scholarly journals Congenital myasthenic syndrome with mild intellectual disability caused by a recurrent SLC25A1 variant

2019 ◽  
Vol 28 (3) ◽  
pp. 373-377 ◽  
Author(s):  
Sunitha Balaraju ◽  
Ana Töpf ◽  
Grace McMacken ◽  
Veeramani Preethish Kumar ◽  
Astrid Pechmann ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Haplotype Analysis ◽  
Missense Variant ◽  
Congenital Myasthenic Syndrome ◽  
Single Family ◽  
Mild Intellectual Disability ◽  
Causative Gene ◽  
Whole Exome ◽  
Original Family ◽  
Myasthenic Syndrome

Abstract Congenital myasthenic syndromes (CMS) are a clinically and genetically heterogeneous group of disorders caused by mutations which lead to impaired neuromuscular transmission. SLC25A1 encodes a mitochondrial citrate carrier, associated mainly with the severe neurometabolic disease combined D-2- and L-2-hydroxyglutaric aciduria (D/L-2-HGA). We previously reported a single family with a homozygous missense variant in SLC25A1 with a phenotype restricted to relatively mild CMS with intellectual disability, but to date no additional cases of this CMS subtype had been reported. Here, we performed whole exome sequencing (WES) in three additional and unrelated families presenting with CMS and mild intellectual disability to identify the underlying causative gene. The WES analysis revealed the presence of a homozygous c.740G>A; p.(Arg247Gln) missense SLC25A1 variant, the same SLC25A1 variant as identified in the original family with this phenotype. Electron microscopy of muscle from two cases revealed enlarged and accumulated mitochondria. Haplotype analysis performed in two unrelated families suggested that this variant is a result of recurrent mutation and not a founder effect. This suggests that p.(Arg247Gln) is associated with a relatively mild CMS phenotype with subtle mitochondrial abnormalities, while other variants in this gene cause more severe neurometabolic disease. In conclusion, the p.(Arg247Gln) SLC25A1 variant should be considered in patients presenting with a presynaptic CMS phenotype, particularly with accompanying intellectual disability.

scholarly journals Novel homozygous variant in the TPO gene associated with congenital hypothyroidism and mild-intellectual disability

2020 ◽  
Vol 7 (1) ◽  
Author(s):  
Amjad Khan ◽  
Muhammad Umair ◽  
Rania Abdulfattah Sharaf ◽  
Muhammad Ismail Khan ◽  
Amir Ullah ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Congenital Hypothyroidism ◽  
Autosomal Recessive ◽  
Missense Variant ◽  
Thyroid Peroxidase ◽  
Mild Intellectual Disability ◽  
Complex Disorder ◽  
Whole Exome ◽  
Hereditary Disorders ◽  
Autosomal Recessive Manner

AbstractCongenital hypothyroidism (CH) is one of the most common hereditary disorders affecting neonates worldwide. CH is a multifactorial complex disorder and can be caused by either environmental factors or genetic factors. We studied one Pakistani family with segregating mutations in CH inherited in an autosomal recessive manner. Using whole-exome sequencing (WES), we found a novel homozygous missense variant (c.2315A>G; p.Tyr772Cys) in the thyroid peroxidase (TPO) gene. Different bioinformatics prediction tools and Sanger sequencing were performed to verify the identified variant. Our findings highlight the importance of this gene in causing CH and mild-intellectual disability (ID) in two affected brothers. WES is a convenient and useful tool for the clinical diagnosis of CH and other associated disorders.

scholarly journals A Novel Missense Variant in the AGRN Gene; Congenital Myasthenic Syndrome Presenting With Head Drop

2017 ◽  
Vol 18 (3) ◽  
pp. 147-151 ◽  
Author(s):  
Mert Karakaya ◽  
Ozge Ceyhan-Birsoy ◽  
Alan H. Beggs ◽  
Haluk Topaloglu
Keyword(s):  
Missense Variant ◽  
Congenital Myasthenic Syndrome ◽  
Myasthenic Syndrome

scholarly journals Case Report: Novel mutations in TBC1D24 are associated with autosomal dominant tonic-clonic and myoclonic epilepsy and recessive Parkinsonism, psychosis, and intellectual disability

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 553 ◽  
Author(s):  
Erika Banuelos ◽  
Keri Ramsey ◽  
Newell Belnap ◽  
Malavika Krishnan ◽  
Chris D. Balak ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Autosomal Dominant ◽  
Epileptic Encephalopathy ◽  
Myoclonic Epilepsy ◽  
Compound Heterozygous ◽  
Missense Mutations ◽  
Single Family ◽  
Whole Exome ◽  
Neurological Phenotype ◽  
Syndromic Hearing Loss

Mutations disrupting presynaptic protein TBC1D24 are associated with a variable neurological phenotype, including DOORS syndrome, myoclonic epilepsy, early-infantile epileptic encephalopathy, and non-syndromic hearing loss. In this report, we describe a family segregating autosomal dominant epilepsy, and a 37-year-old Caucasian female with a severe neurological phenotype including epilepsy, Parkinsonism, psychosis, visual and auditory hallucinations, gait ataxia and intellectual disability. Whole exome sequencing revealed two missense mutations in the TBC1D24 gene segregating within this family (c.1078C>T; p.Arg360Cys and c.404C>T; p.Pro135Leu). The female proband who presents with a severe neurological phenotype carries both of these mutations in a compound heterozygous state. The p.Pro135Leu variant, however, is present in the proband’s mother and sibling as well, and is consistent with an autosomal dominant pattern linked to tonic-clonic and myoclonic epilepsy. In conclusion, we describe a single family in which TBC1D24 mutations cause expanded dominant and recessive phenotypes. In addition, we discuss and highlight that some variants in TBC1D24 might cause a dominant susceptibility to epilepsy

scholarly journals Kabuki Syndrome: Identification of Two Novel Variants in KMT2Dand KDM6A

2021 ◽  
pp. 1-9
Author(s):  
Mehrnoosh Khodaeian ◽  
Ehsan Jafarinia ◽  
Fatemeh Bitarafan ◽  
Shohreh Shafeii ◽  
Navid Almadani ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
De Novo ◽  
Genetic Disorder ◽  
Missense Variant ◽  
Kabuki Syndrome ◽  
Functional Studies ◽  
Large Deletions ◽  
Whole Exome ◽  
Functionally Impaired ◽  
And Function

Kabuki syndrome (KS) is a rare genetic disorder characterized by the following 5 crucial symptoms: dysmorphic facial features, growth retardation, skeletal abnormalities, intellectual disability, and dermatoglyphic malformations. Studies show that most of the KS cases are caused by mutations or large deletions in the KMT2D gene, while the other cases show mutations in KDM6A. We studied 2 patients with suspected KS in 2 unrelated families by whole-exome sequencing to identify the possible genetic cause(s) and by Sanger sequencing to validate the identified variants and check the segregation in other members of the families. Finally, the potential effects of the variants on the structure and function of respective proteins were tested using in silico predictions. Both affected members of the families showed typical manifestations of KS including intellectual disability, developmental delay, and abnormal facial characteristics. A novel heterozygous frameshift variant in the KMT2D gene, c.4981del; p.(Glu1661Serfs*61), and a novel hemizygote missense variant in the KDM6A gene, c.3301G>A; p.(Glu1101Lys), were detected in patients 1 and 2, respectively. The frameshift variant identified in the first family was de novo, while in the second family, the mother was also heterozygous for the missense variant. The frameshift variant in KMT2D is predicted to lead to a truncated protein which is functionally impaired. The Glu1101 residue of KDM6A (UTX) affected in the second patient is located in a conserved region on the surface of the Jumonji domain and predicted to be causative. Our findings provide evidence on the possible pathogenicity of these 2 variants; however, additional functional studies are necessary to confirm their impacts.

scholarly journals NOVEL HOMOZYGOUS VARIANT OF TBC1 DOMAIN FAMILY MEMBER 8 GENE IN FOUR LIBYAN SIBLINGS WITH AUTISTIC SPECTRUM DISORDER AND INTELLECTUAL DISABILITY WITHOUT EPILEPSY

2021 ◽  
pp. 1-4
Author(s):  
ADEL ZEGLAM ◽  
SUAD ALHMADI
Keyword(s):  
Intellectual Disability ◽  
Genetic Analysis ◽  
Single Case ◽  
Molecular Genetic ◽  
Missense Variant ◽  
Molecular Genetic Analysis ◽  
Genetic Changes ◽  
Single Case Report ◽  
Whole Exome ◽  
Number Of Genes

Objective: Recent progress in genetic analysis and investigations have enabled researchers to identify potential genetic changes that may play a role in ASD. The number of genes connected with autism is growing. Whole exome sequencing(WES) identified the homozygous TBC1D8 variant. Aim to report for the first time a TBC1D8 missense variant (c.1883G>A, p. (Arg628Gln) in 4 Libyan children (3 homozygous,1 heterozygous) with severe neurodevelopmental phenotypes ASD and intellectual disability ID . Based on the data of HGMD and ClinVar, variants in only a few autosomal recessive intellectual disability ARID genes seem to be reported frequently. Method: Molecular genetic analysis of (WES) was carried out on blood samples from these children. The outcome of the genetic investigations was interpreted within the context of clinical finding, family history, and suspected mode of inheritance. Results: The number of genes associated with autism is increasing. WES identified the TBC1D8 variant. According to the longest isoform (NM_001102426.1),the nomenclature of this variant is c.1883G>A, p. (Arg628Gln) in TBC1D8 which leads to an amino acid exchange. This variant has not previously reported or described in the literature (PubMed, HGMD). Conclusion: we have provided evidence for a connection between TBC1D8 variant and ASD and ID; however, this evidence should be considered preliminary in the context of a single case report and such findings need to be replicated to gain insight in order to determine if ASD and ID are a characteristic of this variant.

scholarly journals Novel variants identified in CKAP2L in two siblings with Filippi Syndrome

2021 ◽  
pp. mcs.a006130
Author(s):  
Ryan J Patrick ◽  
Jill M Weimer ◽  
Laura Davis-Keppen ◽  
Megan L Landsverk
Keyword(s):  
Intellectual Disability ◽  
Autosomal Recessive ◽  
Missense Variant ◽  
Facial Features ◽  
Loss Of Function ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
The Family ◽  
Novel Variants ◽  
In Trans

Pathogenic variants in CKAP2L have previously been reported in Filippi Syndrome (FS), a rare autosomal recessive, craniodigital syndrome characterized by microcephaly, syndactyly, short stature, intellectual disability, and dysmorphic facial features. To date, fewer than ten patients with pathogenic variants in CKAP2L associated with FS have been reported. All of the previously reported probands have presumed loss-of-function variants (frameshift, canonical splice site, starting methionine) and all but one have been homozygous for a pathogenic variant. Here we describe two brothers who presented with microcephaly, micrognathia, syndactyly, dysmorphic features, and intellectual disability. Whole exome sequencing of the family identified a missense variant, c.2066G>A (p.Arg689His), in trans with a frameshift variant, c.1169_1173del (p.Ile390LysfsTer4), in CKAP2L. To our knowledge, these are the first patients with FS to be reported with a missense variant in CKAP2L and only the second family to be reported with two variants in trans.

scholarly journals Missense mutation in the MEN1 gene discovered through whole exome sequencing co-segregates with familial hyperparathyroidism

2013 ◽  
Vol 95 (4) ◽  
pp. 114-120 ◽  
Author(s):  
OFER ISAKOV ◽  
ERICA S. RINELLA ◽  
DAVID OLCHOVSKY ◽  
ILAN SHIMON ◽  
HARRY OSTRER ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Exome Capture ◽  
Analysis Tool ◽  
Single Family ◽  
Causative Gene ◽  
Single Experiment ◽  
Sequencing Platform ◽  
Whole Exome ◽  
The Family

SummaryFamilial isolated hyperparathyroidism (FIHP) can be encountered in the context of multiple endocrine neoplasia type 1 (MEN1), hyperparathyroidism and jaw tumour syndrome (HPT–JT) and in familial hypocalciuric hypercalcaemia (FHH). In these syndromes, germline mutations in the relevant genes (MEN1, HPRT2 and CaSR, respectively) are detected. In some FIHP cases, the causative gene is still elusive. The objective of this study is to define the genetic basis of FIHP in a Georgian Jewish family with FIHP using whole exome capture and sequencing. DNA extracted from two sibs and one offspring from a single family all affected with multiglandular hyperparathyroidism was subjected to whole exome capturing and sequencing using the Roche NimbleGen V2 chip and the Illumina HiSeq2000 sequencing platform. Genetic variants were detected and annotated using a combination of the Genome Analysis Tool Kit and in-house scripts. Subsequent confirmation of the mutations and co-segregation analyses were carried out by Sanger sequencing in additional affected and unaffected family members. Whole exome capture and sequencing revealed the collection of variations common to the three-sequenced patients, including a very rare previously described missense mutation (c.T1021C: p.W341R) in the MEN1 gene. The p.W341R mutation in the MEN1 gene showed complete co-segregation in the family. Whole exome capture and sequencing led to the discovery of a missense mutation in the MEN1 gene and ruling out of the additional candidates in a single experiment. The limited expressivity of this mutation may imply a specific genotype–phenotype correlation for this mutation.

scholarly journals A Novel Splice-Site Variant in SLC12A6 Causes Andermann Syndrome without Agenesis of the Corpus Callosum

2020 ◽  
Vol 09 (04) ◽  
pp. 293-295
Author(s):  
Naema Al Shibli ◽  
Almundher Al-Maawali ◽  
Alaa Elmanzalawy ◽  
Maryam Al-Nabhani ◽  
Roshan Koul ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Peripheral Neuropathy ◽  
Corpus Callosum ◽  
Splice Site ◽  
Brain Magnetic Resonance Imaging ◽  
Sensory Neuropathy ◽  
Mild Intellectual Disability ◽  
Whole Exome ◽  
Severe Motor ◽  
Demyelinating Peripheral Neuropathy

AbstractAndermann syndrome, otherwise known as agenesis of the corpus callosum with peripheral neuropathy (ACCPN), is an autosomal recessive motor and sensory neuropathy known to be associated with ACC and mild-to-moderate intellectual disability. We present a 7-year-old girl with infantile-onset hypotonia, mild intellectual disability, and severe motor and sensory demyelinating peripheral neuropathy. Brain magnetic resonance imaging showed intact corpus callosum. Whole exome sequencing showed a novel splice-site pathogenic variant in the SLC12A6 gene. We confirm that ACC is not a mandatory feature and suggest that the term ACCPN may be misleading.

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