scholarly journals Case Report: A Case of Epileptic Disorder Associated With a Novel CNTN2 Frameshift Variant in Homozygosity due to Maternal Uniparental Disomy

2021 ◽  
Vol 12 ◽  
Author(s):  
Wenjie Chen ◽  
Fei Chen ◽  
Yiping Shen ◽  
Zhixian Yang ◽  
Jiong Qin
Keyword(s):  
Age Of Onset ◽  
Uniparental Disomy ◽  
Preschool Age ◽  
Case Presentation ◽  
Maternal Uniparental Disomy ◽  
Whole Exome ◽  
Epileptic Disorder ◽  
Heterozygous Variant ◽  
Genetic Features ◽  
Neurodevelopmental Impairment

Background: Contactin 2, encoded by CNTN2 on chromosome 1q32.1, is a neural-specific glycoprotein and plays important roles in neurodevelopment. A deleterious homozygous variant in the CNTN2 gene was previously reported to cause autosomal recessive cortical myoclonic tremor and epilepsy. Since then, there has been no further report confirming the association of CNTN2 and epilepsy. Here, we reported one new case, who presented with epilepsy, carrying a novel homozygous frameshift variant in CNTN2. The clinical and genetic features of the patient were reviewed.Case presentation: The male patient presented with preschool age-of-onset neurodevelopmental impairment and focal seizures of temporal origin, and responded to valproate. A trio-whole exome sequencing revealed a novel homozygous frameshift variant in CNTN2 (c.2873_c.2874delCT, p.Thr958Thrfs). The patient’s mother was a heterozygous carrier while his father was wild-type; they were both unaffected and non-consanguineous. Further study revealed that maternal uniparental disomy (1q32.1) unmasked the heterozygous variant of CNTN2 in the proband.Conclusions: This case enhanced the gene–disease relationship between CNTN2 and epilepsy, which will help to further understand this emerging disorder.

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.

Identification of two novel variants in GAA underlying infantile-onset Pompe disease in two Pakistani families

2020 ◽  
Vol 33 (4) ◽  
pp. 553-556
Author(s):  
Aman Ullah ◽  
Bibi Zubaida ◽  
Huma Arshad Cheema ◽  
Muhammad Naeem
Keyword(s):  
Pompe Disease ◽  
Age Of Onset ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Sequence Variations ◽  
Heterozygous Variant ◽  
Novel Variants ◽  
Carrier Identification ◽  
First Time ◽  
Pakistani Families

AbstractBackgroundPompe disease (PD) is an autosomal recessive metabolic myopathy with an average incidence of one in 40,000 live births. It has a variable age of onset and can be diagnosed within the first 3 months. Heart involvement and muscle weakness are its primary manifestations.Case presentationWe describe two families affected by PD with two rare, novel variants. To date, pathogenic variants in acid α-glucosidase (GAA) alone have accounted for all cases of the disease. Both families were screened for pathogenic sequence variations. This study presents the implications of regulatory or modifier sequences in the disease pathogenesis for the first time. A homozygous missense p.Arg854Gln variant in family A and a single heterozygous variant (p.Asn925His) in family B were found to be segregating according to the disease phenotype. The variants were not detected in our in-house database comprising 50 whole-exome sequences of healthy individuals from a local unrelated Pakistani population. In silico analyses predicted that the variants would have deleterious effects on the protein structure.ConclusionsThe variants likely underlie the infantile-onset PD (IOPD) in these Pakistani families. The study expands the mutation spectrum of GAA associated with IOPD and highlights the insufficiency of screening the GAA coding sequence to determine the cause of IOPD. The work should be helpful in carrier identification, improving genetic counselling, and prenatal diagnosis.

3-M syndrome – a primordial short stature disorder with novel CUL7 mutation in two Indian patients

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Radha Rama Devi Akella
Keyword(s):  
Short Stature ◽  
Autosomal Recessive ◽  
Genetic Diagnosis ◽  
Autosomal Recessive Disorder ◽  
Missense Variant ◽  
Postnatal Growth ◽  
Compound Heterozygous ◽  
Case Presentation ◽  
Whole Exome ◽  
Heterozygous Variant

Abstract Objective To evaluate the cause of short stature in children. Case presentation Two children with suspected skeletal dysplasia and short stature were evaluated. Conclusions The 3-M syndrome is a primordial growth disorder manifesting severe postnatal growth restriction, skeletal anomalies and prominent fleshy heels. The 3-M syndrome is a genetically heterogeneous disorder and the phenotype is similar. This is a rare autosomal recessive disorder with normal intellect. Two affected children have been identified by whole-exome sequencing. One patient harboured a compound heterozygous variant and the other was a homozygous missense variant. The genetic diagnosis helped in counselling the families and facilitated prenatal diagnosis in one (case 1) family.

scholarly journals Leukoencephalopathia, demyelinating peripheral neuropathy and dural ectasia explained by a not formerly described de novo mutation in the SAMD9L gene, ends 27 years of investigations – A case report

2019 ◽  
Author(s):  
Sofia Thunström ◽  
Markus Axelsson
Keyword(s):  
Case Report ◽  
De Novo ◽  
Age Of Onset ◽  
De Novo Mutation ◽  
Missense Mutations ◽  
Case Presentation ◽  
Whole Exome ◽  
Demyelinating Peripheral Neuropathy ◽  
The Brain ◽  
Multiple Cysts

Abstract Background: Missense mutations in SAMD9L gene is associated with ataxia-pancytopenia syndrome (ATXPC), OMIM#159550. Common clinical features in these patients include neurological and hematological symptoms. The phenotype and age of onset is variable. Case presentation: In this case report whole exome sequencing (WES) revealed a not previously reported de novo variant c.2686T>G, p.(Phe896Val) in SAMD9L in a patient with widespread findings of slow developing pathology in the peripheral and central nervous system. The clinical picture was dominated by neurological symptoms, unlike previously described cases, and in addition dural ectasias and multiple cysts in the brain was observed using magnetic resonance imaging. Conclusions: This case underscores the effect of variable expressivity, i.e. different mutations in the same gene can cause different phenotypes.

scholarly journals A Chinese family with Noonan syndrome caused by a heterozygous variant in LZTR1: a case report and literature review

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Xiu Zhao ◽  
Zhuoguang Li ◽  
Li Wang ◽  
Zhangzhang Lan ◽  
Feifei Lin ◽  
...  
Keyword(s):  
Noonan Syndrome ◽  
Autosomal Dominant ◽  
Hormone Deficiency ◽  
Chinese Family ◽  
Sequencing Analysis ◽  
Inherited Disease ◽  
Case Presentation ◽  
Multiple Systems ◽  
Whole Exome ◽  
Heterozygous Variant

Abstract Background Noonan syndrome is an inherited disease involving multiple systems. More than 15 related genes have been discovered, among which LZTR1 was discovered recently. However, the pathogenesis and inheritance pattern of LZTR1 in Noonan syndrome have not yet been elucidated. Case presentation We herein describe a family with LZTR1-related Noonan syndrome. In our study, the proband, sister, mother, maternal aunt and grandmother and female cousin showed the typical or atypical features of Noonan syndrome. Only 3 patients underwent the whole-exome sequencing analysis and results showed that the proband as well as her sister inherited the same heterozygous LZTR1 variant (c.1149 + 1G > T) from their affected mother. Moreover, the proband accompanied by growth hormone deficiency without other associated variants. Conclusion In a Chinese family with Noonan syndrome, we find that the c.1149 + 1G > T variant in LZTR1 gene shows a different autosomal dominant inheritance from previous reports, which changes our understanding of its inheritance and improves our understanding of Noonan syndrome.

Mosaic trisomy 15 and prenatal genetic counselling: a case of Prader-Willi syndrome due to maternal uniparental disomy

2019 ◽  
Vol 8 (1) ◽  
Author(s):  
Mar Velilla Aparicio ◽  
Veronica Seidel ◽  
Maria Asunción Orera Clemente ◽  
Sylvia Marina Caballero ◽  
Manuel Sánchez Luna
Keyword(s):  
Growth Retardation ◽  
Uniparental Disomy ◽  
Chromosome 15 ◽  
Prader Willi Syndrome ◽  
Case Presentation ◽  
Maternal Uniparental Disomy ◽  
Low Level ◽  
Fetal Malformations ◽  
Level 2 ◽  
Mosaic Trisomy

Abstract Background Chromosome abnormalities are a frequent finding in prenatal invasive testing for fetal malformations and/or growth retardation. Case presentation We present a case of low level (8%) mosaic trisomy 15 detected on amniocentesis after fetal heart anomalies and IUGR (intrauterine growth retardation) were found on routine scan. Postnatal karyotype confirmed a very low level (2%) mosaicism in the skin but not in blood lymphocytes or in the urine. Methylation specific testing of chromosome 15 showed maternal uniparental disomy and consequently the newborn was diagnosed with Prader-Willi syndrome (PWS). Conclusions This case illustrates the need of further genetic testing in all trisomy 15 mosaicisms detected in prenatal invasive testing in order to screen for PWS, a more frequent entity than trisomy 15, altogether providing appropriate genetic counseling and adequate clinical management. The recommendation is applicable to prenatally detected mosaic trisomies of other chromosomes carrying imprinted genes, such as 7, 11 and 14.

scholarly journals Leukoencephalopathia, demyelinating peripheral neuropathy and dural ectasia explained by a not formerly described de novo mutation in the SAMD9L gene, ends 27 years of investigations – A case report

2019 ◽  
Author(s):  
Sofia Thunström ◽  
Markus Axelsson
Keyword(s):  
Case Report ◽  
De Novo ◽  
Age Of Onset ◽  
De Novo Mutation ◽  
Missense Mutations ◽  
Case Presentation ◽  
Whole Exome ◽  
Demyelinating Peripheral Neuropathy ◽  
The Brain ◽  
Multiple Cysts

Abstract Background: Missense mutations in SAMD9L gene is associated with ataxia-pancytopenia syndrome (ATXPC), OMIM#159550. Common clinical features in these patients include neurological and hematological symptoms. The phenotype and age of onset is variable. Case presentation: In this case report whole exome sequencing (WES) revealed a not previously reported de novo variant c.2686T>G, p.(Phe896Val) in SAMD9L in a patient with widespread findings of slow developing pathology in the peripheral and central nervous system. The clinical picture was dominated by neurological symptoms, unlike previously described cases, and in addition dural ectasias and multiple cysts in the brain was observed using magnetic resonance imaging. Conclusions: This case underscores the effect of variable expressivity, i.e. different mutations in the same gene can cause different phenotypes.

scholarly journals Exosomes from Plasma of Neuroblastoma Patients Contain Doublestranded DNA Reflecting the Mutational Status of Parental Tumor Cells

2021 ◽  
Vol 22 (7) ◽  
pp. 3667
Author(s):  
Chiara Degli Esposti ◽  
Barbara Iadarola ◽  
Simone Maestri ◽  
Cristina Beltrami ◽  
Denise Lavezzari ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Acquired Resistance ◽  
Membrane Vesicles ◽  
Preschool Age ◽  
Molecular Diagnostic ◽  
Non Invasive ◽  
Mutational Status ◽  
Whole Exome ◽  
Parental Tumor ◽  
Intercellular Communications

Neuroblastoma (NB) is an aggressive infancy tumor, leading cause of death among preschool age diseases. Here we focused on characterization of exosomal DNA (exo-DNA) isolated from plasma cell-derived exosomes of neuroblastoma patients, and its potential use for detection of somatic mutations present in the parental tumor cells. Exosomes are small extracellular membrane vesicles secreted by most cells, playing an important role in intercellular communications. Using an enzymatic method, we provided evidence for the presence of double-stranded DNA in the NB exosomes. Moreover, by whole exome sequencing, we demonstrated that NB exo-DNA represents the entire exome and that it carries tumor-specific genetic mutations, including those occurring on known oncogenes and tumor suppressor genes in neuroblastoma (ALK, CHD5, SHANK2, PHOX2B, TERT, FGFR1, and BRAF). NB exo-DNA can be useful to identify variants responsible for acquired resistance, such as mutations of ALK, TP53, and RAS/MAPK genes that appear in relapsed patients. The possibility to isolate and to enrich NB derived exosomes from plasma using surface markers, and the quick and easy extraction of exo-DNA, gives this methodology a translational potential in the clinic. Exo-DNA can be an attractive non-invasive biomarker for NB molecular diagnostic, especially when tissue biopsy cannot be easily available.

scholarly journals Fibromuscular dysplasia with recurrence after “long-term” following percutaneous transcatheter renal angioplasty: two case reports with a review of 26 patients

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Shuntaro Oribe ◽  
Takafumi Toyohara ◽  
Eikan Mishima ◽  
Takehiro Suzuki ◽  
Koichi Kikuchi ◽  
...  
Keyword(s):  
Fibromuscular Dysplasia ◽  
Age Of Onset ◽  
Case Reports ◽  
Case Presentation ◽  
Renal Angioplasty ◽  
Long Term Follow Up ◽  
Percutaneous Transluminal Renal Angioplasty ◽  
The Difference

Abstract Background Fibromuscular dysplasia (FMD) often causes renal artery stenosis with renovascular hypertension. Recent clinical outcomes encourage percutaneous transluminal renal angioplasty (PTRA) to treat FMD; however, the necessary follow-up period remains unclear. Moreover, previous studies have not revealed the difference in the period until recurrence between two major types of FMD—multifocal and focal. Case presentation We describe two patients with multifocal FMD who developed hypertension during their teenage years and had recurrence of FMD > 10 years after PTRA. We further examined the types of FMD and age of onset in 26 patients who underwent PTRA. The period until recurrence of multifocal FMD was longer than that of focal FMD. Moreover, patients with early-onset multifocal FMD are likely to have a delayed recurrence after PTRA compared to other types. Conclusions Our report suggests that patients with multifocal FMD, especially those with onset at an early age, may need long-term follow-up for at least ≥ 10 years.

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