scholarly journals De novo variants in PAK1 lead to intellectual disability with macrocephaly and seizures

Brain ◽  
2019 ◽  
Vol 142 (11) ◽  
pp. 3351-3359 ◽  
Author(s):  
Susanne Horn ◽  
Margaret Au ◽  
Lina Basel-Salmon ◽  
Pinar Bayrak-Toydemir ◽  
Alexander Chapin ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Brain Development ◽  
Exome Sequencing ◽  
De Novo ◽  
Brain Size ◽  
Gain Of Function ◽  
P21 Activated Kinase ◽  
And Control

Using trio exome sequencing, Horn et al. identify de novo gain-of-function mutations in PAK1 in four unrelated individuals with intellectual disability, macrocephaly and seizures. PAK1 encodes a p21-activated kinase, which has been implicated in brain development and control of brain size.

scholarly journals Case Report: CNNM2 Mutations Cause Damaged Brain Development and Intractable Epilepsy in a Patient Without Hypomagnesemia

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiucui Li ◽  
Shijia Bao ◽  
Wei Wang ◽  
Xulai Shi ◽  
Ying Hu ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Brain Development ◽  
De Novo ◽  
Basolateral Membrane ◽  
Intractable Epilepsy ◽  
Chinese Patient ◽  
Renal Tubules ◽  
Variable Degree ◽  
Mild Intellectual Disability ◽  
Severity Of The Disease

A series of neurological manifestations such as intellectual disability and epilepsy are closely related to hypomagnesemia. Cyclin M2 (CNNM2) proteins, as a member of magnesium (Mg2+) transporters, were found along the basolateral membrane of distal renal tubules and involved in the reabsorption of Mg2+. Homozygous and heterozygous variants in CNNM2 reported so far were responsible for a variable degree of hypomagnesemia, several of which also showed varying degrees of neurological phenotypes such as intellectual disability and epilepsy. Here, we report a de novo heterozygous CNNM2 variant (c.2228C > T, p.Ser743Phe) in a Chinese patient, which is the variant located in the cyclic nucleotide monophosphate-binding homology (CNBH) domain of CNNM2 proteins. The patient presented with mild intellectual disability and refractory epilepsy but without hypomagnesemia. Thus, we reviewed the literature and analyzed the phenotypes related to CNNM2 variants, and then concluded that the number of variant alleles and the changed protein domains correlates with the severity of the disease, and speculated that the CNBH domain of CNNM2 possibly plays a limited role in Mg2+ transport but a significant role in brain development. Furthermore, it can be speculated that neurological phenotypes such as intellectual disability and seizures can be purely caused by CNNM2 variants.

scholarly journals TU47. EXOME SEQUENCING STUDY FOR IDENTIFICATION OF DE NOVO MUTATIONS OF IDIOPATHIC INTELLECTUAL DISABILITY IN CHILDREN FROM THE 2004 PELOTAS (BRAZIL) BIRTH COHORT

2021 ◽  
Vol 51 ◽  
pp. e120
Author(s):  
Karen Sánchez-Luquez ◽  
Simone Menezes Karam ◽  
Alicia Matijasevich ◽  
Iná da Silva dos Santos ◽  
Aluísio J D Barros ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Exome Sequencing ◽  
Birth Cohort ◽  
De Novo ◽  
De Novo Mutations

scholarly journals Case report : a novel ASXL3 gene variant in a Sudanese boy

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Ke Wu ◽  
Yan Cong
Keyword(s):  
Intellectual Disability ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Psychomotor Development ◽  
Gene Variant ◽  
Feeding Difficulties ◽  
Severe Intellectual Disability ◽  
Whole Exome

Abstract Background Bainbridge-Ropers syndrome (BRPS) [OMIM#615485] is a neurodevelopmental disorder, characterized by delayed psychomotor development with generalized hypotonia, moderate to severe intellectual disability, poor or absent speech, feeding difficulties, growth failure, dysmorphic craniofacial features and minor skeletal features. The aim of this study was to investigate the genetic etiology of a Sudanese boy with severe developmental delay, intellectual disability, and craniofacial phenotype using trio-based whole-exome sequencing. To our knowledge, no patients with ASXL3 gene variant c.3043C>T have been reported detailedly in literature. Case presentation The patient (male, 3 years 6 months) was the first born of a healthy non-consanguineous couple originating from Sudan, treated for “psychomotor retardation” for more than 8 months in Yiwu. The patient exhibited severely delayed milestones in physiological and intellectual developmental stages, language impairment, poor eye-contact, lack of subtle motions of fingers, fear of claustrophobic space, hypotonia, clinodactyly, autistic features. Peripheral blood samples were collected from the patient and his parents. Trio-based whole-exome sequencing(Trio-WES) identified a de novo heterozygous ASXL3 gene variant c.3043C>T;p.Q1015X. Sanger sequencing verified variants of this family. Conclusion Trio-WES analysis identified a de novo nonsense variant (c.3043C>T) of ASXL3 gene in a Sudanese boy. To our knowledge, the patient with this variant has not been reported previously in literature. This study presents a new case for ASXL3 gene variants, which expanded the mutational and phenotypic spectrum.

scholarly journals Mapping Autosomal Recessive Intellectual Disability: Combined Microarray and Exome Sequencing Identifies 26 Novel Candidate Genes in 192 Consanguineous Families

2016 ◽  
Author(s):  
Ricardo Harripaul ◽  
Nasim Vasli ◽  
Anna Mikhailov ◽  
Muhammad Arshad Rafiq ◽  
Kirti Mittal ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Exome Sequencing ◽  
Autosomal Recessive ◽  
De Novo ◽  
Clinical Diagnostics ◽  
High Yield ◽  
Disease Genes ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Whole Exome

Approximately 1% of the global population is affected by intellectual disability (ID), and the majority receive no molecular diagnosis. Previous studies have indicated high levels of genetic heterogeneity, with estimates of more than 2500 autosomal ID genes, the majority of which are autosomal recessive (AR). Here, we combined microarray genotyping, homozygosity-by-descent (HBD) mapping, copy number variation (CNV) analysis, and whole exome sequencing (WES) to identify disease genes/mutations in 192 multiplex Pakistani and Iranian consanguineous families with non-syndromic ID. We identified definite or candidate mutations (or CNVs) in 51% of families in 72 different genes, including 26 not previously reported for ARID. The new ARID genes include nine with loss-of-function mutations(ABI2, MAPK8, MPDZ, PIDD1, SLAIN1, TBC1D23, TRAPPC6B, UBA7,andUSP44),and missense mutations include the first reports of variants inBDNForTET1associated with ID. The genes identified also showed overlap withde novogene sets for other neuropsychiatric disorders. Transcriptional studies showed prominent expression in the prenatal brain. The high yield of AR mutations for ID indicated that this approach has excellent clinical potential and should inform clinical diagnostics, including clinical whole exome and genome sequencing, for populations in which consanguinity is common. As with other AR disorders, the relevance will also apply to outbred populations.

Quando il disturbo del neurosviluppo ha un substrato genetico: un caso di sindrome di Kleefstra

2021 ◽  
Vol 24 (4) ◽  
pp. 114-117
Author(s):  
Lorena Sorasio ◽  
Luisa Franceschi ◽  
Lisa Pavinato ◽  
Antonella Peduto
Keyword(s):  
Intellectual Disability ◽  
Exome Sequencing ◽  
Point Mutation ◽  
Neurodevelopmental Disorders ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Diagnostic Classification ◽  
Molecular Cytogenetic ◽  
Sequencing Technologies ◽  
Molecular Cytogenetic Techniques

Neurodevelopmental disorders (ND) have an important prevalence in children; intellectual disability in particular occurs in a heterogeneous group of genetic conditions. The evolution of molecular cytogenetic techniques and the recent advances in exome sequencing technologies have enormously implemented the possibilities of diagnostic classification in children with cognitive disabilities due to genetics. The paper presents the case of a patient with a neurodevelopmental disorder who was diagnosed with Kleefstra (KS) syndrome, caused by a point mutation de novo of EHMT1 gene.

scholarly journals Intellectual disability and non-compaction cardiomyopathy with a de novo NONO mutation identified by exome sequencing

2016 ◽  
Vol 24 (11) ◽  
pp. 1635-1638 ◽  
Author(s):  
Eyal Reinstein ◽  
Shay Tzur ◽  
Rony Cohen ◽  
Concetta Bormans ◽  
Doron M Behar
Keyword(s):  
Intellectual Disability ◽  
Exome Sequencing ◽  
De Novo

scholarly journals Central nervous system: cholesterol turnover, brain development and neurodegeneration

2009 ◽  
Vol 390 (4) ◽  
Author(s):  
John M. Dietschy
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Body Weight ◽  
Brain Development ◽  
Cholesterol Synthesis ◽  
De Novo ◽  
Brain Size ◽  
Average Amount ◽  
Early Brain Development ◽  
The Central Nervous System

Abstract The average amount of cholesterol in the whole animal equals approximately 2100 mg/kg body weight, and 15% and 23% of this sterol in the mouse and human, respectively, is found in the central nervous system. There is no detectable uptake across the blood-brain barrier of cholesterol carried in lipoproteins in the plasma, even in the newborn. However, high rates of de novo cholesterol synthesis in the glia and neurons provide the sterol necessary for early brain development. Once a stable brain size is achieved in the adult, cholesterol synthesis continues, albeit at a much lower rate, and this synthesis is just balanced by the excretion of an equal amount of sterol, either as 24(S)-hydroxycholesterol or, presumably, as cholesterol itself.

scholarly journals A Novel De Novo Frameshift Mutation in KAT6A Identified by Whole Exome Sequencing

2018 ◽  
Vol 08 (01) ◽  
pp. 010-014 ◽  
Author(s):  
Wafa Alazaizeh ◽  
Asem Alkhateeb
Keyword(s):  
Intellectual Disability ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Frameshift Mutation ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Brain Magnetic Resonance Imaging ◽  
Comparative Genomic ◽  
Feeding Difficulties ◽  
Whole Exome

AbstractIntellectual disability is a common condition with multiple etiologies. The number of monogenic causes has increased steadily in recent years due to the implementation of next generation sequencing. Here, we describe a 2-year-old boy with global developmental delay and intellectual disability. The child had feeding difficulties since birth. He had delayed motor skills and muscular hypotonia. Brain magnetic resonance imaging revealed diffuse white matter loss and thinning of the corpus callosum. Banded karyotype and comparative genomic hybridization (CGH) array were normal. Whole exome sequencing revealed a novel de novo frameshift mutation c.3390delA (p.Lys1130Asnfs*4) in KAT6A gene (NM_006766.4). The heterozygous mutation was confirmed by Sanger sequencing in the patient and its absence in his parents. KAT6A that encodes a histone acetyltransferase has been recently found to be associated with a neurodevelopmental disorder autosomal dominant mental retardation 32 (OMIM: no. 616268). Features of this disorder are nonspecific, which makes it difficult to characterize the condition based on the clinical symptoms alone. Therefore, our findings confirm the utility of whole exome sequencing to quickly and reliably identify the etiology of such conditions.

Coexistence of a Homozygous Chromosome 4q35.2 Deletion and Hidden IQSEC2 Pathogenic Variant in a Child with Intellectual Disability

2021 ◽  
pp. 1-7
Author(s):  
Tuğba Karaman Mercan ◽  
Ozden Altiok Clark ◽  
Ozgur Erkal ◽  
Banu Nur ◽  
Ercan Mihci ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Array Cgh ◽  
De Novo ◽  
Homozygous Deletion ◽  
Clinical Findings ◽  
Chromosome 4 ◽  
Heterozygous Deletion ◽  
Whole Exome

Terminal deletions in the long arm of chromosome 4 are an uncommon event, with a worldwide incidence of approximately 0.001%. The majority of these deletions occur de novo. Terminal deletion cases are usually accompanied by clinical findings that include facial and cardiac anomalies, as well as intellectual disability. In this study, we describe the case of a 2-year-old girl, the fourth child born to consanguineous parents. While her karyotype was normal, a homozygous deletion was identified in the chromosome 4q35.2 region by subtelomeric FISH. A heterozygous deletion of the chromosome 4q35.2 region was observed in both parents. According to the literature, this is the first report of a case that has inherited a homozygous deletion of chromosome 4qter from carrier parents. Subsequent array-CGH analyses were performed on both the case and her parents. Whole-exome sequencing was also carried out to determine potential variants. We detected a NM_001111125.3:c.2329G&#x3e;T (p.Glu777Ter) nonsense variant of the <i>IQSEC2</i> gene in the girl, a variant that is related to X-linked intellectual disability.

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