An Adolescent with a Rare De Novo Distal Trisomy 6p and Distal Monosomy 6q Chromosomal Combination

We report on a 12-year-old female with both a partial duplication and deletion involving chromosome 6. The duplication involves 6p25.3p24.3 (7.585 Mb) while the deletion includes 6q27q27 (6.244 Mb). This chromosomal abnormality is also described as distal trisomy 6p and distal monosomy 6q. The patient has a Chiari II malformation, hydrocephalus, agenesis of the corpus callosum, microcephaly, bilateral renal duplicated collecting system, scoliosis, and myelomeningocele associated with a neurogenic bladder and bladder reflux. Additional features have included seizures, feeding dysfunction, failure to thrive, sleep apnea, global developmental delay, intellectual disability, and absent speech. To our knowledge, our report is just the sixth case in the literature with concomitant distal 6p duplication and distal 6q deletion. Although a majority of chromosomal duplication-deletion cases have resulted from a parental pericentric inversion, the parents of our case have normal chromosomes. This is the first reported de novo case of distal 6p duplication and distal 6q deletion. Alternate explanations for the origin of the patient’s chromosome abnormalities include parental gonadal mosaicism, nonallelic homologous recombination, or potentially intrachromosomal transposition of the telomeres of chromosome 6. Nonpaternity was considered but ruled out by whole exome sequencing analysis.

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

Pediatric Research ◽

10.1038/s41390-021-01509-3 ◽

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.

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De novo variants in H3-3A and H3-3B are associated with neurodevelopmental delay, dysmorphic features, and structural brain abnormalities

npj Genomic Medicine ◽

10.1038/s41525-021-00268-8 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Volkan Okur ◽

Zefu Chen ◽

Liesbeth Vossaert ◽

Sandra Peacock ◽

Jill Rosenfeld ◽

...

Keyword(s):

De Novo ◽

Failure To Thrive ◽

Global Developmental Delay ◽

Death Domain ◽

Brain Abnormalities ◽

Neurodevelopmental Delay ◽

Histone H3 Variant ◽

Loss Variant ◽

Stop Loss ◽

Structural Brain

AbstractThe histone H3 variant H3.3, encoded by two genes H3-3A and H3-3B, can replace canonical isoforms H3.1 and H3.2. H3.3 is important in chromatin compaction, early embryonic development, and lineage commitment. The role of H3.3 in somatic cancers has been studied extensively, but its association with a congenital disorder has emerged just recently. Here we report eleven de novo missense variants and one de novo stop-loss variant in H3-3A (n = 6) and H3-3B (n = 6) from Baylor Genetics exome cohort (n = 11) and Matchmaker Exchange (n = 1), of which detailed phenotyping was conducted for 10 individuals (H3-3A = 4 and H3-3B = 6) that showed major phenotypes including global developmental delay, short stature, failure to thrive, dysmorphic facial features, structural brain abnormalities, hypotonia, and visual impairment. Three variant constructs (p.R129H, p.M121I, and p.I52N) showed significant decrease in protein expression, while one variant (p.R41C) accumulated at greater levels than wild-type control. One H3.3 variant construct (p.R129H) was found to have stronger interaction with the chaperone death domain-associated protein 6.

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Case Report: De novo Variants of KMT2E Cause O'Donnell-Luria-Rodan Syndrome: Additional Cases and Literature Review

Frontiers in Pediatrics ◽

10.3389/fped.2021.641841 ◽

2021 ◽

Vol 9 ◽

Author(s):

Yang Li ◽

Lijuan Fan ◽

Rong Luo ◽

Zuozhen Yang ◽

Meng Yuan ◽

...

Keyword(s):

Developmental Delay ◽

De Novo ◽

Clinical Manifestations ◽

Global Developmental Delay ◽

Feeding Difficulties ◽

Gene Testing ◽

Whole Exome ◽

Systemic Disorder ◽

Synonymous Variant ◽

Genetics And Genomics

Introduction: O'Donnell-Luria-Rodan syndrome was recently identified as an autosomal dominant systemic disorder caused by variants in KMT2E. It is characterized by global developmental delay, some patients also exhibit autism, seizures, hypotonia, and/or feeding difficulties.Methods: Whole-exome sequencing of family trios were performed for two independent children with unexplained recurrent seizures and developmental delay. Both cases were identified as having de novo variants in KMT2E. We also collected and summarized the clinical data and diagnosed them with O'Donnell-Luria-Rodan syndrome. Structural-prediction programs were used to draw the variants' locations.Results: A 186 G>A synonymous variant [NM_182931.3:exon4: c.186G>A (p.Ala62=)] was found in one family, resulting in alternative splicing acid. A 5417 C>T transition variant [NM_182931.3:exon27: c.5417C>T (p.Pro1806Leu)] was found in another family, resulting in 1806 Pro-to-Leu substitution. Both variants were classified as likely pathogenic according to the ACMG (American College of Medical Genetics and Genomics) guidelines and verified by Sanger sequencing.Conclusion: To date, three studies of O'Donnell-Luria-Rodan syndrome have been reported with heterogeneous clinical manifestations. As a newly recognized inherited systemic disorder, O'Donnell-Luria-Rodan syndrome needs to be paid more attention, especially in gene testing.

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A severe clinical phenotype of Noonan syndrome with neonatal hypertrophic cardiomyopathy in the second case worldwide with RAF1 S259Y neomutation

Genetics Research ◽

10.1017/s0016672319000041 ◽

2019 ◽

Vol 101 ◽

Author(s):

Hager Jaouadi ◽

Amel Ben Chehida ◽

Lilia Kraoua ◽

Heather C. Etchevers ◽

Laurent Argiro ◽

...

Keyword(s):

Hypertrophic Cardiomyopathy ◽

Noonan Syndrome ◽

De Novo ◽

Mapk Pathway ◽

Failure To Thrive ◽

Clinical Severity ◽

Facial Dysmorphism ◽

Stunted Growth ◽

Whole Exome ◽

Tunisian Patient

AbstractNoonan syndrome and related disorders are a group of clinically and genetically heterogeneous conditions caused by mutations in genes of the RAS/MAPK pathway. Noonan syndrome causes multiple congenital anomalies, which are frequently accompanied by hypertrophic cardiomyopathy (HCM). We report here a Tunisian patient with a severe phenotype of Noonan syndrome including neonatal HCM, facial dysmorphism, severe failure to thrive, cutaneous abnormalities, pectus excavatum and severe stunted growth, who died in her eighth month of life. Using whole exome sequencing, we identified a de novo mutation in exon 7 of the RAF1 gene: c.776C > A (p.Ser259Tyr). This mutation affects a highly conserved serine residue, a main mediator of Raf-1 inhibition via phosphorylation. To our knowledge the c.776C > A mutation has been previously reported in only one case with prenatally diagnosed Noonan syndrome. Our study further supports the striking correlation of RAF1 mutations with HCM and highlights the clinical severity of Noonan syndrome associated with a RAF1 p.Ser259Tyr mutation.

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Chronic Candida infection, bronchiectasis, immunoglobulin abnormalities, and stunting: a case report of a natural mutation of STAT1 (c.986C>G) in an adolescent male

BMC Infectious Diseases ◽

10.1186/s12879-020-05734-9 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Yali Yu ◽

Fei Xu ◽

Hui Shen ◽

Jiang Wu

Keyword(s):

De Novo ◽

Signal Transmission ◽

Elevated Serum ◽

De Novo Mutation ◽

Adolescent Male ◽

Heterozygous Mutation ◽

Chronic Mucocutaneous Candidiasis ◽

Sequencing Analysis ◽

Whole Exome ◽

Natural Mutation

Abstract Background Chronic mucocutaneous candidiasis (CMC) is the most common clinical symptom of singer transducer and signal transducer and activator of transcription 1 (STAT1) gain-of-function (GOF) mutations. Bronchiectasis is a chronic lung disease that is characterized by permanent bronchiectasis, causing cough, expectoration, and even haemoptysis. The underlying pathogeny is not yet clear. Immunoglobulin (Ig) A is derived from memory B cells and correlates with immune-related diseases. STAT1 is closely associated with signal transmission and immune regulation. Case presentation We report a 17-year-old male patient carrying a GOF mutation in STAT1. The variant led to CMC, bronchiectasis, and elevated serum IgA levels, as well as stunting. Whole-exome sequencing (WES) revealed a c.986C>G (p.P329R) heterozygous mutation in the STAT1 gene. Conclusion Further Sanger sequencing analysis of STAT1 in the patient and his parents showed that the patient harboured a de novo mutation.

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

10.21203/rs.3.rs-60924/v1 ◽

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.

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

10.21203/rs.3.rs-60924/v2 ◽

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.

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Novel HIVEP2 Variant p.Q1248* is Associated with Developmental Delay: A Case Report

Journal of Pediatric Genetics ◽

10.1055/s-0039-1683973 ◽

2019 ◽

Vol 08 (03) ◽

pp. 157-159

Author(s):

Angita Jain ◽

Paldeep S. Atwal

Keyword(s):

Developmental Delay ◽

De Novo ◽

Global Developmental Delay ◽

Type I ◽

Gene Variant ◽

Medical Genetic ◽

Whole Exome ◽

Enhancer Binding Protein ◽

Immunodeficiency Virus ◽

Novel Variant

AbstractIn this report, we describe a 5-year-old boy with global developmental delay who presented for medical genetic evaluation. We performed whole exome sequencing that revealed the involvement of a heterogenous variant p.Gln1248Ter (CAG > TAG): c.3742 C > T inherited de novo in exon 5 of HIVEP2 (human immunodeficiency virus type I enhancer binding protein 2; NM_006734.3). The gene variant p.Q1248* is interpreted to be associated as a cause of the intellectual disability. We review pathomechanisms of HIVEP2 and discuss the reasoning behind the pathogenicity of this novel variant. To the best of our knowledge, this the first reported case that demonstrates the p.Q1248* variant as pathogenic.

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

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-020-01594-3 ◽

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.

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12q14 microduplication: a new clinical entity reciprocal to the microdeletion syndrome?

BMC Medical Genomics ◽

10.1186/s12920-019-0653-x ◽

2020 ◽

Vol 13 (1) ◽

Cited By ~ 1

Author(s):

Sofia Dória ◽

Daniela Alves ◽

Maria João Pinho ◽

Joel Pinto ◽

Miguel Leão

Keyword(s):

Growth Regulation ◽

De Novo ◽

Failure To Thrive ◽

Clinical Entity ◽

Pcr Analysis ◽

Comparative Genomic ◽

Microdeletion Syndrome ◽

Pathogenic Variants ◽

Whole Exome

Abstract Background 12q14 microdeletion syndrome is characterized by low birth weight and failure to thrive, proportionate short stature and developmental delay. The opposite syndrome (microduplication) has not yet been characterized. Our main objective is the recognition of a new clinical entity - 12q14 microduplication syndrome. - as well as confirming the role of HMGA2 gene in growth regulation. Case presentation Array Comparative Genomic Hybridization (CGH), Karyotype, Fluorescence in situ Hybridization, Quantitative-PCR analysis and Whole exome sequencing (WES) were performed in a girl presenting overgrowth and obesity. Array CGH identified a 1.5 Mb 12q14.3 microduplication involving HMGA2, GRIP1, IRAK3, MSRB3 and TMBIM4 genes. Karyotype and FISH showed that duplication was a de novo insertion of 12q14.3 region on chromosome 9p resulting in an interstitial microduplication. Q-PCR confirmed the duplication only in the proband. WES revealed no pathogenic variants. Conclusions Phenotypic comparison with patients with 12q14 microdeletion syndrome showed a reciprocal presentation, suggesting a phenotypically recognizable 12q14 microduplication syndrome as well as confirming the role of HMGA2 gene in growth regulation. It is also indicative that other genes, such as IRAK3 and MSRB3 might have of role in weight gain and obesity.

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