The Genetics of Intellectual Disability

Jansen, Sandra; Vissers, Lisenka E.L.M.; Vries, Bert B.A. de

doi:10.3390/brainsci13020231

Cited by 26 publications

(10 citation statements)

References 129 publications

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“…To accurately delineate the severity of ID in most patients, it is essential to assess both adaptive functioning and IQ [ 56 ]. Approximately 2–3% of the worldwide population is affected by ID (IQ < 70) [ 57 ]. Due to ID’s genetically heterogeneous nature, a genetic basis can be quite challenging to reach.…”

Section: Resultsmentioning

confidence: 99%

Trisomy 22 Mosaicism from Prenatal to Postnatal Findings: A Case Series and Systematic Review of the Literature

Trevisan,

Meroni,

Leoni

et al. 2024

Genes

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Background: Among aneuploidies compatible with life, trisomy 22 mosaicism is extremely rare, and only about 25 postnatal and 18 prenatal cases have been described in the literature so far. The condition is mainly characterized by facial and body asymmetry, cardiac heart defects, facial dysmorphisms, growth failure, delayed puberty, and variable degrees of neurodevelopmental delay. Problem: The scattered information regarding the condition and the dearth of data on its natural history and developmental outcomes restrict genetic counseling, particularly in prenatal settings. Moreover, a prompt diagnosis is frequently delayed by the negative selection of trisomic cells in blood, with mosaicism percentage varying among tissues, which often entails the need for further testing. Purpose/topic: The aim of our work is to provide assistance in prenatal and postnatal genetic counseling by systematically delineating the current knowledge of the condition. This entails defining the prenatal and postnatal characteristics of the condition and presenting novel data from three cases, both prenatally and postnatally. Additionally, we report the developmental outcomes observed in two new patients.

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Section: Resultsmentioning

confidence: 99%

Trisomy 22 Mosaicism from Prenatal to Postnatal Findings: A Case Series and Systematic Review of the Literature

Trevisan,

Meroni,

Leoni

et al. 2024

Genes

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“…ID is a genetically heterogeneous disease with up to 700 genes linked to it or associated disorders by 2015 [4], and around 1,300 genes listed in the approved gene panel for ID (v5.0 from 22 March 2023) available at Genomics England’s PanelApp [5]. However, the prevailing view is that more ID-causal genes are yet to be discovered, and the effects of all possible mutations within ID-causing genes have not yet been assessed [4, 6, 7]. Searching and describing novel rare mutations inside known ID genes and identifying new candidate genes may improve the molecular diagnosis of ID and lead to a better understanding of the underlying molecular disease mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Rare splice and missense variants with evidence of pathogenicity in consanguineous families with autosomal recessive intellectual disability from Pakistan

Waheed,

Eveleigh,

Perley

et al. 2024

Preprint

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Intellectual disability (ID) is a neurodevelopmental disorder affecting up to 1-3% of people worldwide. Genetic factors, including rare de novo or rare homozygous mutations, explain many cases of autosomal dominant or recessive forms of ID. ID is clinically and genetically heterogeneous, with hundreds of genes associated with it. In this study, we performed high-depth whole-genome sequencing of twenty individuals from five consanguineous families from Pakistan, with nine individuals affected by mild or severe ID. We identified one splice and five missense rare variants (at allele frequencies below 0.001%) in a homozygous state in the affected individuals with supporting and moderate evidence of pathogenicity based on guidance from the American College of Medical Genetics and Genomics. These six variants mapped to different genes (SRD5A3, RDH11, RTF2, PCDHA2, ADAMTS17, and TRPC3), and only SRD5A3 had previously been known to cause ID. The p.Tyr169Cys mutation inside SRD5A3 was predicted to be deleterious and affect protein structure by multiple in silico tools. In addition, we found one missense mutation, p.Pro1505Ser, inside UNC13B with conflicting evidence of pathogenic and benign effects. Further functional studies are required to confirm the pathogenicity of these variants and understand their role in ID. Our findings provide additional needed information for interpreting rare variants in the genetic testing of ID.

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“…(9) Burden analysis studies in large cohorts of NDD patients are a powerful approach to identify novel candidate genes. (9,10) These studies generate impressive lists of genes that are statistically proven or at least likely to play a role in NDD. However, it remains di cult to report variants in any of these candidate genes as a diagnostic result as the gene is not (yet) associated with any speci c phenotype.…”

Section: Introductionmentioning

confidence: 99%

Burden re-analysis of neurodevelopmental disorder cohorts for prioritization of candidate genes and establishment of LEO1 as a novel disease gene

Weckhuysen,

smal,

Majdoub

et al. 2024

Preprint

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This study aimed to uncover novel genes associated with neurodevelopmental disorders (NDD) by leveraging recent large-scale de novo burden analysis studies to enhance a virtual gene panel used in a diagnostic setting. We re-analyzed historical trio-exome sequencing data from 745 individuals with NDD according to the most recent diagnostic standards, resulting in a cohort of 567 unsolved individuals. Next, we designed a virtual gene panel containing candidate genes from three large de novo burden analysis studies in NDD and prioritized candidate genes by stringent filtering for ultra-rare de novo variants with high pathogenicity scores. Our analysis revealed an increased burden of de novo variants in our selected candidate genes within the unsolved NDD cohort and identified qualifying de novo variants in seven candidate genes: RIF1, CAMK2D, RAB11FIP4, AGO3, PCBP2, LEO1, and VCP. Clinical data were collected from six new individuals with de novo or inherited LEO1 variants and three new individuals with de novo PCBP2 variants. Our findings confirm LEO1 as a risk gene for autism and intellectual disability. Furthermore, we prioritize PCBP2 as a candidate gene for NDD associated with motor and language delay. In summary, by leveraging de novo burden analysis studies, employing a stringent variant filtering pipeline, and engaging in targeted patient recruitment, our study contributes to the identification of novel genes implicated in NDDs.

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The Genetics of Intellectual Disability

Cited by 26 publications

References 129 publications

Trisomy 22 Mosaicism from Prenatal to Postnatal Findings: A Case Series and Systematic Review of the Literature

Trisomy 22 Mosaicism from Prenatal to Postnatal Findings: A Case Series and Systematic Review of the Literature

Rare splice and missense variants with evidence of pathogenicity in consanguineous families with autosomal recessive intellectual disability from Pakistan

Burden re-analysis of neurodevelopmental disorder cohorts for prioritization of candidate genes and establishment of LEO1 as a novel disease gene

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