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 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 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.

Rett-like Syndrome in a Pediatric Patient—A Challenging Diagnosis

2020 ◽  
Author(s):  
Sofia Simões Ferreira ◽  
Marta Mesquita ◽  
Joana Nunes ◽  
Isabel Alonso ◽  
Miguel Leão ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Exome Sequencing ◽  
Pediatric Patient ◽  
Neurodevelopmental Disorders ◽  
De Novo ◽  
Hand Movements ◽  
Gene Variants ◽  
Neurodevelopmental Delay ◽  
Whole Exome ◽  
Rett’S Syndrome

AbstractNeurodevelopmental disorders with features overlapping Rett's syndrome frequently remain unexplained in patients without disease-causing variants in MECP2. Variants in IQSEC2 frequently cause nonsyndromic X-linked intellectual disability (XLID), although de novo variants may cause a severe syndrome that resembles Rett and Angelman's syndrome. We report a 7-year-old girl presenting severe neurodevelopmental delay, stereotypic hand movements, hypotonia, autistic-like features, inappropriate laughing/screaming spells, and symmetrical hypomyelination. A whole exome sequencing detected a novel de novo heterozygous truncating variant within the IQSEC2 gene. Variants of IQSEC2 should be considered in patients with Rett–Angelman phenotype spectrum and autistic features when those causes were excluded.

scholarly journals Whole Exome Sequencing in Coloboma/Microphthalmia: Identification of Novel and Recurrent Variants in Seven Genes

Genes ◽  
2021 ◽  
Vol 12 (1) ◽  
pp. 65
Author(s):  
Patricia Haug ◽  
Samuel Koller ◽  
Jordi Maggi ◽  
Elena Lang ◽  
Silke Feil ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Screening ◽  
De Novo ◽  
Efficient Tool ◽  
Sequencing Technologies ◽  
Whole Exome ◽  
Screening And Identification ◽  
High Throughput Dna Sequencing ◽  
New Mutations

Coloboma and microphthalmia (C/M) are related congenital eye malformations, which can cause significant visual impairment. Molecular diagnosis is challenging as the genes associated to date with C/M account for only a small percentage of cases. Overall, the genetic cause remains unknown in up to 80% of patients. High throughput DNA sequencing technologies, including whole-exome sequencing (WES), are therefore a useful and efficient tool for genetic screening and identification of new mutations and novel genes in C/M. In this study, we analyzed the DNA of 19 patients with C/M from 15 unrelated families using singleton WES and data analysis for 307 genes of interest. We identified seven novel and one recurrent potentially disease-causing variants in CRIM1, CHD7, FAT1, PTCH1, PUF60, BRPF1, and TGFB2 in 47% of our families, three of which occurred de novo. The detection rate in patients with ocular and extraocular manifestations (67%) was higher than in patients with an isolated ocular phenotype (46%). Our study highlights the significant genetic heterogeneity in C/M cohorts and emphasizes the diagnostic power of WES for the screening of patients and families with C/M.

Recurrent de novo missense variants in GNB2 can cause syndromic intellectual disability

2021 ◽  
pp. jmedgenet-2020-107462
Author(s):  
Natalie B Tan ◽  
Alistair T Pagnamenta ◽  
Matteo P Ferla ◽  
Jonathan Gadian ◽  
Brian HY Chung ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
G Proteins ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Missense Variant ◽  
Cellular Functions ◽  
Missense Variants ◽  
Neurodevelopmental Disease ◽  
Genes Encoding ◽  
International Data

PurposeBinding proteins (G-proteins) mediate signalling pathways involved in diverse cellular functions and comprise Gα and Gβγ units. Human diseases have been reported for all five Gβ proteins. A de novo missense variant in GNB2 was recently reported in one individual with developmental delay/intellectual disability (DD/ID) and dysmorphism. We aim to confirm GNB2 as a neurodevelopmental disease gene, and elucidate the GNB2-associated neurodevelopmental phenotype in a patient cohort.MethodsWe discovered a GNB2 variant in the index case via exome sequencing and sought individuals with GNB2 variants via international data-sharing initiatives. In silico modelling of the variants was assessed, along with multiple lines of evidence in keeping with American College of Medical Genetics and Genomics guidelines for interpretation of sequence variants.ResultsWe identified 12 unrelated individuals with five de novo missense variants in GNB2, four of which are recurrent: p.(Ala73Thr), p.(Gly77Arg), p.(Lys89Glu) and p.(Lys89Thr). All individuals have DD/ID with variable dysmorphism and extraneurologic features. The variants are located at the universally conserved shared interface with the Gα subunit, which modelling suggests weaken this interaction.ConclusionMissense variants in GNB2 cause a congenital neurodevelopmental disorder with variable syndromic features, broadening the spectrum of multisystem phenotypes associated with variants in genes encoding G-proteins.

Genomic Syndromes in Schizophrenia

2013 ◽  
pp. 247-255
Author(s):  
George Kirov ◽  
Michael C. O’Donovan ◽  
Michael J. Owen
Keyword(s):  
Intellectual Disability ◽  
Developmental Delay ◽  
Neurodevelopmental Disorders ◽  
Copy Number ◽  
De Novo ◽  
Copy Number Variants ◽  
Individual Risk ◽  
Genomic Deletions ◽  
Pathogenic Cnvs ◽  
Cognition And Learning

Several submicroscopic genomic deletions and duplications known as copy number variants (CNVs) have been reported to increase susceptibility to schizophrenia. Those for which the evidence is particularly strong include deletions at chromosomal segments 1q21.1, 3q29, 15q11.2, 15q13.3, 17q12 and 22q11.2, duplications at 15q11.2-q13.1, 16p13.1, and 16p11.2, and deletions atthe gene NRXN1. The effect of each on individual risk is relatively large, but it does not appear that any of them is alone sufficient to cause disorder in carriers. These CNVs often arise as new mutations(de novo). Analyses of genes enriched among schizophrenia implicated CNVs highlight the involvement in the disorder of post-synaptic processes relevant to glutamatergicsignalling, cognition and learning. CNVs that contribute to schizophrenia risk also contribute to other neurodevelopmental disorders, including intellectual disability, developmental delay and autism. As a result of selection, all known pathogenic CNVs are rare, and none makes a sizeable contribution to overall population risk of schizophrenia, although the study of these mutations is nevertheless providing important insights into the origins of the disorder.

scholarly journals Specific effect of the fragile-X mental retardation-1 gene (FMR1) on white matter microstructure

2015 ◽  
Vol 207 (2) ◽  
pp. 143-148 ◽  
Author(s):  
Tamar Green ◽  
Naama Barnea-Goraly ◽  
Mira Raman ◽  
Scott S. Hall ◽  
Amy A. Lightbody ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Intellectual Disability ◽  
White Matter ◽  
Neurodevelopmental Disorders ◽  
Fragile X ◽  
Neurodevelopmental Disorder ◽  
Specific Effect ◽  
Radial Diffusivity ◽  
Fragile X Mental Retardation ◽  
White Matter Microstructure

BackgroundFragile-X syndrome (FXS) is a neurodevelopmental disorder associated with intellectual disability and neurobiological abnormalities including white matter microstructural differences. White matter differences have been found relative to neurotypical individuals.AimsTo examine whether FXS white matter differences are related specifically to FXS or more generally to the presence of intellectual disability.MethodWe used voxel-based and tract-based analytic approaches to compare individuals with FXS (n = 40) with gender- and IQ-matched controls (n = 30).ResultsIndividuals with FXS had increased fractional anisotropy and decreased radial diffusivity values compared with IQ-matched controls in the inferior longitudinal, inferior fronto-occipital and uncinate fasciculi.ConclusionsThe genetic variation associated with FXS affects white matter microstructure independently of overall IQ. White matter differences, found in FXS relative to IQ-matched controls, are distinct from reported differences relative to neurotypical controls. This underscores the need to consider cognitive ability differences when investigating white matter microstructure in neurodevelopmental disorders.

scholarly journals Case Report: A Novel De Novo Missense Mutation of the GRIA2 Gene in a Chinese Case of Neurodevelopmental Disorder With Language Impairment

2021 ◽  
Vol 12 ◽  
Author(s):  
Bingbo Zhou ◽  
Chuan Zhang ◽  
Lei Zheng ◽  
Zhiqiang Wang ◽  
Xue Chen ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Missense Mutation ◽  
Developmental Delay ◽  
Whole Exome Sequencing ◽  
Language Impairment ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Behavioral Abnormalities ◽  
Whole Exome ◽  
Chinese Case

Introduction: Neurodevelopmental disorders with language impairment and behavioral abnormalities (NEDLIB) are a disease caused by heterozygous variants in the glutamate ionotropic receptor AMPA type subunit 2 (GRIA2) gene, which manifest as impaired mental development or developmental delay, behavioral abnormalities including autistic characteristics, and language disorders. Currently, only a few mutations in the GRIA2 gene have been discovered.Methods: A GRIA2 variation was detected in a patient by whole-exome sequencing, and the site was validated by Sanger sequencing from the family.Results: We report a Chinese case of NEDLIB in a girl with language impairment and developmental delay through whole-exome sequencing (WES). Genetic analysis showed that there was a de novo missense mutation, c.1934T > G (p.Leu645Arg), in the GRIA2 gene (NM_001083619.1), which has never been reported before.Conclusion: Our case shows the potential diagnostic role of WES in NEDLIB, expands the GRIA2 gene mutation spectrum, and further deepens the understanding of NEDLIB. Deepening the study of the genetic and clinical heterogeneity, treatment, and prognosis of the disease is still our future challenge and focus.

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 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.

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