Co-Occurrence of Fragile X Syndrome with a Second Genetic Condition: Three Independent Cases of Double Diagnosis

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and autism caused by the instability of a CGG trinucleotide repeat in exon 1 of the FMR1 gene. The co-occurrence of FXS with other genetic disorders has only been occasionally reported. Here, we describe three independent cases of FXS co-segregation with three different genetic conditions, consisting of Duchenne muscular dystrophy (DMD), PPP2R5D--related neurodevelopmental disorder, and 2p25.3 deletion. The co-occurrence of DMD and FXS has been reported only once in a young boy, while in an independent family two affected boys were described, the elder diagnosed with FXS and the younger with DMD. This represents the second case in which both conditions coexist in a 5-year-old boy, inherited from his heterozygous mother. The next double diagnosis had never been reported before: through exome sequencing, a girl with FXS who was of 7 years of age with macrocephaly and severe psychomotor delay was found to carry a de novo variant in the PPP2R5D gene. Finally, a maternally inherited 2p25.3 deletion associated with a decreased level of the MYT1L transcript, only in the patient, was observed in a 33-year-old FXS male with severe seizures compared to his mother and two sex- and age-matched controls. All of these patients represent very rare instances of genetic conditions with clinical features that can be modified by FXS and vice versa.

Download Full-text

Faculty Opinions recommendation of Promoter-bound trinucleotide repeat mRNA drives epigenetic silencing in fragile X syndrome.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718290968.793493498 ◽

2014 ◽

Author(s):

Tony Weil

Keyword(s):

Fragile X Syndrome ◽

Trinucleotide Repeat ◽

Fragile X ◽

Epigenetic Silencing

Download Full-text

SENP1 in the retrosplenial agranular cortex regulates core autistic-like symptoms in mice

10.1101/2021.01.24.427868 ◽

2021 ◽

Author(s):

Kan Yang ◽

Yuhan Shi ◽

Xiujuan Du ◽

Yuefang Zhang ◽

Shifang Shan ◽

...

Keyword(s):

Social Interaction ◽

De Novo ◽

Fragile X ◽

Neurodevelopmental Disorder ◽

Autism Spectrum ◽

Repetitive Behaviors ◽

Genetic Components ◽

Truncating Mutation ◽

Synaptic Functions ◽

Core Symptoms

AbstractAutism spectrum disorder (ASD) is a highly heritable complex neurodevelopmental disorder. While the core symptoms of ASD are defects of social interaction and repetitive behaviors, over 50% of ASD patients have comorbidity of intellectual disabilities (ID) or developmental delay (DD), raising the question whether there are genetic components and neural circuits specific for core symptoms of ASD. Here, by focusing on ASD patients who do not show compound ID or DD, we identified a de novo heterozygous gene-truncating mutation of the Sentrin-specific peptidase1 (SENP1) gene, coding the small ubiquitin-like modifiers (SUMO) deconjugating enzyme, as a potentially new candidate gene for ASD. We found that Senp1 haploinsufficient mice exhibited core symptoms of autism such as deficits in social interaction and repetitive behaviors, but normal learning and memory ability. Moreover, we found that the inhibitory and excitatory synaptic functions were severely affected in the retrosplenial agranular (RSA) cortex of Senp1 haploinsufficient mice. Lack of Senp1 led to over SUMOylation and degradation of fragile X mental retardation protein (FMRP) proteins, which is coded by the FMR1 gene, also implicated in syndromic autism. Importantly, re-introducing SENP1 or FMRP specifically in RSA fully rescued the defects of synaptic functions and core autistic-like symptoms of Senp1 haploinsufficient mice. Taken together, these results elucidate that disruption of the SENP1-FMRP regulatory axis in the RSA may cause core autistic symptoms, which further provide a candidate brain region for therapeutic intervene of ASD by neural modulation approaches.

Download Full-text

Integrative analysis identifies key molecular signatures underlying neurodevelopmental deficits in fragile X syndrome

10.1101/606038 ◽

2019 ◽

Cited By ~ 1

Author(s):

Kagistia Hana Utami ◽

Niels H. Skotte ◽

Ana R. Colaço ◽

Nur Amirah Binte Mohammad Yusof ◽

Bernice Sim ◽

...

Keyword(s):

Fragile X Syndrome ◽

Fragile X ◽

Neurodevelopmental Disorder ◽

Embryonic Stem ◽

Neural Progenitor Cell ◽

Integrative Analysis ◽

Network Activity ◽

Neural Cells ◽

Molecular Signatures ◽

Neurodevelopmental Abnormalities

AbstractFragile X syndrome (FXS) is an incurable neurodevelopmental disorder with no effective treatment. FXS is caused by epigenetic silencing ofFMR1and loss of FMRP expression. To investigate the consequences of FMRP deficiency in the context of human physiology, we established isogenicFMR1knockout (FMR1KO) human embryonic stem cells (hESCs). Integrative analysis of the transcriptomic and proteomic profiles of hESC-derived FMRP-deficient neurons revealed several dysregulated pathways important for brain development including processes related to axon development, neurotransmission, and the cell cycle. We functionally validated alterations in a number of these pathways, showing abnormal neural rosette formation and increased neural progenitor cell proliferation inFMR1KO cells. We further demonstrated neurite outgrowth and branching deficits along with impaired electrophysiological network activity in FMRP-deficient neurons. Using isogenicFMR1KO hESC-derived neurons, we reveal key molecular signatures and neurodevelopmental abnormalities arising from loss of FMRP. We anticipate that theFMR1KO hESCs and the neuronal transcriptome and proteome datasets will provide a platform to delineate the pathophysiology of FXS in human neural cells.

Download Full-text

Altered steady state and activity-dependent de novo protein expression in fragile X syndrome

Nature Communications ◽

10.1038/s41467-019-09553-8 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 9

Author(s):

Heather Bowling ◽

Aditi Bhattacharya ◽

Guoan Zhang ◽

Danyal Alam ◽

Joseph Z. Lebowitz ◽

...

Keyword(s):

Steady State ◽

Protein Expression ◽

Fragile X Syndrome ◽

De Novo ◽

Fragile X ◽

Activity Dependent

Download Full-text

Novel de novo variant in EBF3 is likely to impact DNA binding in a patient with a neurodevelopmental disorder and expanded phenotypes: patient report, in silico functional assessment, and review of published cases

Molecular Case Studies ◽

10.1101/mcs.a001743 ◽

2017 ◽

Vol 3 (3) ◽

pp. a001743 ◽

Cited By ~ 11

Author(s):

Patrick R. Blackburn ◽

Sarah S. Barnett ◽

Michael T. Zimmermann ◽

Margot A. Cousin ◽

Charu Kaiwar ◽

...

Keyword(s):

Dna Binding ◽

Functional Assessment ◽

In Silico ◽

De Novo ◽

Neurodevelopmental Disorder ◽

Patient Report ◽

De Novo Variant

Download Full-text

Impaired inhibitory control of cortical synchronization in fragile X syndrome

Journal of Neurophysiology ◽

10.1152/jn.00421.2011 ◽

2011 ◽

Vol 106 (5) ◽

pp. 2264-2272 ◽

Cited By ~ 60

Author(s):

Scott M. Paluszkiewicz ◽

Jose Luis Olmos-Serrano ◽

Joshua G. Corbin ◽

Molly M. Huntsman

Keyword(s):

Fragile X Syndrome ◽

Pyramidal Neurons ◽

Metabotropic Glutamate Receptor ◽

Fragile X ◽

Neurodevelopmental Disorder ◽

Synaptic Inhibition ◽

Cortical Interneuron ◽

Metabotropic Glutamate ◽

Group I ◽

Functional Defect

Fragile X syndrome (FXS) is a neurodevelopmental disorder characterized by severe cognitive impairments, sensory hypersensitivity, and comorbidities with autism and epilepsy. Fmr1 knockout (KO) mouse models of FXS exhibit alterations in excitatory and inhibitory neurotransmission, but it is largely unknown how aberrant function of specific neuronal subtypes contributes to these deficits. In this study we show specific inhibitory circuit dysfunction in layer II/III of somatosensory cortex of Fmr1 KO mice. We demonstrate reduced activation of somatostatin-expressing low-threshold-spiking (LTS) interneurons in response to the group I metabotropic glutamate receptor (mGluR) agonist 3,5-dihydroxyphenylglycine (DHPG) in Fmr1 KO mice, resulting in impaired synaptic inhibition. Paired recordings from pyramidal neurons revealed reductions in synchronized synaptic inhibition and coordinated spike synchrony in response to DHPG, indicating a weakened LTS interneuron network in Fmr1 KO mice. Together, these findings reveal a functional defect in a single subtype of cortical interneuron in Fmr1 KO mice. This defect is linked to altered activity of the cortical network in line with the FXS phenotype.

Download Full-text

Re: March Supplement 1993; “Canadian Guidelines for Prenatal Diagnosis of Genetic Disorders: An Update” (page 21, section 3, iv, (a)-PND for Fragile X syndrome via cytogenetic and DNA markers)

Journal SOGC ◽

10.1016/s0849-5831(16)30744-3 ◽

1995 ◽

Vol 17 (8) ◽

pp. 737

Author(s):

Beverley Ann Lee

Keyword(s):

Prenatal Diagnosis ◽

Fragile X Syndrome ◽

Dna Markers ◽

Fragile X ◽

Genetic Disorders

Download Full-text

DeNovoCNN: A deep learning approach to de novo variant calling in next generation sequencing data

10.1101/2021.09.20.461072 ◽

2021 ◽

Author(s):

Gelana Khazeeva ◽

Karolis Sablauskas ◽

Bart van der Sanden ◽

Wouter Steyaert ◽

Michael Kwint ◽

...

Keyword(s):

Exome Sequencing ◽

De Novo ◽

Genetic Disorders ◽

Variant Calling ◽

Next Generation Sequencing Data ◽

Sequencing Data ◽

Accurate Identification ◽

Whole Exome ◽

De Novo Variant ◽

Generation Sequencing

De novo mutations (DNMs) are an important cause of genetic disorders. The accurate identification of DNMs from sequencing data is therefore fundamental to rare disease research and diagnostics. Unfortunately, identifying reliable DNMs remains a major challenge due to sequence errors, uneven coverage, and mapping artifacts. Here, we developed a deep convolutional neural network (CNN) DNM caller (DeNovoCNN), that encodes alignment of sequence reads for a trio as 160×164 resolution images. DeNovoCNN was trained on DNMs of whole exome sequencing (WES) of 2003 trios achieving on average 99.2% recall and 93.8% precision. We find that DeNovoCNN has increased recall/sensitivity and precision compared to existing de novo calling approaches (GATK, DeNovoGear, Samtools) based on the Genome in a Bottle reference dataset. Sanger validations of DNMs called in both exome and genome datasets confirm that DeNovoCNN outperforms existing methods. Most importantly, we show that DeNovoCNN is robust against different exome sequencing and analyses approaches, thereby allowing it to be applied on other datasets. DeNovoCNN is freely available and can be run on existing alignment (BAM/CRAM) and variant calling (VCF) files from WES and WGS without a need for variant recalling.

Download Full-text

Common Variant Associations with Fragile X Syndrome

10.1101/115998 ◽

2017 ◽

Author(s):

James J Crowley ◽

Jin Szatkiewicz ◽

Anna K Kähler ◽

Paola Giusti-Rodriguez ◽

NaEshia Ancalade ◽

...

Keyword(s):

Fragile X Syndrome ◽

Odds Ratio ◽

De Novo ◽

Fragile X ◽

De Novo Mutation ◽

Risk Haplotype ◽

Functional Genomic ◽

Cgg Repeats ◽

Genome Wide ◽

Protective Haplotype

AbstractFragile X syndrome is a common cause of intellectual disability. It is usually caused by a de novo mutation which often occur on multiple haplotypes and should not be detectible using genome-wide association (GWA). We conducted GWA 89 male FXS cases and 266 male controls, and detected multiple genome-wide significant signals near FMR1 (odds ratio=8.10, P=2.5×10−10). These findings withstood robust attempts at falsification. Fine-mapping did not serve to narrow the interval (minimum P=1.13×l0−14), and functional genomic integration (including 5C data we generated for this region) did not provide a mechanistic hypothesis. Controls carrying a risk haplotype had significantly longer and more variable FMR1 CGG repeats than controls with the protective haplotype (P=4.75×10−5) which may predispose toward increases in CGG number to the pre-mutation range over many generations. This is a salutary reminder of the complexity of even “simple” monogenetic disorders.

Download Full-text