic neonatal seizures

2021 ◽  
Author(s):  
Adam L. Numis ◽  
Gilberto da Gente ◽  
Elliott H. Sherr ◽  
Hannah C. Glass
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
List Type ◽  
Sequencing Analysis ◽  
Neonatal Seizures ◽  
Pathogenic Variants ◽  
Targeted Analysis ◽  
Whole Exome ◽  
Epilepsy Gene

Abstract Background The contribution of pathogenic gene variants with development of epilepsy after acute symptomatic neonatal seizures is not known. Methods Case–control study of 20 trios in children with a history of acute symptomatic neonatal seizures: 10 with and 10 without post-neonatal epilepsy. We performed whole-exome sequencing (WES) and identified pathogenic de novo, transmitted, and non-transmitted variants from established and candidate epilepsy association genes and correlated prevalence of these variants with epilepsy outcomes. We performed a sensitivity analysis with genes associated with coronary artery disease (CAD). We analyzed variants throughout the exome to evaluate for differential enrichment of functional properties using exploratory KEGG searches. Results Querying 200 established and candidate epilepsy genes, pathogenic variants were identified in 5 children with post-neonatal epilepsy yet in only 1 child without subsequent epilepsy. There was no difference in the number of trios with non-transmitted pathogenic variants in epilepsy or CAD genes. An exploratory KEGG analysis demonstrated a relative enrichment in cell death pathways in children without subsequent epilepsy. Conclusions In this pilot study, children with epilepsy after acute symptomatic neonatal seizures had a higher prevalence of coding variants with a targeted epilepsy gene sequencing analysis compared to those patients without subsequent epilepsy. Impact We performed whole-exome sequencing (WES) in 20 trios, including 10 children with epilepsy and 10 without epilepsy, both after acute symptomatic neonatal seizures. Children with post-neonatal epilepsy had a higher burden of pathogenic variants in epilepsy-associated genes compared to those without post-neonatal epilepsy. Future studies evaluating this association may lead to a better understanding of the risk of epilepsy after acute symptomatic neonatal seizures and elucidate molecular pathways that are dysregulated after brain injury and implicated in epileptogenesis.

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 large deletion in the COL2A1 gene expands the spectrum of pathogenic variants causing bulldog calf syndrome in cattle

2020 ◽  
Vol 62 (1) ◽  
Author(s):  
Joana Gonçalves Pontes Jacinto ◽  
Irene Monika Häfliger ◽  
Anna Letko ◽  
Cord Drögemüller ◽  
Jørgen Steen Agerholm
Keyword(s):  
De Novo ◽  
Genetic Disorders ◽  
Polymerase Chain Reaction Analysis ◽  
Large Deletion ◽  
Whole Genome Sequence ◽  
De Novo Mutation ◽  
Loss Of Function ◽  
Single Nucleotide Variants ◽  
Pathogenic Variants ◽  
Base Pair Deletion

Abstract Background Congenital bovine chondrodysplasia, also known as bulldog calf syndrome, is characterized by disproportionate growth of bones resulting in a shortened and compressed body, mainly due to reduced length of the spine and the long bones of the limbs. In addition, severe facial dysmorphisms including palatoschisis and shortening of the viscerocranium are present. Abnormalities in the gene collagen type II alpha 1 chain (COL2A1) have been associated with some cases of the bulldog calf syndrome. Until now, six pathogenic single-nucleotide variants have been found in COL2A1. Here we present a novel variant in COL2A1 of a Holstein calf and provide an overview of the phenotypic and allelic heterogeneity of the COL2A1-related bulldog calf syndrome in cattle. Case presentation The calf was aborted at gestation day 264 and showed generalized disproportionate dwarfism, with a shortened compressed body and limbs, and dysplasia of the viscerocranium; a phenotype resembling bulldog calf syndrome due to an abnormality in COL2A1. Whole-genome sequence (WGS) data was obtained and revealed a heterozygous 3513 base pair deletion encompassing 10 of the 54 coding exons of COL2A1. Polymerase chain reaction analysis and Sanger sequencing confirmed the breakpoints of the deletion and its absence in the genomes of both parents. Conclusions The pathological and genetic findings were consistent with a case of “bulldog calf syndrome”. The identified variant causing the syndrome was the result of a de novo mutation event that either occurred post-zygotically in the developing embryo or was inherited because of low-level mosaicism in one of the parents. The identified loss-of-function variant is pathogenic due to COL2A1 haploinsufficiency and represents the first structural variant causing bulldog calf syndrome in cattle. Furthermore, this case report highlights the utility of WGS-based precise diagnostics for understanding congenital disorders in cattle and the need for continued surveillance for genetic disorders in cattle.

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 De Novo and Inherited Pathogenic Variants in KDM3B Cause Intellectual Disability, Short Stature, and Facial Dysmorphism

2019 ◽  
Vol 104 (4) ◽  
pp. 758-766 ◽  
Author(s):  
Illja J. Diets ◽  
Roos van der Donk ◽  
Kristina Baltrunaite ◽  
Esmé Waanders ◽  
Margot R.F. Reijnders ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Short Stature ◽  
De Novo ◽  
Facial Dysmorphism ◽  
Pathogenic Variants

A systematic study and literature review of parental somatic mosaicism of FBN1 pathogenic variants in Marfan syndrome

2021 ◽  
pp. jmedgenet-2020-107604
Author(s):  
Paula Fernández-Álvarez ◽  
Marta Codina-Sola ◽  
Irene Valenzuela ◽  
Gisela Teixidó-Turá ◽  
Anna Cueto-González ◽  
...  
Keyword(s):  
Marfan Syndrome ◽  
De Novo ◽  
Normal Population ◽  
Genetic Disorders ◽  
Somatic Mosaicism ◽  
Clinical Signs ◽  
Systematic Analysis ◽  
Pathogenic Variants ◽  
Fibrillin 1 ◽  
Minor Criteria

BackgroundA proportion of de novo variants in patients affected by genetic disorders, particularly those with autosomal dominant (AD) inheritance, could be the consequence of somatic mosaicism in one of the progenitors. There is growing evidence that germline and somatic mosaicism are more common and play a greater role in genetic disorders than previously acknowledged. In Marfan syndrome (MFS), caused by pathogenic variants in the fibrillin-1 gene (FBN1) gene, approximately 25% of the disease-causing variants are reported as de novo. Only a few cases of parental mosaicism have been reported in MFS.MethodsEmploying an amplicon-based deep sequencing (ADS) method, we carried out a systematic analysis of 60 parents of 30 FBN1 positive, consecutive patients with MFS with an apparently de novo pathogenic variant.ResultsOut of the 60 parents studied (30 families), the majority (n=51, 85%) had a systemic score of 0, seven had a score of 1 and two a score of 2, all due to minor criteria common in the normal population. We detected two families with somatic mosaicism in one of the progenitors, with a rate of 6.6% (2/30) of apparently de novo cases.ConclusionsThe search for parental somatic mosaicism should be routinely implemented in de novo cases of MFS, to offer appropriate genetic and reproductive counselling as well as to reveal masked, isolated clinical signs of MFS in progenitors that may require specific follow-up.

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 One NF1 Mutation may Conceal Another

Genes ◽  
2019 ◽  
Vol 10 (9) ◽  
pp. 633
Author(s):  
Laurence Pacot ◽  
Cyril Burin des Roziers ◽  
Ingrid Laurendeau ◽  
Audrey Briand-Suleau ◽  
Audrey Coustier ◽  
...  
Keyword(s):  
De Novo ◽  
Mapk Pathway ◽  
Neurofibromatosis Type ◽  
Negative Regulator ◽  
Loss Of Function ◽  
Complete Penetrance ◽  
Pathogenic Variants ◽  
Legius Syndrome ◽  
Nf1 Gene ◽  
Dominant Disease

Neurofibromatosis type 1 (NF1) is an autosomal dominant disease with complete penetrance but high variable expressivity. NF1 is caused by loss-of-function mutations in the NF1 gene, a negative regulator of the RAS-MAPK pathway. The NF1 gene has one of the highest mutation rates in human disorders, which may explain the outbreak of independent de novo variants in the same family. Here, we report the co-occurrence of pathogenic variants in the NF1 and SPRED1 genes in six families with NF1 and Legius syndrome, using next-generation sequencing. In five of these families, we observed the co-occurrence of two independent NF1 variants. All NF1 variants were classified as pathogenic, according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP) guidelines. In the sixth family, one sibling inherited a complete deletion of the NF1 gene from her mother and carried a variant of unknown significance in the SPRED1 gene. This variant was also present in her brother, who was diagnosed with Legius syndrome, a differential diagnosis of NF1. This work illustrates the complexity of molecular diagnosis in a not-so-rare genetic disease.

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

2020 ◽  
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 ◽  
Pathogenic Variants ◽  
Large Size ◽  
A Cell ◽  
Growth Phenotype

ABSTRACTPurposePathogenic 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 non-specific 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.MethodsUsing 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.ResultsWe 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.ConclusionsWe designed a cell-based assay to test the pathogenicity of CAD variants, identifying 11 CAD deficient individuals, who could benefit from uridine therapy.

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