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 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

scholarly journals SAT-081 Hidden in Plain Sight: Rethinking Our Approach to Allan-Herndon-Dudley Syndrome

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Alyssa M Dye ◽  
Grace Bazan Nelson ◽  
Alicia Marie Diaz-Thomas
Keyword(s):  
Exome Sequencing ◽  
Developmental Delay ◽  
Whole Exome Sequencing ◽  
Brain Mri ◽  
Chromosomal Microarray ◽  
Global Developmental Delay ◽  
Neurological Manifestations ◽  
Free T4 ◽  
Phase 2 Trial ◽  
Whole Exome

Abstract Background: Allan-Herndon-Dudley (AHD) is a rare X-linked disorder with neurological manifestations secondary to a mutation in monocarboxylate transporter 8, a protein that transports T3 into nerve cells in the brain. AHD is characterized by increased serum free T3, decreased serum free T4 and normal serum TSH levels as well as the severe neurological manifestations including global developmental delay, hypotonia, and joint contractures (1). A phase 2 trial using triodyothyroacetic acid has shown promise in treating this disorder (2). We report on three children who were diagnosed by whole exome sequencing after presenting with neurological manifestations. Clinical Cases: Patient 1 presented at 4 months to the neurology clinic for seizures. He had a normal newborn screen. Worsening developmental delays and central hypotonia prompted a brain MRI that revealed delayed myelination for age. At 6 months a chromosomal microarray and metabolic work-up were performed and were nondiagnostic. Whole exome sequencing was obtained at the age of 4.5 years revealing a mutation in the SLC16A2 gene (p.Ser210Tyr). Thyroid studies were consistent with the diagnosis. Patient 2 presented to neurology at 9 months for developmental delay. A brain MRI was obtained which was within normal limits. At 14 months an acylcarnitine profile was obtained which indicated a possible CPT1 deficiency, which did not fit his clinical picture. Chromosomal microarray as well as work-up for inborn errors of metabolism were performed and were nondiagnostic. Thyroid studies were obtained which showed low free T4 with normal TSH. Whole exome sequencing was obtained at the age of 2.5 years, which revealed a mutation in SLC16A2 (p.R371C). Patient 3 presented as sibling of patient 2 with known AHD syndrome. Testing for SLC16A2 was performed at the age of 5 months and returned positive for same mutation as sibling (p.R371C). Conclusion: Allan-Herndon-Dudley syndrome is a rare neurological disease secondary to a mutation in the T3 transporter protein to nervous tissue. A high index of suspicion as well as thyroid studies should be obtained in patients presenting with central hypotonia and global developmental delay with normal newborn screens, particularly in states that use TSH as a screening test. This is especially important as treatments are becoming available that may help prevent neurological devastation seen in these patients. References: 1. Dumitrescu AM, Fu J, Dempsey MA, Refetoff S. MCT8-Specific Thyroid Hormone Cell-Membrane Transporter Deficiency. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews®. Seattle (WA): University of Washington, Seattle; 1993 2. Groeneweg S, Peeters RP, Moran C, et al. Effectiveness and safety of the tri-iodothyronine analogue Triac in children and adults with MCT8 deficiency: an international, single-arm, open-label, phase 2 trial. Lancet Diabetes Endocrinol. 2019;7(9):695-706.

scholarly journals Whole Exome Sequencing Reveals a Novel AUTS2 In-Frame Deletion in a Boy with Global Developmental Delay, Absent Speech, Dysmorphic Features, and Cerebral Anomalies

Genes ◽  
2021 ◽  
Vol 12 (2) ◽  
pp. 229
Author(s):  
Pietro Palumbo ◽  
Ester Di Muro ◽  
Maria Accadia ◽  
Mario Benvenuto ◽  
Marilena Carmela Di Giacomo ◽  
...  
Keyword(s):  
Corpus Callosum ◽  
Exome Sequencing ◽  
Developmental Delay ◽  
Whole Exome Sequencing ◽  
Molecular Mechanisms ◽  
Autism Spectrum ◽  
Copy Number Variations ◽  
Cerebellar Vermis ◽  
Global Developmental Delay ◽  
Whole Exome

Neurodevelopmental disorders (NDDs) are a group of highly prevalent, clinically and genetically heterogeneous pediatric disorders comprising, according to the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-V), intellectual disability, developmental delay, autism spectrum disorders, and other neurological and cognitive disorders manifesting in the developmental age. To date, more than 1000 genes have been implicated in the etiopathogenesis of NNDs. Among them, AUTS2 (OMIM # 607270) encodes a protein involved in neural migration and neuritogenesis, and causes NNDs with different molecular mechanisms including copy number variations, single or multiple exonic deletion and single nucleotide variants. We describes a 9-year-old boy with global developmental delay, absent speech, minor craniofacial anomalies, hypoplasia of the cerebellar vermis and thinning of the corpus callosum, resulted carrier of the de novo AUTS2 c.1603_1626del deletion at whole exome sequencing (WES) predicted to cause the loss of eight amino acids [p.(His535_Thr542del)]. Notably, our patient is the first reported so far in medical literature carrying an in-frame deletion and the first in which absent language, hypoplasia of the cerebellar vermis and thinning of the corpus callosum has been observed thus useful to expand the molecular spectrum of AUTS2 pathogenic variants and to broaden our knowledge on the clinical phenotype associated.

scholarly journals Spectrum of Movement Disorders in GNAO1 Encephalopathy: in-depth Phenotyping and Literature Review

2020 ◽  
Author(s):  
Soo Yeon Kim ◽  
YoungKyu Shim ◽  
Young Joon Ko ◽  
Soojin Park ◽  
Se Song Jang ◽  
...  
Keyword(s):  
Literature Review ◽  
Exome Sequencing ◽  
Developmental Delay ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Epileptic Encephalopathy ◽  
Global Developmental Delay ◽  
Pathogenic Variants ◽  
Whole Exome

Abstract Background GNAO1 encephalopathy is a rare neurodevelopmental disorder characterized by distinct movement presentations and early onset epileptic encephalopathy. Here, we report the in-depth phenotyping of genetically confirmed patients with GNAO1 encephalopathy, focusing on movement presentations. Results Six patients who participated in Korean Undiagnosed Disease Program were diagnosed to have pathogenic or likely pathogenic variants in GNAO1 using whole exome sequencing. All medical records and personal video clips were analyzed with a literature review. Three of the 6 patients were male. Mean follow-up duration was 39 months (range, 7–78 months) and age at last examination was 8.0 years (range, 3.3–16.9 years). Initial complaints were hypotonia or developmental delay in 5 and right-hand clumsiness in 1 patient, which were noticed at 20 months of age on average (range, 0–75 months). All patients showed global developmental delay and 4 had severely retarded development. Five patients (5/6, 83.3%) had many different movement symptoms with various onset and progression. The symptoms included stereotyped hands movement, non-epileptic myoclonus, dyskinesia, dystonia and choreoathetosis. Whole exome sequencing identified 6 different variants in GNAO1. Three were novel de novo variants and atypical presentation was noted in a patient. One variant turned out to be inherited from patient’s mother who had mosaic variant. Distinct phenotypes in patients with variant p.Glu246Lys and p.Arg209His were elucidated by in-depth phenotyping and literature review. Conclusions We reported 6 patients with GNAO1 encephalopathy showing an extremely diverse clinical spectrum on video. Some characteristic movement features identified by careful inspection may also provide important diagnostic insight and practice guidelines.

scholarly journals Spectrum of Movement Disorders in GNAO1 Encephalopathy: In-Depth Phenotyping and Case-by-Case Analysis

2020 ◽  
Author(s):  
Soo Yeon Kim ◽  
YoungKyu Shim ◽  
Young Joon Ko ◽  
Soojin Park ◽  
Se Song Jang ◽  
...  
Keyword(s):  
Literature Review ◽  
Exome Sequencing ◽  
Developmental Delay ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Epileptic Encephalopathy ◽  
Global Developmental Delay ◽  
Pathogenic Variants ◽  
Whole Exome

Abstract Background: GNAO1 encephalopathy is a rare neurodevelopmental disorder characterized by distinct movement presentations and early onset epileptic encephalopathy. Here, we report the in-depth phenotyping of genetically confirmed patients with GNAO1 encephalopathy, focusing on movement presentations.Results: Six patients who participated in Korean Undiagnosed Disease Program were diagnosed to have pathogenic or likely pathogenic variants in GNAO1 using whole exome sequencing. All medical records and personal video clips were analyzed with a literature review. Three of the 6 patients were male. Median follow-up duration was 41 months (range, 7–78 months) and age at last examination was 7.4 years (range, 3.3–16.9 years). Initial complaints were hypotonia or developmental delay in 5 and right-hand clumsiness in 1 patient, which were noticed at median age of 3 months (range, 0–75 months). All patients showed global developmental delay and 4 had severely retarded development. Five patients (5/6, 83.3%) had many different movement symptoms with various onset and progression. The symptoms included stereotyped hands movement, non-epileptic myoclonus, dyskinesia, dystonia and choreoathetosis. Whole exome sequencing identified 6 different variants in GNAO1. Three were novel de novo variants and atypical presentation was noted in a patient. One variant turned out to be inherited from patient’s mother who had mosaic variant. Distinct and characteristics movement phenotypes in patients with variant p.Glu246Lys and p.Arg209His were elucidated by in-depth phenotyping and literature review. Conclusions: We reported 6 patients with GNAO1 encephalopathy showing an extremely diverse clinical spectrum on video. Some characteristic movement features identified by careful inspection may also provide important diagnostic insight and practice guidelines.

scholarly journals Spectrum of movement disorders in GNAO1 encephalopathy: in-depth phenotyping and case-by-case analysis

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Soo Yeon Kim ◽  
YoungKyu Shim ◽  
Young Joon Ko ◽  
Soojin Park ◽  
Se Song Jang ◽  
...  
Keyword(s):  
Literature Review ◽  
Exome Sequencing ◽  
Developmental Delay ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Epileptic Encephalopathy ◽  
Global Developmental Delay ◽  
Pathogenic Variants ◽  
Whole Exome

Abstract Background GNAO1 encephalopathy is a rare neurodevelopmental disorder characterized by distinct movement presentations and early onset epileptic encephalopathy. Here, we report the in-depth phenotyping of genetically confirmed patients with GNAO1 encephalopathy, focusing on movement presentations. Results Six patients who participated in Korean Undiagnosed Disease Program were diagnosed to have pathogenic or likely pathogenic variants in GNAO1 using whole exome sequencing. All medical records and personal video clips were analyzed with a literature review. Three of the 6 patients were male. Median follow-up duration was 41 months (range 7–78 months) and age at last examination was 7.4 years (range 3.3–16.9 years). Initial complaints were hypotonia or developmental delay in 5 and right-hand clumsiness in 1 patient, which were noticed at median age of 3 months (range 0–75 months). All patients showed global developmental delay and 4 had severely retarded development. Five patients (5/6, 83.3%) had many different movement symptoms with various onset and progression. The symptoms included stereotyped hands movement, non-epileptic myoclonus, dyskinesia, dystonia and choreoathetosis. Whole exome sequencing identified 6 different variants in GNAO1. Three were novel de novo variants and atypical presentation was noted in a patient. One variant turned out to be inherited from patient’s mother who had mosaic variant. Distinct and characteristics movement phenotypes in patients with variant p.Glu246Lys and p.Arg209His were elucidated by in-depth phenotyping and literature review. Conclusions We reported 6 patients with GNAO1 encephalopathy showing an extremely diverse clinical spectrum on video. Some characteristic movement features identified by careful inspection may also provide important diagnostic insight and practice guidelines.

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.

scholarly journals One test for all: whole exome sequencing significantly improves the diagnostic yield in growth retarded patients referred for molecular testing for Silver–Russell syndrome

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Robert Meyer ◽  
Matthias Begemann ◽  
Christian Thomas Hübner ◽  
Daniela Dey ◽  
Alma Kuechler ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Diagnostic Yield ◽  
Uniparental Disomy ◽  
Molecular Testing ◽  
Main Body ◽  
Comprehensive Overview ◽  
Maternal Uniparental Disomy ◽  
Whole Exome ◽  
Silver Russell Syndrome

Abstract Background Silver-Russell syndrome (SRS) is an imprinting disorder which is characterised by severe primordial growth retardation, relative macrocephaly and a typical facial gestalt. The clinical heterogeneity of SRS is reflected by a broad spectrum of molecular changes with hypomethylation in 11p15 and maternal uniparental disomy of chromosome 7 (upd(7)mat) as the most frequent findings. Monogenetic causes are rare, but a clinical overlap with numerous other disorders has been reported. However, a comprehensive overview on the contribution of mutations in differential diagnostic genes to phenotypes reminiscent to SRS is missing due to the lack of appropriate tests. With the implementation of next generation sequencing (NGS) tools this limitation can now be circumvented. Main body We analysed 75 patients referred for molecular testing for SRS by a NGS-based multigene panel, whole exome sequencing (WES), and trio-based WES. In 21/75 patients a disease-causing variant could be identified among them variants in known SRS genes (IGF2, PLAG1, HMGA2). Several patients carried variants in genes which have not yet been considered as differential diagnoses of SRS. Conclusions WES approaches significantly increase the diagnostic yield in patients referred for SRS testing. Several of the identified monogenetic disorders have a major impact on clinical management and genetic counseling.

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