scholarly journals Compound Phenotype Due to Recessive Variants in LARP7 and OTOG Genes Disclosed by an Integrated Approach of SNP-Array and Whole Exome Sequencing

Genes ◽  
2020 ◽  
Vol 11 (4) ◽  
pp. 379
Author(s):  
Pietro Palumbo ◽  
Orazio Palumbo ◽  
Maria Pia Leone ◽  
Ester di Muro ◽  
Stefano Castellana ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Neurodevelopmental Disorders ◽  
Snp Array ◽  
Integrated Approach ◽  
Medical Genetics ◽  
Global Developmental Delay ◽  
Facial Dysmorphism ◽  
Whole Exome ◽  
Number Of Patients

Neurodevelopmental disorders are a challenge in medical genetics due to genetic heterogeneity and complex genotype-phenotype correlations. For this reason, the resolution of single cases not belonging to well-defined syndromes often requires an integrated approach of multiple whole-genome technologies. Such an approach has also unexpectedly revealed a complex molecular basis in an increasing number of patients, for whom the original suspect of a pleiotropic syndrome has been resolved as the summation effect of multiple genes. We describe a 10-year-old boy, the third son of first-cousin parents, with global developmental delay, facial dysmorphism, and bilateral deafness. SNP-array analysis revealed regions of homozygosity (ROHs) in multiple chromosome regions. Whole-exome sequencing prioritized on gene-mapping into the ROHs showed homozygosity for the likely pathogenic c.1097_1098delAG p. (Arg366Thrfs*2) frameshift substitution in LARP7 and the likely pathogenic c.5743C>T p.(Arg1915*) nonsense variant in OTOG. Recessive variants in LARP7 cause Alazami syndrome, while variants in OTOG cause an extremely rare autosomal recessive form of neurosensorial deafness. Previously unreported features were acrocyanosis and palmoplantar hyperhidrosis. This case highlights the utility of encouraging technological updates in medical genetics laboratories involved in the study of neurodevelopmental disorders and integrating laboratory outputs with the competencies of next-generation clinicians.

Paternal uniparental disomy of chromosome 19 in a pair of monochorionic diamniotic twins with dysmorphic features and developmental delay

2018 ◽  
Vol 55 (12) ◽  
pp. 847-852 ◽  
Author(s):  
Kit San Yeung ◽  
Matthew Sai Pong Ho ◽  
So Lun Lee ◽  
Anita Sik Yau Kan ◽  
Kelvin Yuen Kwong Chan ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Developmental Delay ◽  
Whole Exome Sequencing ◽  
Snp Array ◽  
Uniparental Disomy ◽  
Global Developmental Delay ◽  
Chromosome 19 ◽  
Dysmorphic Features ◽  
Whole Exome ◽  
Paternal Uniparental Disomy

BackgroundWe report here clinical, cytogenetic and molecular data for a pair of monochorionic diamniotic twins with paternal isodisomy for chromosome 19. Both twins presented with dysmorphic features and global developmental delay. This represents, to our knowledge, the first individual human case of paternal uniparental disomy for chromosome 19 (UPD19).MethodsWhole-exome sequencing, together with conventional karyotype and SNP array analysis were performed along with genome-wide DNA methylation array for delineation of the underlying molecular defects.ResultsConventional karyotyping on amniocytes and lymphocytes showed normal karyotypes for both twins. Whole-exome sequencing did not identify any pathogenic sequence variants but >5000 homozygous exonic variants on chromosome 19, suggestive of UPD19. SNP arrays on blood and buccal DNA both showed paternal isodisomy for chromosome 19. Losses of imprinting for known imprinted genes on chromosome 19 were identified, including ZNF331, PEG3, ZIM2 and MIMT1. In addition, imprinting defects were also identified in genes located on other chromosomes, including GPR1-AS, JAKMP1 and NHP2L1.ConclusionImprinting defects are the most likely cause for the dysmorphism and developmental delay in this first report of monozygotic twins with UPD19. However, epigenotype-phenotype correlation will require identification of additional individuals with UPD19 and further molecular analysis.

scholarly journals Whole-exome sequencing in an individual with severe global developmental delay and intractable epilepsy identifies a novel, de novoGRIN2Amutation

Epilepsia ◽  
2014 ◽  
Vol 55 (7) ◽  
pp. e75-e79 ◽  
Author(s):  
Sunita Venkateswaran ◽  
Ken A. Myers ◽  
Amanda C. Smith ◽  
Chandree L. Beaulieu ◽  
Jeremy A. Schwartzentruber ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Developmental Delay ◽  
Whole Exome Sequencing ◽  
Intractable Epilepsy ◽  
Global Developmental Delay ◽  
Whole Exome

Whole exome sequencing unraveled the mystery of neurodevelopmental disorders in three Iranian families

Gene Reports ◽  
2018 ◽  
Vol 13 ◽  
pp. 141-145
Author(s):  
Zeinab Ravesh ◽  
Soudeh Ghafouri-Fard ◽  
Masoumeh Rostami ◽  
Nasrin Alipour ◽  
Vahid Reza Yassaee ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Neurodevelopmental Disorders ◽  
Whole Exome

Whole exome sequencing identifies a novel 5 Mb deletion at 14q12 region in a patient with global developmental delay, microcephaly and seizures

Gene ◽  
2018 ◽  
Vol 673 ◽  
pp. 56-60 ◽  
Author(s):  
Venugopal S. Vineeth ◽  
Usha R. Dutta ◽  
Karthik Tallapaka ◽  
Aneek Das Bhowmik ◽  
Ashwin Dalal
Keyword(s):  
Exome Sequencing ◽  
Developmental Delay ◽  
Whole Exome Sequencing ◽  
Global Developmental Delay ◽  
Whole Exome

Whole exome sequencing and copy-number variation analysis of 20 NF2-associated spinal and cranial meningiomas.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2051-2051
Author(s):  
Ramita Dewan ◽  
Alexander Pemov ◽  
Nancy F Hansen ◽  
Settara C Chandrasekharappa ◽  
Jim Mullikin ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Snp Array ◽  
Neurofibromatosis Type ◽  
Large Chromosome ◽  
Nucleotide Substitutions ◽  
Genetic Event ◽  
Multiple Tumor ◽  
Small Indels ◽  
Whole Exome

2051 Background: Neurofibromatosis type 2 is a heritable tumor predisposition syndrome characterized by the growth of multiple tumor types in the nervous system, including bilateral vestibular schwannomas, meningiomas and ependymomas. Recent genomic sequencing studies have revealed that NF2 inactivation is the most frequent genetic event in sporadic meningiomas. In line with Knudson’s hypothesis, it is accepted that somatic inactivation of the wildtype NF2 allele initiates tumor growth in NF2 patients, but little is known of what other genes or pathways influence meningioma tumorigenesis. Methods: To investigate this question, we performed whole exome sequencing (WES) (Illumina Hi-Seq 2500 platform, 96 Mb SeqCap EZ Exome + UTR Library, NimbleGen) and SNP-array analysis (HumanOmniExpressExome-8, v1.2 arrays, Illumina) of twenty spinal and cranial meningioma samples from seven NF2 patients. Mutation validation was completed via orthogonal sequencing (IonTorrent, ThermoFisher). Results: We identified NF2 germline mutations in all patients, including five nonsense, one splice site and one likely pathogenic intronic mutation. We found that the predominant mechanism of somatic NF2 inactivation in the tumors was loss of heterozygosity (LOH): we identified large chromosome 22 deletions containing NF2 in nineteen out of twenty meningiomas. The second most frequent chromosomal aberration was a deletion within chromosome 1p, followed by entire chromosome X deletion and rearrangements in chromosome 17q. The remaining samples exhibited normal diploid genomic architecture. Somatic mutations included about twenty point substitutions and small indels. Conclusions: Our study revealed that somatic inactivation of NF2 is the most frequent and only recurrent genetic event in NF2-associated meningiomas. Large LOH events are the most prevalent second hit mechanism and may also represent a common path of meningioma progression. Somatic single nucleotide substitutions and small indels are rare in these tumors. Interestingly, we did not identify mutations in TRAF7, KLF4, AKT1, or SMO, which have been found to be critical for non-NF2 meningioma growth.

scholarly journals Whole-exome sequencing identifies a novel mutation in spermine synthase gene (SMS) associated with Snyder-Robinson Syndrome

2020 ◽  
Author(s):  
Talal J. Qazi ◽  
Qiao Wu ◽  
Ailikemu Aierken ◽  
Daru Lu ◽  
Ihtisham Bukhari ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Mutational Analysis ◽  
Novel Mutation ◽  
Pathogenic Variant ◽  
Facial Dysmorphism ◽  
Pakistani Family ◽  
Spermine Synthase ◽  
Whole Exome

Abstract Background: Loss of function mutations in the spermine synthase gene (SMS) have been reported to cause a rare X-linked intellectual disability known as Snyder-Robinson Syndrome (SRS). Besides intellectual disability, SRS is also characterized by reduced bone density, osteoporosis and facial dysmorphism. SRS phenotypes evolve with age from childhood to adulthood. Methods: Whole exome sequencing was performed to know the causative gene/pathogenic variant. Later we confirmed the pathogenic variant through Sanger sequencing. Furthermore, we also performed the mutational analysis through HOPE SERVER and SWISS-MODEL. Also, radiographs were also obtained for affected individual to confirm the disease features. Results: In this article, we report the first Pakistani family consisting of three patients with SRS and a novel missense pathogenic variant in the SMS gene (c.905 C>T p.(Ser302Leu)). In addition to the typical phenotypes, one patient presented with early-onset seizures. Clinical features, genetic and in-silico analysis linked the affected patients of the family with Snyder-Robinson and suggest that this novel mutation affects the spermine synthase activity Conclusion: A novel missense variant in the SMS, c.905C >T p. (Ser302Leu), causing Snyder- Robinson Syndrome (SRS) is reported in three members of Pakistani Family.

scholarly journals Whole exome sequencing identifies a novel mutation in spermine synthase gene (SMS) associated with Snyder-Robinson Syndrome

2020 ◽  
Author(s):  
Talal J. Qazi ◽  
Qiao Wu ◽  
Ailikemu Aierken ◽  
Daru Lu ◽  
Ihtisham Bukhari ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Mutational Analysis ◽  
Novel Mutation ◽  
Pathogenic Variant ◽  
Facial Dysmorphism ◽  
Pakistani Family ◽  
Spermine Synthase ◽  
Whole Exome

Abstract Background: Loss of function mutations in the spermine synthase gene (SMS) have been reported to cause a rare X-linked intellectual disability known as Snyder-Robinson Syndrome (SRS). Besides intellectual disability, SRS is also characterized by reduced bone density, osteoporosis and facial dysmorphism. SRS phenotypes evolve with age from childhood to adulthood. Methods: Whole exome sequencing was performed to know the causative gene/pathogenic variant. Later we confirmed the pathogenic variant through Sanger sequencing. Furthermore, we also performed the mutational analysis through HOPE SERVER and SWISS-MODEL. Also, radiographs were also obtained for affected individual to confirm the disease features. Results: In this article, we report the first Pakistani family consisting of three patients with SRS and a novel missense pathogenic variant in the SMS gene (c.905 C>T p.(Ser302Leu)). In addition to the typical phenotypes, one patient presented with early-onset seizures. Clinical features, genetic and in-silico analysis linked the affected patients of the family with Snyder-Robinson and suggest that this novel mutation affects the spermine synthase activityConclusion: A novel missense variant in the SMS, c.905C >T p. (Ser302Leu), causing Snyder- Robinson Syndrome (SRS) is reported in three members of Pakistani Family.

scholarly journals Comprehensive genetic analysis by whole exome sequencing in 352 Korean pediatric patients with unknown neurodevelopmental disorders

2018 ◽  
Author(s):  
Youngha Lee ◽  
Jin Sook Lee ◽  
Soo Yeon Kim ◽  
Jaeso Cho ◽  
Yongjin Yoo ◽  
...  
Keyword(s):  
Genetic Analysis ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Variants ◽  
Neurodevelopmental Disorders ◽  
Pediatric Patients ◽  
Medical System ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Novel Variants

AbstractImportanceAccurate diagnosis of pediatric patients with complicated neurological problems demands a well-coordinated combination of robust genetic analytic capability and delicate clinical evaluation. It should be tested whether this challenge can be augmented by whole exome sequencing (WES).ObjectiveTo evaluate the utility of WES-based diagnosis and discovery of novel variants of undiagnosed patients with complex neurodevelopmental problems in a country with a centralized medical system.Design, setting, and participantsA cohort of 352 Korean patients, believed to cover a major portion of the entire country from July 2014 to April 2017, with a broad spectrum of neurodevelopmental disorders without any pathogenic variants revealed by conventional methods were evaluated by trio-based WES at Seoul National University Children’s Hospital.ExposuresWES of patients and parents and subsequent evaluation of genetic variants.Main outcomes and measuresGenetic variants from each patient were evaluated for known disease association and novel variants were assessed for possible involvement with neurodevelopment process.ResultsWe identified disease-causing variants, including newly discovered variants, in 57.4% of the probands, who had underwent a mean of 5.6 years of undiagnosed periods and visited mean of 2.3 tertiary hospitals. The cohort included 112 patients with variants that were previously reported as pathogenic (31.8%), 16 patients with copy number variants (4.5%) and 27 patients with variants that were associated with different clinical symptoms (7.7%). We also discovered potentially pathogenic variants from 47 patients that required further functional assessments (13.4%) and demonstrated potential implications in neurodevelopmental disorders. Following the genetic analysis, we provided more precise treatments to selected patients. A few clinical vignettes are presented that illuminate the potential diagnostic pitfalls that one could have encountered without this approach.Conclusions and relevanceOur results highlight the utility of WES-based diagnosis for improved patient care in a country with a centralized medical system and discovery of novel pathophysiology mechanisms.Key pointsQuestionWhat is the advantage of whole exome sequencing based diagnosis of pediatric neurology patients with unknown rare symptoms in a large tertiary clinic in a country with a centralized medical system?FindingsWhole exome sequencing of 352 Korean patients, with a mean of 5.7 years of undiagnosed period, yielded 44.0% of conservative diagnostic yield. A number of cases were directly benefitted by trio-based WES via termination of diagnostic odyssey, genetic counseling for next offspring, or suggestion of more effective and customized treatment options.MeaningWe report on the establishment of a national-level whole exome-based diagnosis system, with emphasis on deliberate integration of clinical interpretation and genetic analysis. Whole exome sequencing should be a choice of diagnostic tools for pediatric neurologic patients with ambiguous symptoms.

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