PURA syndrome: clinical delineation and genotype-phenotype study in 32 individuals with review of published literature

BackgroundDe novo mutations in PURA have recently been described to cause PURA syndrome, a neurodevelopmental disorder characterised by severe intellectual disability (ID), epilepsy, feeding difficulties and neonatal hypotonia.ObjectivesTo delineate the clinical spectrum of PURA syndrome and study genotype-phenotype correlations.MethodsDiagnostic or research-based exome or Sanger sequencing was performed in individuals with ID. We systematically collected clinical and mutation data on newly ascertained PURA syndrome individuals, evaluated data of previously reported individuals and performed a computational analysis of photographs. We classified mutations based on predicted effect using 3D in silico models of crystal structures of Drosophila-derived Pur-alpha homologues. Finally, we explored genotype-phenotype correlations by analysis of both recurrent mutations as well as mutation classes.ResultsWe report mutations in PURA (purine-rich element binding protein A) in 32 individuals, the largest cohort described so far. Evaluation of clinical data, including 22 previously published cases, revealed that all have moderate to severe ID and neonatal-onset symptoms, including hypotonia (96%), respiratory problems (57%), feeding difficulties (77%), exaggerated startle response (44%), hypersomnolence (66%) and hypothermia (35%). Epilepsy (54%) and gastrointestinal (69%), ophthalmological (51%) and endocrine problems (42%) were observed frequently. Computational analysis of facial photographs showed subtle facial dysmorphism. No strong genotype-phenotype correlation was identified by subgrouping mutations into functional classes.ConclusionWe delineate the clinical spectrum of PURA syndrome with the identification of 32 additional individuals. The identification of one individual through targeted Sanger sequencing points towards the clinical recognisability of the syndrome. Genotype-phenotype analysis showed no significant correlation between mutation classes and disease severity.

Download Full-text

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.

Download Full-text

De Novo Mutations of CCNK Cause a Syndromic Neurodevelopmental Disorder with Distinctive Facial Dysmorphism

The American Journal of Human Genetics ◽

10.1016/j.ajhg.2018.07.019 ◽

2018 ◽

Vol 103 (3) ◽

pp. 448-455 ◽

Cited By ~ 6

Author(s):

Yanjie Fan ◽

Wu Yin ◽

Bing Hu ◽

Antonie D. Kline ◽

Victor Wei Zhang ◽

...

Keyword(s):

De Novo ◽

Neurodevelopmental Disorder ◽

Facial Dysmorphism ◽

De Novo Mutations

Download Full-text

A New Case of de novo Variant c.892C>T (p.Arg298Trp) in NACC1: A First Case Report From China

Frontiers in Pediatrics ◽

10.3389/fped.2021.754261 ◽

2021 ◽

Vol 9 ◽

Author(s):

Baiyu Lyu ◽

Yan Dong ◽

Juan Kang

Keyword(s):

Intellectual Disability ◽

Congenital Cataract ◽

De Novo ◽

Neurodevelopmental Disorder ◽

Brain Mri ◽

Case Presentation ◽

Feeding Difficulties ◽

Severe Intellectual Disability ◽

First Case ◽

Infantile Epilepsy

Background: The nucleus accumbens associated 1 (NACC1) gene is a transcription factor member of the BTB/POZ family. A de novo heterozygous c.892C>T (p.Arg298Trp) variant in the NACC1 may define a syndrome characterized by intellectual disability, infantile epilepsy, congenital cataract, and feeding difficulties.Case Presentation: We report a new case with a neurodevelopmental disorder characterized by severe intellectual disability, infantile epilepsy, congenital cataract, and feeding difficulties. Brain MRI reveals brain dysplasia. We observe a de novo heterozygous c.892C>T (p.Arg298Trp) variant in the NACC1 gene in this case. Now, the child regularly goes to the hospital for rehabilitation training (once a month). Sodium Valproate (10 mg/kg/day) and Clobazam (10 mg/kg/day) are used in the treatment of epilepsy. A total of three articles were screened, and two papers were excluded. The search revealed one article related to a syndrome caused by a de novo heterozygous c.892C>T (p.Arg298Trp) variant in the NACC1; they screened the main clinical features of eight cases of a syndrome, which were summarized and analyzed.Conclusions: The NACC1 gene is a member of the BTB/POZ family of transcription factors. A de novo heterozygous c.892C>T (p.Arg298Trp) variant in the NACC1 may define a syndrome characterized by intellectual disability, infantile epilepsy, congenital cataract, and feeding difficulties. At present, there is no effective cure. In the future, we need more cases to determine the phenotype–genotype correlation of NACC1 variants. Many questions remain to be answered, and many challenges remain to be faced. Future transcriptional studies may further clarify this rare, recurrent variant, and could potentially lead to targeted therapies.

Download Full-text

MED12-Related (Neuro)Developmental Disorders: A Question of Causality

Genes ◽

10.3390/genes12050663 ◽

2021 ◽

Vol 12 (5) ◽

pp. 663

Author(s):

Stijn van de Plassche ◽

Arjan PM de Brouwer

Keyword(s):

Developmental Disorders ◽

De Novo ◽

Expression Patterns ◽

Mediator Complex ◽

Gene Expression Patterns ◽

Facial Dysmorphism ◽

Regulation Of Transcription ◽

Feeding Difficulties ◽

Missense Variants ◽

Pathogenic Variants

MED12 is a member of the Mediator complex that is involved in the regulation of transcription. Missense variants in MED12 cause FG syndrome, Lujan-Fryns syndrome, and Ohdo syndrome, as well as non-syndromic intellectual disability (ID) in hemizygous males. Recently, female patients with de novo missense variants and de novo protein truncating variants in MED12 were described, resulting in a clinical spectrum centered around ID and Hardikar syndrome without ID. The missense variants are found throughout MED12, whether they are inherited in hemizygous males or de novo in females. They can result in syndromic or nonsyndromic ID. The de novo nonsense variants resulting in Hardikar syndrome that is characterized by facial clefting, pigmentary retinopathy, biliary anomalies, and intestinal malrotation, are found more N-terminally, whereas the more C-terminally positioned variants are de novo protein truncating variants that cause a severe, syndromic phenotype consisting of ID, facial dysmorphism, short stature, skeletal abnormalities, feeding difficulties, and variable other abnormalities. This broad range of distinct phenotypes calls for a method to distinguish between pathogenic and non-pathogenic variants in MED12. We propose an isogenic iNeuron model to establish the unique gene expression patterns that are associated with the specific MED12 variants. The discovery of these patterns would help in future diagnostics and determine the causality of the MED12 variants.

Download Full-text

Acute pre-B lymphoblastic leukemia and congenital anomalies in a child with a de novo 22q11.1q11.22 duplication

Balkan Journal of Medical Genetics ◽

10.2478/bjmg-2018-0002 ◽

2018 ◽

Vol 21 (1) ◽

pp. 87-91 ◽

Cited By ~ 1

Author(s):

M Vaisvilas ◽

V Dirse ◽

B Aleksiuniene ◽

I Tamuliene ◽

L Cimbalistiene ◽

...

Keyword(s):

Congenital Heart ◽

De Novo ◽

Heart Defects ◽

Lymphoblastic Leukemia ◽

Snp Array ◽

Facial Dysmorphism ◽

Severe Intellectual Disability ◽

Leukemic Clone ◽

Cell Growth And Differentiation ◽

Facial Dysmorphia

Abstract Microdeletions and microduplications are recurrent in the q11.2 region of chromosome 22. The 22q11.2 duplication syndrome is an extremely variable disorder with a phenotype ranging from severe intellectual disability, facial dysmorphism, heart defects, and urogenital abnormalities to very mild symptoms. Both benign and malignant hematological entities are rare. A male patient was diagnosed with mild facial dysmorphia, congenital heart anomalies shortly after birth and acute bowel obstruction due to malrotation of the intestine at the age of 3 years. A whole-genome single nucleotide polymorphism (SNP) array revealed a de novo 6.6 Mb duplication in the 22q11.1q11.22 chromosomal region. A year later, the patient was diagnosed with acute pre-B lymphoblastic leukemia (pre-B ALL). Five genes, CDC45, CLTCL1, DGCR2, GP1BB and SEPT5, in the 22q11.1q11.22 region are potentially responsible for cell cycle division. We hypothesized that dosage imbalance of genes implicated in the rearrangement could have disrupted the balance between cell growth and differentiation and played a role in the initiation of malignancy with a hyperdiploid leukemic clone, whereas over-expression of the TBX1 gene might have been responsible for congenital heart defects and mild facial dysmorphia.

Download Full-text

SLC12A2 variants cause a neurodevelopmental disorder or cochleovestibular defect

Brain ◽

10.1093/brain/awaa176 ◽

2020 ◽

Vol 143 (8) ◽

pp. 2380-2387 ◽

Cited By ~ 2

Author(s):

Alisdair McNeill ◽

Emanuela Iovino ◽

Luke Mansard ◽

Christel Vache ◽

David Baux ◽

...

Keyword(s):

Hearing Loss ◽

Sensorineural Hearing Loss ◽

Developmental Disorders ◽

De Novo ◽

Neurodevelopmental Disorder ◽

Sensorineural Deafness ◽

Sensorineural Hearing ◽

De Novo Mutation ◽

Xenopus Laevis Oocytes ◽

De Novo Mutations

Abstract The SLC12 gene family consists of SLC12A1–SLC12A9, encoding electroneutral cation-coupled chloride co-transporters. SCL12A2 has been shown to play a role in corticogenesis and therefore represents a strong candidate neurodevelopmental disorder gene. Through trio exome sequencing we identified de novo mutations in SLC12A2 in six children with neurodevelopmental disorders. All had developmental delay or intellectual disability ranging from mild to severe. Two had sensorineural deafness. We also identified SLC12A2 variants in three individuals with non-syndromic bilateral sensorineural hearing loss and vestibular areflexia. The SLC12A2 de novo mutation rate was demonstrated to be significantly elevated in the deciphering developmental disorders cohort. All tested variants were shown to reduce co-transporter function in Xenopus laevis oocytes. Analysis of SLC12A2 expression in foetal brain at 16–18 weeks post-conception revealed high expression in radial glial cells, compatible with a role in neurogenesis. Gene co-expression analysis in cells robustly expressing SLC12A2 at 16–18 weeks post-conception identified a transcriptomic programme associated with active neurogenesis. We identify SLC12A2 de novo mutations as the cause of a novel neurodevelopmental disorder and bilateral non-syndromic sensorineural hearing loss and provide further data supporting a role for this gene in human neurodevelopment.

Download Full-text

Molecular Dissection of Neurodevelopmental Disorder-Causing Mutations in CYFIP2

Cells ◽

10.3390/cells9061355 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1355

Author(s):

Matthias Schaks ◽

Michael Reinke ◽

Walter Witke ◽

Klemens Rottner

Keyword(s):

De Novo ◽

Neurodevelopmental Disorder ◽

Small Gtpases ◽

Normal Brain ◽

Loss Of Function ◽

De Novo Mutations ◽

Neuronal Morphogenesis ◽

Variable Extent ◽

Regulatory Complex ◽

Almost All

Actin remodeling is frequently regulated by antagonistic activities driving protrusion and contraction downstream of Rac and Rho small GTPases, respectively. WAVE regulatory complex (WRC), which primarily operates downstream of Rac, plays pivotal roles in neuronal morphogenesis. Recently, two independent studies described de novo mutations in the CYFIP2 subunit of WRC, which caused intellectual disability (ID) in humans. Although mutations had been proposed to effect WRC activation, no experimental evidence for this was provided. Here, we made use of CRISPR/Cas9-engineered B16-F1 cell lines that were reconstituted with ID-causing CYFIP variants in different experimental contexts. Almost all CYFIP2-derived mutations (7 out of 8) promoted WRC activation, but to variable extent and with at least two independent mechanisms. The majority of mutations occurs in a conserved WAVE-binding region, required for WRC transinhibition. One mutation is positioned closely adjacent to the Rac-binding A site and appears to ease Rac-mediated WRC activation. As opposed to these gain-of-function mutations, a truncating mutant represented a loss-of-function variant and failed to interact with WRC components. Collectively, our data show that explored CYFIP2 mutations frequently, but not always, coincide with WRC activation and suggest that normal brain development requires a delicate and precisely tuned balance of neuronal WRC activity.

Download Full-text

De novo mutations in beta-catenin (CTNNB1) appear to be a frequent cause of intellectual disability: expanding the mutational and clinical spectrum

Human Genetics ◽

10.1007/s00439-014-1498-1 ◽

2014 ◽

Vol 134 (1) ◽

pp. 97-109 ◽

Cited By ~ 42

Author(s):

Alma Kuechler ◽

Marjolein H. Willemsen ◽

Beate Albrecht ◽

Carlos A. Bacino ◽

Dennis W. Bartholomew ◽

...

Keyword(s):

Intellectual Disability ◽

De Novo ◽

Clinical Spectrum ◽

Beta Catenin ◽

De Novo Mutations

Download Full-text

Contribution of de novo and mosaic TP53 mutations to Li-Fraumeni syndrome

Journal of Medical Genetics ◽

10.1136/jmedgenet-2017-104976 ◽

2017 ◽

Vol 55 (3) ◽

pp. 173-180 ◽

Cited By ~ 32

Author(s):

Mariette Renaux-Petel ◽

Françoise Charbonnier ◽

Jean-Christophe Théry ◽

Pierre Fermey ◽

Gwendoline Lienard ◽

...

Keyword(s):

Sanger Sequencing ◽

De Novo ◽

Multiple Primary Cancers ◽

Breast Cancers ◽

De Novo Mutations ◽

Li Fraumeni Syndrome ◽

Medical Laboratories ◽

Li Fraumeni ◽

Adrenocortical Carcinomas ◽

Generation Sequencing

BackgroundDevelopment of tumours such as adrenocortical carcinomas (ACC), choroid plexus tumours (CPT) or female breast cancers before age 31 or multiple primary cancers belonging to the Li-Fraumeni (LFS) spectrum is, independently of the familial history, highly suggestive of a germline TP53 mutation. The aim of this study was to determine the contribution of de novo and mosaic mutations to LFS.Methods and resultsAmong 328 unrelated patients harbouring a germline TP53 mutation identified by Sanger sequencing and/or QMPSF, we could show that the mutations had occurred de novo in 40 cases, without detectable parental age effect. Sanger sequencing revealed two mosaic mutations in a child with ACC and in an unaffected father of a child with medulloblastoma. Re-analysis of blood DNA by next-generation sequencing, performed at a depth above 500X, from 108 patients suggestive of LFS without detectable TP53 mutations, allowed us to identify 6 additional cases of mosaic TP53 mutations, in 2/49 children with ACC, 2/21 children with CPT, in 1/31 women with breast cancer before age 31 and in a patient who developed an osteosarcoma at age 12, a breast carcinoma and a breast sarcoma at age 35.ConclusionsThis study performed on a large series of TP53 mutation carriers allows estimating the contribution to LFS of de novo mutations to at least 14% (48/336) and suggests that approximately one-fifth of these de novo mutations occur during embryonic development. Considering the medical impact of TP53 mutation identification, medical laboratories in charge of TP53 testing should ensure the detection of mosaic mutations.

Download Full-text