scholarly journals Biallelic intragenic duplication in ADGRB3 (BAI3) gene associated with intellectual disability, cerebellar atrophy, and behavioral disorder

2019 ◽  
Vol 27 (4) ◽  
pp. 594-602
Author(s):  
Carmela Scuderi ◽  
Lucia Saccuzzo ◽  
Mirella Vinci ◽  
Lucia Castiglia ◽  
Ornella Galesi ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Cerebellar Atrophy ◽  
Behavioral Disorder ◽  
Intragenic Duplication

IL1RAPL1 Gene Deletion in a Female Patient with Developmental Delay and Continuous Spike-Wave during Sleep

2021 ◽  
Author(s):  
Evan Jiang ◽  
Mark P. Fitzgerald ◽  
Katherine L. Helbig ◽  
Ethan M. Goldberg
Keyword(s):  
Intellectual Disability ◽  
Developmental Delay ◽  
Synapse Formation ◽  
De Novo ◽  
Interleukin 1 ◽  
Autism Spectrum ◽  
Neurological Dysfunction ◽  
Behavioral Disorder ◽  
Clinical Genetic ◽  
Severe Intellectual Disability

AbstractInterleukin-1 receptor accessory protein-like 1 (IL1RAPL1) encodes a protein that is highly expressed in neurons and has been shown to regulate neurite outgrowth as well as synapse formation and synaptic transmission. Clinically, mutations in or deletions of IL1RAPL1 have been associated with a spectrum of neurological dysfunction including autism spectrum disorder and nonsyndromic X-linked developmental delay/intellectual disability of varying severity. Nearly all reported cases are in males; in the few reported cases involving females, the clinical presentation was mild or the deletion was identified in phenotypically normal carriers in accordance with X-linked inheritance. Using genome-wide microarray analysis, we identified a novel de novo 373 kb interstitial deletion of the X chromosome (Xp21.1-p21.2) that includes exons 4 to 6 of the IL1RAPL1 gene in an 8-year-old girl with severe intellectual disability and behavioral disorder with a history of developmental regression. Overnight continuous video electroencephalography revealed electrical status epilepticus in sleep (ESES). This case expands the clinical genetic spectrum of IL1RAPL1-related neurodevelopmental disorders and highlights a new genetic association of ESES.

scholarly journals Cerebellar ataxia, neuropathy, hearing loss, and intellectual disability due to AIFM1 mutation

2020 ◽  
Vol 6 (3) ◽  
pp. e420 ◽  
Author(s):  
Massimo Pandolfo ◽  
Myriam Rai ◽  
Gauthier Remiche ◽  
Laurence Desmyter ◽  
Isabelle Vandernoot
Keyword(s):  
Hearing Loss ◽  
Intellectual Disability ◽  
Cerebellar Ataxia ◽  
X Chromosome ◽  
Behavior Disorder ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Behavioral Disorder ◽  
Maternal Uncle ◽  
And Behavior

ObjectiveTo describe the clinical and molecular genetic findings in a family segregating a novel mutation in the AIFM1 gene on the X chromosome.MethodsWe studied the clinical features and performed brain MRI scans, nerve conduction studies, audiometry, cognitive testing, and clinical exome sequencing (CES) in the proband, his mother, and maternal uncle. We used in silico tools, X chromosome inactivation assessment, and Western blot analysis to predict the consequences of an AIFM1 variant identified by CES and demonstrate its pathogenicity.ResultsThe proband and his maternal uncle presented with childhood-onset nonprogressive cerebellar ataxia, hearing loss, intellectual disability (ID), peripheral neuropathy, and mood and behavioral disorder. The proband's mother had mild cerebellar ataxia, ID, and mood and behavior disorder, but no neuropathy or hearing loss. The 3 subjects shared a variant (c.1195G>A; p.Gly399Ser) in exon 12 of the AIFM1 gene, which is not reported in the exome/genome sequence databases, affecting a critical amino acid for protein function involved in NAD(H) binding and predicted to be pathogenic with very high probability by variant analysis programs. X chromosome inactivation was highly skewed in the proband's mother. The mutation did not cause quantitative changes in protein abundance.ConclusionsOur report extends the molecular and phenotypic spectrum of AIFM1 mutations. Specific findings include limited progression of neurologic abnormalities after the first decade and the coexistence of mood and behavior disorder. This family also shows the confounding effect on the phenotype of nongenetic factors, such as alcohol and drug use and side effects of medication.

A Novel SETBP1 Gene Disruption by a De Novo Balanced Translocation in a Patient with Speech Impairment, Intellectual, and Behavioral Disorder

2020 ◽  
Author(s):  
Ivona Vrkić Boban ◽  
Futoshi Sekiguchi ◽  
Mirela Lozić ◽  
Noriko Miyake ◽  
Naomichi Matsumoto ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Autosomal Dominant ◽  
De Novo ◽  
Chromosomal Abnormalities ◽  
Chromosome Translocation ◽  
Behavioral Disorder ◽  
Behavioral Difficulties ◽  
Speech Impairment ◽  
Balanced Translocation ◽  
Severe Intellectual Disability

AbstractBalanced chromosomal abnormalities (BCAs) can disrupt gene function resulting in disease. To date, BCA disrupting the SET binding protein 1 (SETBP1) gene has not been reported. On the other hand, de novo heterozygous variants in the highly conserved 11-bp region in SETBP1 can result in the Schinzel–Giedion syndrome. This condition is characterized by severe intellectual disability, a characteristic face, and multiple-system anomalies. Further other types of mutations involving SETBP1 are associated with a different phenotype, mental retardation, autosomal dominant 29 (MRD29), which has mild dysmorphic features, developmental delay, and behavioral disorders. Here we report a male patient who has moderate intellectual disability, mild behavioral difficulties, and severe expressive speech impairment resulting from a de novo balanced chromosome translocation, t(12;18)(q22;q12.3). By whole genome sequencing, we determined the breakpoints at the nucleotide level. The 18q12.3 breakpoint was located between exons 2 and 3 of SETBP1. Phenotypic features of our patient are compatible with those with MRD29. This is the first reported BCA disrupting SETBP1.

Exome sequencing reveals a novelCWF19L1mutation associated with intellectual disability and cerebellar atrophy

2016 ◽  
Vol 170 (6) ◽  
pp. 1502-1509 ◽  
Author(s):  
Christina Evers ◽  
Lilian Kaufmann ◽  
Angelika Seitz ◽  
Nagarajan Paramasivam ◽  
Martin Granzow ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Exome Sequencing ◽  
Cerebellar Atrophy

scholarly journals Biallelic inheritance in a single Pakistani family with intellectual disability implicates new candidate gene RDH14

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Stephen F. Pastore ◽  
Tahir Muhammad ◽  
Ricardo Harripaul ◽  
Rebecca Lau ◽  
Muhammad Tariq Masood Khan ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Autosomal Recessive ◽  
Ion Homeostasis ◽  
Cerebellar Atrophy ◽  
Chloride Ion ◽  
Hek293 Cells ◽  
Retinol Dehydrogenase ◽  
Gene Encoding ◽  
Whole Exome ◽  
Transcription Data

AbstractIn a multi-branch family from Pakistan, individuals presenting with palmoplantar keratoderma segregate in autosomal dominant fashion, and individuals with intellectual disability (ID) segregate in apparent autosomal recessive fashion. Initial attempts to identify the ID locus using homozygosity-by-descent (HBD) mapping were unsuccessful. However, following an assumption of locus heterogeneity, a reiterative HBD approach in concert with whole exome sequencing (WES) was employed. We identified a known disease-linked mutation in the polymicrogyria gene, ADGRG1, in two affected members. In the remaining two (living) affected members, HBD mapping cross-referenced with WES data identified a single biallelic frameshifting variant in the gene encoding retinol dehydrogenase 14 (RDH14). Transcription data indicate that RDH14 is expressed in brain, but not in retina. Magnetic resonance imaging for the individuals with this RDH14 mutation show no signs of polymicrogyria, however cerebellar atrophy was a notable feature. RDH14 in HEK293 cells localized mainly in the nucleoplasm. Co-immunoprecipitation studies confirmed binding to the proton-activated chloride channel 1 (PACC1/TMEM206), which is greatly diminished by the mutation. Our studies suggest RDH14 as a candidate for autosomal recessive ID and cerebellar atrophy, implicating either disrupted retinoic acid signaling, or, through PACC1, disrupted chloride ion homeostasis in the brain as a putative disease mechanism.

scholarly journals Autosomal-Recessive Intellectual Disability with Cerebellar Atrophy Syndrome Caused by Mutation of the Manganese and Zinc Transporter Gene SLC39A8

2015 ◽  
Vol 97 (6) ◽  
pp. 886-893 ◽  
Author(s):  
Kym M. Boycott ◽  
Chandree L. Beaulieu ◽  
Kristin D. Kernohan ◽  
Ola H. Gebril ◽  
Aziz Mhanni ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Autosomal Recessive ◽  
Cerebellar Atrophy ◽  
Zinc Transporter ◽  
Transporter Gene

scholarly journals Calcium channelopathies and intellectual disability: a systematic review

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Miriam Kessi ◽  
Baiyu Chen ◽  
Jing Peng ◽  
Fangling Yan ◽  
Lifen Yang ◽  
...  
Keyword(s):  
Systematic Review ◽  
Intellectual Disability ◽  
Calcium Channel ◽  
Developmental Delay ◽  
Cerebellar Atrophy ◽  
Dominant Negative ◽  
Main Body ◽  
Loss Of Function ◽  
Gain Of Function ◽  
Gain And Loss

Abstract Background Calcium ions are involved in several human cellular processes including corticogenesis, transcription, and synaptogenesis. Nevertheless, the relationship between calcium channelopathies (CCs) and intellectual disability (ID)/global developmental delay (GDD) has been poorly investigated. We hypothesised that CCs play a major role in the development of ID/GDD and that both gain- and loss-of-function variants of calcium channel genes can induce ID/GDD. As a result, we performed a systematic review to investigate the contribution of CCs, potential mechanisms underlying their involvement in ID/GDD, advancements in cell and animal models, treatments, brain anomalies in patients with CCs, and the existing gaps in the knowledge. We performed a systematic search in PubMed, Embase, ClinVar, OMIM, ClinGen, Gene Reviews, DECIPHER and LOVD databases to search for articles/records published before March 2021. The following search strategies were employed: ID and calcium channel, mental retardation and calcium channel, GDD and calcium channel, developmental delay and calcium channel. Main body A total of 59 reports describing 159 cases were found in PubMed, Embase, ClinVar, and LOVD databases. Variations in ten calcium channel genes including CACNA1A, CACNA1C, CACNA1I, CACNA1H, CACNA1D, CACNA2D1, CACNA2D2, CACNA1E, CACNA1F, and CACNA1G were found to be associated with ID/GDD. Most variants exhibited gain-of-function effect. Severe to profound ID/GDD was observed more for the cases with gain-of-function variants as compared to those with loss-of-function. CACNA1E, CACNA1G, CACNA1F, CACNA2D2 and CACNA1A associated with more severe phenotype. Furthermore, 157 copy number variations (CNVs) spanning calcium genes were identified in DECIPHER database. The leading genes included CACNA1C, CACNA1A, and CACNA1E. Overall, the underlying mechanisms included gain- and/ or loss-of-function, alteration in kinetics (activation, inactivation) and dominant-negative effects of truncated forms of alpha1 subunits. Forty of the identified cases featured cerebellar atrophy. We identified only a few cell and animal studies that focused on the mechanisms of ID/GDD in relation to CCs. There is a scarcity of studies on treatment options for ID/GDD both in vivo and in vitro. Conclusion Our results suggest that CCs play a major role in ID/GDD. While both gain- and loss-of-function variants are associated with ID/GDD, the mechanisms underlying their involvement need further scrutiny.

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