A novel de novo DDX3X missense variant in a female with brachycephaly and intellectual disability: a case report

Abstract Background De novo pathogenic variants in the DDX3X gene are reported to account for 1–3% of unexplained intellectual disability (ID) in females, leading to the rare disease known as DDX3X syndrome (MRXSSB, OMIM #300958). Besides ID, these patients manifest a variable clinical presentation, which includes neurological and behavioral defects, and abnormal brain MRIs. Case presentation We report a 10-year-old girl affected by delayed psychomotor development, delayed myelination, and polymicrogyria (PMG). We identified a novel de novo missense mutation in the DDX3X gene (c.625C > G) by whole exome sequencing (WES). The DDX3X gene encodes a DEAD-box ATP-dependent RNA-helicase broadly implicated in gene expression through regulation of mRNA metabolism. The identified mutation is located just upstream the helicase domain and is suggested to impair the protein activity, thus resulting in the altered translation of DDX3X-dependent mRNAs. The proband, presenting with the typical PMG phenotype related to the syndrome, does not show other clinical signs frequently reported in presence of missense DDX3X mutations that are associated with a most severe clinical presentation. In addition, she has brachycephaly, never described in female DDX3X patients, and macroglossia, that has never been associated with the syndrome. Conclusions This case expands the knowledge of DDX3X pathogenic variants and the associated DDX3X syndrome phenotypic spectrum.

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A Novel De Novo Ddx3x Missense Variant in a Female With Brachycephaly and Intellectual Disability: A Case Report

10.21203/rs.3.rs-118205/v1 ◽

2020 ◽

Author(s):

Giada Moresco ◽

Jole Costanza ◽

Carlo Santaniello ◽

Ornella Rondinone ◽

Federico Grilli ◽

...

Keyword(s):

Intellectual Disability ◽

Clinical Presentation ◽

De Novo ◽

Clinical Signs ◽

Missense Variant ◽

Psychomotor Development ◽

Helicase Domain ◽

Protein Activity ◽

Mrna Metabolism ◽

Pathogenic Variants

Abstract Background: De novo pathogenic variants in the DDX3X gene are reported to account for 1–3% of unexplained intellectual disability (ID) in females, leading to the rare disease known as DDX3X syndrome (MRXSSB, OMIM #300958). Besides ID, these patients manifest a variable clinical presentation, which includes neurological and behavioral defects, and abnormal brain MRIs. Case presentation: We report a 10-year-old girl affected by delayed psychomotor development, delayed myelination, and polymicrogyria (PMG). We identified a novel de novo missense mutation in the DDX3X gene (c.C625G) by exome sequencing. The DDX3X gene encodes a DEAD-box ATP-dependent RNA-helicase broadly implicated in gene expression through regulation of mRNA metabolism. The identified mutation is located just upstream the helicase domain and is suggested to impair the protein activity, thus resulting in the altered translation of DDX3X-dependent mRNAs. The proband, presenting with the typical PMG phenotype related to the syndrome, does not show other clinical signs frequently reported in presence of missense DDX3X mutations that are associated with a most severe clinical presentation. In addition, she has brachycephaly, never described in female DDX3X patients, and macroglossia, that has never been associated with the syndrome.Conclusions: This case expands the knowledge of DDX3X pathogenic variants and the associated DDX3X syndrome phenotypic spectrum.

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A Novel Missense Variant in the Gene PPP2R5D Causes a Rare Neurodevelopmental Disorder with Increased Phenotype

BioMed Research International ◽

10.1155/2021/6661860 ◽

2021 ◽

Vol 2021 ◽

pp. 1-7

Author(s):

Lulu Yan ◽

Ru Shen ◽

Zongfu Cao ◽

Chunxiao Han ◽

Yuxin Zhang ◽

...

Keyword(s):

De Novo ◽

Genetic Disorder ◽

Neurodevelopmental Disorder ◽

Three Dimensional ◽

Missense Variant ◽

Pathogenic Variant ◽

Dimensional Structure ◽

Chinese Family ◽

Speech Impairment ◽

Pathogenic Variants

PPP2R5D-related neurodevelopmental disorder, which is mainly caused by de novo missense variants in the PPP2R5D gene, is a rare autosomal dominant genetic disorder with about 100 patients and a total of thirteen pathogenic variants known to exist globally so far. Here, we present a 24-month-old Chinese boy with developmental delay and other common clinical characteristics of PPP2R5D-related neurodevelopmental disorder including hypotonia, macrocephaly, intellectual disability, speech impairment, and behavioral abnormality. Trio-whole exome sequencing (WES) and Sanger sequencing were performed to identify the causal gene variant. The pathogenicity of the variant was evaluated using bioinformatics tools. We identified a novel pathogenic variant in the PPP2R5D gene (c.620G>T, p.Trp207Leu). The variant is located in the variant hotspot region of this gene and is predicted to cause PPP2R5D protein dysfunction due to an increase in local hydrophobicity and unstable three-dimensional structure. We report a novel pathogenic variant of PPP2R5D associated with PPP2R5D-related neurodevelopmental disorder from a Chinese family. Our findings expanded the phenotypic and mutational spectrum of PPP2R5D-related neurodevelopmental disorder.

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

Journal of Medical Genetics ◽

10.1136/jmedgenet-2020-107462 ◽

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.

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Hemizygous FLNA variant in West syndrome without periventricular nodular heterotopia

Human Genome Variation ◽

10.1038/s41439-020-00131-9 ◽

2020 ◽

Vol 7 (1) ◽

Author(s):

Yoshitaka Hiromoto ◽

Yoshiteru Azuma ◽

Yuichi Suzuki ◽

Megumi Hoshina ◽

Yuri Uchiyama ◽

...

Keyword(s):

De Novo ◽

Missense Variant ◽

West Syndrome ◽

Periventricular Nodular Heterotopia ◽

Psychomotor Delay ◽

Pathogenic Variants ◽

Whole Exome ◽

Epileptic Patients ◽

Nodular Heterotopia ◽

Refractory Seizures

AbstractPathogenic FLNA variants can be identified in patients with seizures accompanied by periventricular nodular heterotopia (PVNH). It is unusual to find FLNA aberrations in epileptic patients without PVNH on brain imaging. We report a boy with cryptogenic West syndrome followed by refractory seizures and psychomotor delay. We performed whole-exome sequencing and identified a de novo missense variant in FLNA. It is noteworthy that this patient showed no PVNH. As no other pathogenic variants were found in epilepsy-related genes, this FLNA variant likely caused West syndrome but with no PVNH.

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Gene discoveries in autism are biased towards comorbidity with intellectual disability

Journal of Medical Genetics ◽

10.1136/jmedgenet-2019-106476 ◽

2020 ◽

Vol 57 (9) ◽

pp. 647-652

Author(s):

Matthew Jensen ◽

Corrine Smolen ◽

Santhosh Girirajan

Keyword(s):

Intellectual Disability ◽

Genetic Factors ◽

De Novo ◽

High Functioning Autism ◽

Copy Number Variants ◽

Social Responsiveness ◽

High Functioning ◽

Pathogenic Variants ◽

Increased Risk ◽

Normal Cognitive Function

BackgroundAutism typically presents with highly heterogeneous features, including frequent comorbidity with intellectual disability (ID). The overlap between these phenotypes has confounded the diagnosis and discovery of genetic factors associated with autism. We analysed pathogenic de novo genetic variants in individuals with autism who had either ID or normal cognitive function to determine whether genes associated with autism also contribute towards ID comorbidity.MethodsWe analysed 2290 individuals from the Simons Simplex Collection for de novo likely gene-disruptive (LGD) variants and copy-number variants (CNVs), and determined their relevance towards IQ and Social Responsiveness Scale (SRS) measures.ResultsIndividuals who carried de novo variants in a set of 173 autism-associated genes showed an average 12.8-point decrease in IQ scores (p=5.49×10−6) and 2.8-point increase in SRS scores (p=0.013) compared with individuals without such variants. Furthermore, individuals with high-functioning autism (IQ >100) had lower frequencies of de novo LGD variants (42 of 397 vs 86 of 562, p=0.021) and CNVs (9 of 397 vs 24 of 562, p=0.065) compared with individuals who manifested both autism and ID (IQ <70). Pathogenic variants disrupting autism-associated genes conferred a 4.85-fold increased risk (p=0.011) for comorbid ID, while de novo variants observed in individuals with high-functioning autism disrupted genes with little functional relevance towards neurodevelopment.ConclusionsPathogenic de novo variants disrupting autism-associated genes contribute towards autism and ID comorbidity, while other genetic factors are likely to be causal for high-functioning autism.

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Rapidly Progressive Multisutural Craniosynostosis in a Patient With Jackson-Weiss Syndrome and a De Novo FGFR2 Pathogenic Variant

The Cleft Palate-Craniofacial Journal ◽

10.1177/1055665619851642 ◽

2019 ◽

Vol 56 (10) ◽

pp. 1386-1392

Author(s):

Karel-Bart Celie ◽

Melissa Yuan ◽

Christopher Cunniff ◽

Jarrod Bogue ◽

Caitlin Hoffman ◽

...

Keyword(s):

Clinical Outcomes ◽

Early Treatment ◽

Clinical Presentation ◽

De Novo ◽

Pathogenic Variant ◽

Medical Complications ◽

3 Dimensional ◽

Constitutive Activation ◽

Pathogenic Variants ◽

Dimensional Modeling

Little is currently known about the mechanisms by which pathogenic variants of FGFR2 produce changes in the FGFR protein and influence the clinical presentation of affected individuals. We report on a patient with a de novo pathogenic variant of FGFR2 and a phenotype consistent with Jackson-Weiss syndrome who presented with delayed, rapidly progressive multisutural craniosynostosis and associated medical complications. Using 3-dimensional modeling of the FGFR protein, we provide evidence that this variant resulted in abnormal dimerization and constitutive activation of FGFR, leading to the Jackson-Weiss phenotype. Knowledge regarding the correlation between genotype and phenotype of persons with FGFR2-related craniosynostosis has the potential to allow for anticipation of medical complications, institution of early treatment, and improved clinical outcomes.

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X-linked neonatal-onset epileptic encephalopathy associated with a gain-of-function variant p.R660T in GRIA3

PLoS Genetics ◽

10.1371/journal.pgen.1009608 ◽

2021 ◽

Vol 17 (6) ◽

pp. e1009608

Author(s):

Jia-Hui Sun ◽

Jiang Chen ◽

Fernando Eduardo Ayala Valenzuela ◽

Carolyn Brown ◽

Diane Masser-Frye ◽

...

Keyword(s):

Developmental Delay ◽

Prolonged Exposure ◽

De Novo ◽

Missense Variant ◽

Epileptic Encephalopathy ◽

Global Developmental Delay ◽

Decay Kinetics ◽

Gain Of Function ◽

Ca1 Neurons ◽

Pathogenic Variants

The X-linked GRIA3 gene encodes the GLUA3 subunit of AMPA-type glutamate receptors. Pathogenic variants in this gene were previously reported in neurodevelopmental diseases, mostly in male patients but rarely in females. Here we report a de novo pathogenic missense variant in GRIA3 (c.1979G>C; p. R660T) identified in a 1-year-old female patient with severe epilepsy and global developmental delay. When exogenously expressed in human embryonic kidney (HEK) cells, GLUA3_R660T showed slower desensitization and deactivation kinetics compared to wildtype (wt) GLUA3 receptors. Substantial non-desensitized currents were observed with the mutant but not for wt GLUA3 with prolonged exposure to glutamate. When co-expressed with GLUA2, the decay kinetics were similarly slowed in GLUA2/A3_R660T with non-desensitized steady state currents. In cultured cerebellar granule neurons, miniature excitatory postsynaptic currents (mEPSCs) were significantly slower in R660T transfected cells than those expressing wt GLUA3. When overexpressed in hippocampal CA1 neurons by in utero electroporation, the evoked EPSCs and mEPSCs were slower in neurons expressing R660T mutant compared to those expressing wt GLUA3. Therefore our study provides functional evidence that a gain of function (GoF) variant in GRIA3 may cause epileptic encephalopathy and global developmental delay in a female subject by enhancing synaptic transmission.

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

BMC Pediatrics ◽

10.1186/s12887-021-03038-8 ◽

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.

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