scholarly journals Gene discoveries in autism are biased towards comorbidity with intellectual disability

2019 ◽  
Author(s):  
Matthew Jensen ◽  
Corrine Smolen ◽  
Santhosh Girirajan
Keyword(s):  
Intellectual Disability ◽  
Genetic Factors ◽  
De Novo ◽  
High Functioning Autism ◽  
Case Reports ◽  
Expression Patterns ◽  
High Functioning ◽  
Pathogenic Variants ◽  
Increased Risk ◽  
Normal Cognitive Function

AbstractAutism typically presents with a highly heterogeneous set of features, including frequent comorbidity with intellectual disability (ID). The overlap between these two phenotypes has confounded the accurate diagnosis and discovery of genetic factors associated with autism. We analyzed genetic variants in 2,290 individuals with autism from the Simons Simplex Collection (SSC) who have either ID or normal cognitive function to determine whether genes associated with autism also contribute towards ID comorbidity. We found that individuals who carried variants in a set of 173 reported autism-associated genes showed decreased IQ (p=5.49×10−6) and increased autism severity (p=0.013) compared with individuals without such variants. A subset of autism-associated genes also showed strong evidence for ID comorbidity in published case reports. We also found that individuals with high-functioning autism (IQ>100) had lower frequencies of CNVs (p=0.065) and LGD variants (p=0.021) compared with individuals who manifested both autism and ID (IQ<70). These data indicated that de novo LGD variants conferred a 1.53-fold higher risk (p=0.035) towards comorbid ID, while LGD mutations specifically disrupting autism-associated genes conferred a 4.85-fold increased risk (p=0.011) for comorbid ID. Furthermore, de novo LGD variants in individuals with high-functioning autism were more likely to disrupt genes with little functional relevance towards neurodevelopment, as demonstrated by evidence from pathogenicity metrics, expression patterns in the developing brain, and mouse model phenotypes. Overall, our data suggest that de novo pathogenic variants disrupting genes associated with autism contribute towards autism and ID comorbidity, while other genetic factors are likely to be causal for high-functioning autism.

scholarly journals Gene discoveries in autism are biased towards comorbidity with intellectual disability

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.

scholarly journals Migration and autism spectrum disorder: population-based study

2012 ◽  
Vol 201 (2) ◽  
pp. 109-115 ◽  
Author(s):  
Cecilia Magnusson ◽  
Dheeraj Rai ◽  
Anna Goodman ◽  
Michael Lundberg ◽  
Selma Idring ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Intellectual Disability ◽  
High Functioning Autism ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
High Functioning ◽  
Increased Risk ◽  
Timing Of Migration ◽  
Low Functioning ◽  
Migrant Parents

BackgroundMigration has been implicated as a risk factor for autism, but evidence is limited and inconsistent.AimsTo investigate the relationship between parental migration status and risk of autism spectrum disorder, taking into consideration the importance of region of origin, timing of migration and possible discrepancies in associations between autism subtypes.MethodRecord-linkage study within the total child population of Stockholm County between 2001 and 2007. Individuals with high- and low-functioning autism were defined as having autism spectrum disorder with and without comorbid intellectual disability, and ascertained via health and habilitation service registers.ResultsIn total, 4952 individuals with autism spectrum disorder were identified, comprising 2855 children with high-functioning autism and 2097 children with low-functioning autism. Children of migrant parents were at increased risk of low-functioning autism (odds ratio (OR) = 1.5, 95% CI 1.3–1.7); this risk was highest when parents migrated from regions with a low human development index, and peaked when migration occurred around pregnancy (OR = 2.3, 95% CI 1.7–3.0). A decreased risk of high-functioning autism was observed in children of migrant parents, regardless of area of origin or timing of migration. Parental age, income or obstetric complications did not fully explain any of these associations.ConclusionsEnvironmental factors associated with migration may contribute to the development of autism presenting with comorbid intellectual disability, especially when actingin utero.High- and low-functioning autism may have partly different aetiologies, and should be studied separately.

scholarly journals Truncating Variant Burden in High Functioning Autism and Pleiotropic Effects of LRP1 Across Psychiatric Phenotypes

2018 ◽  
Author(s):  
Bàrbara Torrico ◽  
Alex D Shaw ◽  
Roberto Mosca ◽  
Norma Vivó-Luque ◽  
Amaia Hervás ◽  
...  
Keyword(s):  
Rare Variants ◽  
De Novo ◽  
High Functioning Autism ◽  
Meta Analysis ◽  
Autism Spectrum ◽  
Pleiotropic Effects ◽  
Psychiatric Diseases ◽  
High Functioning ◽  
Pathogenic Variants ◽  
Functional Consequences

AbstractPrevious research has implicated de novo (DN) and inherited truncating mutations in autism spectrum disorder (ASD). We aim to investigate whether the load of inherited truncating mutations contribute similarly to high functioning autism (HFA), and to characterise genes harbouring DN variants in HFA.We performed whole-exome sequencing (WES) in 20 HFA families (average IQ = 100). No difference was observed in the number of transmitted versus non-transmitted truncating alleles to HFA (117 vs 130, P = 0.32). Transmitted truncating and DN variants in HFA were not enriched in GO or KEGG categories, nor autism-related gene sets. However, in a HFA patient we identified a DN variant in a canonical splice site of LRP1, a post-synaptic density gene that is a target for the FMRP. This DN leads to in-frame skipping of exon-29, removing 2 of 6 blades of the β-propeller domain-4 of LRP1, with putative functional consequences. Results using large datasets implicate LRP1 across psychiatric diseases: i) DN are associated with ASD (P = 0.039) and schizophrenia (P = 0.008) from combined sequencing projects; ii) Common variants using Psychiatric Genomics Consortium GWAS datasets show gene-based association in schizophrenia (P = 6.6E-07) and across six psychiatric diseases (meta-analysis P = 8.1E-05); and iii) burden of ultra-rare pathogenic variants is higher in ASD (P = 1.2E-05), using WES from 6,135 schizophrenia patients, 1,778 ASD patients and 6,245 controls. Previous and current studies suggest an impact of truncating mutations restricted to severe ASD phenotypes associated with intellectual disability. We provide evidence for pleiotropic effects of common and rare variants in the LRP1 gene across psychiatric phenotypes.

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

2021 ◽  
Vol 47 (1) ◽  
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.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.

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

Genes ◽  
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.

scholarly journals Cas9-targeted nanopore sequencing reveals epigenetic heterogeneity after de novo assembly of native full-length hepatitis B virus genomes

2021 ◽  
Vol 7 (5) ◽  
Author(s):  
Chloe Goldsmith ◽  
Damien Cohen ◽  
Anaëlle Dubois ◽  
Maria Guadalupe Martinez ◽  
Kilian Petitjean ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
De Novo ◽  
Expression Patterns ◽  
Cellular Transformation ◽  
Hbv Dna ◽  
Nanopore Sequencing ◽  
Infected People ◽  
Increased Risk ◽  
B Virus

Hepatitis B virus (HBV) contains a 3.2 kb DNA genome and causes acute and chronic hepatitis. HBV infection is a global health problem, with 350 million chronically infected people at increased risk of developing liver disease and hepatocellular carcinoma (HCC). Methylation of HBV DNA in a CpG context (5mCpG) can alter the expression patterns of viral genes related to infection and cellular transformation. Moreover, it may also provide clues as to why certain infections are cleared or persist with or without progression to cancer. The detection of 5mCpG often requires techniques that damage DNA or introduce bias through a myriad of limitations. Therefore, we developed a method for the detection of 5mCpG on the HBV genome that does not rely on bisulfite conversion or PCR. With Cas9-guided RNPs to specifically target the HBV genome, we enriched in HBV DNA from primary human hepatocytes (PHHs) infected with different HBV genotypes, as well as enriching in HBV from infected patient liver tissue, followed by sequencing with Oxford Nanopore Technologies MinION. Detection of 5mCpG by nanopore sequencing was benchmarked with bisulfite-quantitative methyl-specific qPCR (BS-qMSP). The 5mCpG levels in HBV determined by BS-qMSP and nanopore sequencing were highly correlated. Our nanopore sequencing approach achieved a coverage of ~2000× of HBV depending on infection efficiency, sufficient coverage to perform a de novo assembly and detect small fluctuations in HBV methylation, providing the first de novo assembly of native HBV DNA, as well as the first landscape of 5mCpG from native HBV sequences. Moreover, by capturing entire HBV genomes, we explored the epigenetic heterogeneity of HBV in infected patients and identified four epigenetically distinct clusters based on methylation profiles. This method is a novel approach that enables the enrichment of viral DNA in a mixture of nucleic acid material from different species and will serve as a valuable tool for infectious disease monitoring.

scholarly journals De Novo and Inherited Pathogenic Variants in KDM3B Cause Intellectual Disability, Short Stature, and Facial Dysmorphism

2019 ◽  
Vol 104 (4) ◽  
pp. 758-766 ◽  
Author(s):  
Illja J. Diets ◽  
Roos van der Donk ◽  
Kristina Baltrunaite ◽  
Esmé Waanders ◽  
Margot R.F. Reijnders ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Short Stature ◽  
De Novo ◽  
Facial Dysmorphism ◽  
Pathogenic Variants

scholarly journals Obstetric complications and mild to moderate intellectual disability

2009 ◽  
Vol 194 (3) ◽  
pp. 224-228 ◽  
Author(s):  
Jessika E. Sussmann ◽  
Andrew M. McIntosh ◽  
Stephen M. Lawrie ◽  
Eve C. Johnstone
Keyword(s):  
Intellectual Disability ◽  
Genetic Factors ◽  
Special Care ◽  
Foetal Distress ◽  
Neonatal Complications ◽  
Moderate Intellectual Disability ◽  
Special Care Baby Unit ◽  
Increased Risk ◽  
Pregnancy And Delivery

BackgroundMild to moderate intellectual disability affects 2.5% of the general population and is associated with an increased risk of several psychiatric disorders. Most cases are of unknown aetiology although genetic factors have an important role.AimsTo investigate the role of obstetric and neonatal complications in the aetiology of mild to moderate intellectual disability.MethodObstetric and neonatal complications recorded at the time of pregnancy and delivery were compared between participants with mild to moderate intellectual disability, age-matched siblings and unrelated controls using logistic regression.ResultsAdmission to a special care baby unit and not being breastfed on discharge were more common in people with mild to moderate intellectual disability. Not being breastfed on discharge was also more common in those with intellectual disability than unaffected siblings. Foetal distress was more common among controls than among those with mild to moderate intellectual disability.ConclusionsAdmission to a special care baby unit and not being breastfed on discharge may be related to the aetiology of intellectual disability, although the direction of this association is unclear.

scholarly journals Does clozapine cause or worsen obsessive compulsive symptoms? An analysis and literature review

2011 ◽  
Vol 1 (6) ◽  
pp. 181-188 ◽  
Author(s):  
Stephen Bleakley ◽  
David Brown ◽  
David Taylor
Keyword(s):  
Obsessive Compulsive Disorder ◽  
De Novo ◽  
Case Reports ◽  
Obsessive Compulsive ◽  
Cross Sectional ◽  
Obsessive Compulsive Symptoms ◽  
Compulsive Disorder ◽  
Clozapine Treatment ◽  
Increased Risk ◽  
The Common

Background: Clozapine is the most effective antipsychotic in treatment-resistant schizophrenia but its use portends with a high burden of adverse reactions. One adverse event reported both in case reports and cross-sectional surveys is the emergence or worsening of obsessive compulsive symptoms (OCS). Objectives: This study presents a retrospective review of a UK cohort of clozapine-treated individuals with the aim to further investigate the complex relationship between clozapine and OCS. Methods: An extensive review of the medical records of 49 patients receiving clozapine in the Southampton area was undertaken. We searched for a diagnosis of obsessive compulsive disorder, signs or symptoms of obsessive compulsive disorder or the prescribing of selected antidepressants the year before clozapine initiation and the year after. Results: Fifteen patients (31%) had reports of OCS during the 2-year data collection period. Twelve patients (24%) had OCS before clozapine initiation while only 7 (14%) had symptoms after clozapine was initiated. De novo OCS were reported in three (6%) cases after 5–9 months of clozapine treatment. Conclusions: As with previous studies it was not possible to establish a definitive link between clozapine and OCS. Clinicians should be mindful of the common comorbidity of OCS and schizophrenia and the possible increased risk incurred when starting clozapine.

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