BBGRE: brain and body genetic resource exchange

Ahn, Joo Wook; Dixit, Abhishek; Johnston, Caroline; Ogilvie, Caroline Mackie; Collier, David A.; Curran, Sarah; Dobson, Richard

doi:10.1093/database/bat067

Cited by 4 publications

(5 citation statements)

References 14 publications

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“…They are used for estimating the ratios between maternal and paternal duplications. “new data” indicate cases/cohort analysed for the purpose of the current study BBGRE: Brain & Body Genetic Resource Exchange, https://bbgre.brc.iop.kcl.ac.uk/ , Ahn et al [ 18 ] …”

Section: Resultsmentioning

confidence: 99%

“…Among 51,001 probands with DD/ASD/MCA from two large studies on referrals to clinical genetics clinics with DD/ASD/MCA [ 18 , 21 ], two from ASD cohorts and the current study [ 5 , 17 ], 53 (0.1%) had an interstitial 15q11.2-q13.3 duplication. Isodicentric chr15 (idic15) and interstitial triplications reported in these 51,001 probands (N = 6) were excluded from analysis, while no triplications were observed in SZ or control subjects.…”

Section: Resultsmentioning

confidence: 99%

“…We established the parental origin of 15q11.2-q13.3 duplications for carriers from studies where it was previously unknown or not reported ( Table 1 and S1 Table ). These were the studies/datasets by Gawlick, Alexic, the BBGRE database [ 18 ] ( https://bbgre.brc.iop.kcl.ac.uk/ ), and new carriers in the Icelandic population and three published datasets [ 12 , 16 , 23 ]. Parental origin was established by one of several methods.…”

Section: Methodsmentioning

confidence: 99%

“…In the Icelandic sample parental origin was either determined with methylation-sensitive Southern analysis [ 5 ] or by long-range haplotype analysis ( S1 Text ). Microsatellite analysis was used for the BBGRE dataset [ 18 ].…”

Section: Methodsmentioning

confidence: 99%

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Parental Origin of Interstitial Duplications at 15q11.2-q13.3 in Schizophrenia and Neurodevelopmental Disorders

et al. 2016

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Duplications at 15q11.2-q13.3 overlapping the Prader-Willi/Angelman syndrome (PWS/AS) region have been associated with developmental delay (DD), autism spectrum disorder (ASD) and schizophrenia (SZ). Due to presence of imprinted genes within the region, the parental origin of these duplications may be key to the pathogenicity. Duplications of maternal origin are associated with disease, whereas the pathogenicity of paternal ones is unclear. To clarify the role of maternal and paternal duplications, we conducted the largest and most detailed study to date of parental origin of 15q11.2-q13.3 interstitial duplications in DD, ASD and SZ cohorts. We show, for the first time, that paternal duplications lead to an increased risk of developing DD/ASD/multiple congenital anomalies (MCA), but do not appear to increase risk for SZ. The importance of the epigenetic status of 15q11.2-q13.3 duplications was further underlined by analysis of a number of families, in which the duplication was paternally derived in the mother, who was unaffected, whereas her offspring, who inherited a maternally derived duplication, suffered from psychotic illness. Interestingly, the most consistent clinical characteristics of SZ patients with 15q11.2-q13.3 duplications were learning or developmental problems, found in 76% of carriers. Despite their lower pathogenicity, paternal duplications are less frequent in the general population with a general population prevalence of 0.0033% compared to 0.0069% for maternal duplications. This may be due to lower fecundity of male carriers and differential survival of embryos, something echoed in the findings that both types of duplications are de novo in just over 50% of cases. Isodicentric chromosome 15 (idic15) or interstitial triplications were not observed in SZ patients or in controls. Overall, this study refines the distinct roles of maternal and paternal interstitial duplications at 15q11.2-q13.3, underlining the critical importance of maternally expressed imprinted genes in the contribution of Copy Number Variants (CNVs) at this interval to the incidence of psychotic illness. This work will have tangible benefits for patients with 15q11.2-q13.3 duplications by aiding genetic counseling.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Parental Origin of Interstitial Duplications at 15q11.2-q13.3 in Schizophrenia and Neurodevelopmental Disorders

et al. 2016

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“…We have previously described the protocols, analysis, and interpretation using an Agilent oligonucleotide array 60K platform (AMAID 028469 and 017457) and a patient versus patient hybridization strategy and 3‐probe minimum aberration call in Ahn et al. (, ). The average probe density over ELP4 is 8.5 Kb, giving a limit of around 25 Kb for detection.…”

Section: Methodsmentioning

confidence: 99%

Microdeletions ofELP4Are Associated with Language Impairment, Autism Spectrum Disorder, and Mental Retardation

et al. 2015

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Copy-number variations (CNVs) are important in the aetiology of neurodevelopmental disorders and show broad phenotypic manifestations. We compared the presence of small CNVs disrupting the ELP4-PAX6 locus in 4,092 UK individuals with a range of neurodevelopmental conditions, clinically referred for array comparative genomic hybridization, with WTCCC controls (n = 4,783). The phenotypic analysis was then extended using the DECIPHER database. We followed up association using an autism patient cohort (n = 3,143) compared with six additional control groups (n = 6,469). In the clinical discovery series, we identified eight cases with ELP4 deletions, and one with a partial duplication of ELP4 and PAX6. These cases were referred for neurological phenotypes including language impairment, developmental delay, autism, and epilepsy. Six further cases with a primary diagnosis of autism spectrum disorder (ASD) and similar secondary phenotypes were identified with ELP4 deletions, as well as another six (out of nine) with neurodevelopmental phenotypes from DECIPHER. CNVs at ELP4 were only present in 1/11,252 controls. We found a significant excess of CNVs in discovery cases compared with controls, P = 7.5 × 10(-3) , as well as for autism, P = 2.7 × 10(-3) . Our results suggest that ELP4 deletions are highly likely to be pathogenic, predisposing to a range of neurodevelopmental phenotypes from ASD to language impairment and epilepsy.

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Impact of intragenicNRXN1deletions on early cortical development

Dutan,

Gatford,

Carneiro

et al. 2024

Preprint

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BackgroundDeletions inNRXN1are strongly associated with neurodevelopmental and psychiatric conditions. While exonic deletions are well-studied, intragenic deletions, particularly in intron 5, are less understood and generally consider benign. Recent studies show exonic deletions impact isoform diversity during neurodevelopment, affecting neurogenesis and neuronal function. However, whether intragenic deletions impact isoform expression and neurodevelopment remains underexplored.MethodsWe used hiPSCs from typically developing individuals (control) and those withNRXN1intron 5 deletions to study neurodevelopment. HiPSCs were differentiated towards a cortical fate, withNRXN1isoform expression, molecular differences, and neuronal morphology examined.ResultsWe observed distinctNRXN1isoform expression dynamics during early neurodevelopment, with two expression peaks post-neuronal induction andNRXN1βbeing most highly expressed. BothNRXN1deletion and control lines showed similar acquisition of regional and cell fate identity, but significant differences inNRXN1isoform expression were observed between deletion and control lines, and between deletion lines. RNA sequencing revealed genotype-dependent alterations, particularly in pathways related to synaptic function and neuronal morphology. Consistent with these findings,NRXN1deletion lines exhibited altered dendrite outgrowth, with variations between deletion lines.ConclusionsOur results indicate a potential role for intron 5 in controllingNRXN1isoform expression during neurodevelopment. Alterations in gene expression profiles, correlated with morphological changes, suggest a role forNRXN1isoforms in shaping dendritic morphology. Molecular and cellular differences observed between lines with identical intronic deletions suggest that additional factors, such as genetic background or biological sex, may also play an important role in these phenotypes. Collectively, these findings indicate thatNRXN1intronic deletions are not benign, influencing isoform expression, cellular phenotypes, and neurodevelopment.

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BBGRE: brain and body genetic resource exchange

Cited by 4 publications

References 14 publications

Parental Origin of Interstitial Duplications at 15q11.2-q13.3 in Schizophrenia and Neurodevelopmental Disorders

Parental Origin of Interstitial Duplications at 15q11.2-q13.3 in Schizophrenia and Neurodevelopmental Disorders

Microdeletions ofELP4Are Associated with Language Impairment, Autism Spectrum Disorder, and Mental Retardation

Impact of intragenicNRXN1deletions on early cortical development

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