A variant in TAF1 is associated with a new syndrome with severe intellectual disability and characteristic dysmorphic features

We describe the discovery of a new genetic syndrome, RykDax syndrome, driven by a whole genome sequencing (WGS) study of one family from Utah with two affected male brothers, presenting with severe intellectual disability (ID), a characteristic intergluteal crease, and very distinctive facial features including a broad, upturned nose, sagging cheeks, downward sloping palpebral fissures, prominent periorbital ridges, deep-set eyes, relative hypertelorism, thin upper lip, a high-arched palate, prominent ears with thickened helices, and a pointed chin. This Caucasian family was recruited from Utah, USA. Illumina-based WGS was performed on 10 members of this family, with additional Complete Genomics-based WGS performed on the nuclear portion of the family (mother, father and the two affected males). Using WGS datasets from 10 members of this family, we can increase the reliability of the biological inferences with an integrative bioinformatic pipeline. In combination with insights from clinical evaluations and medical diagnostic analyses, these DNA sequencing data were used in the study of three plausible genetic disease models that might uncover genetic contribution to the syndrome. We found a 2 to 5-fold difference in the number of variants detected as being relevant for various disease models when using different sets of sequencing data and analysis pipelines. We derived greater accuracy when more pipelines were used in conjunction with data encompassing a larger portion of the family, with the number of putative de-novo mutations being reduced by 80%, due to false negative calls in the parents. The boys carry a maternally inherited missense variant in a X-chromosomal gene TAF1, which we consider as disease relevant. TAF1 is the largest subunit of the general transcription factor IID (TFIID) multi-protein complex, and our results implicate mutations in TAF1 as playing a critical role in the development of this new intellectual disability syndrome.

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De Novo Mutations in Moderate or Severe Intellectual Disability

PLoS Genetics ◽

10.1371/journal.pgen.1004772 ◽

2014 ◽

Vol 10 (10) ◽

pp. e1004772 ◽

Cited By ~ 219

Author(s):

Fadi F. Hamdan ◽

Myriam Srour ◽

Jose-Mario Capo-Chichi ◽

Hussein Daoud ◽

Christina Nassif ◽

...

Keyword(s):

Intellectual Disability ◽

De Novo ◽

De Novo Mutations ◽

Severe Intellectual Disability

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De Novo Mutations in the Genome Organizer CTCF Cause Intellectual Disability

The American Journal of Human Genetics ◽

10.1016/j.ajhg.2013.05.007 ◽

2013 ◽

Vol 93 (1) ◽

pp. 124-131 ◽

Cited By ~ 75

Author(s):

Anne Gregor ◽

Martin Oti ◽

Evelyn N. Kouwenhoven ◽

Juliane Hoyer ◽

Heinrich Sticht ◽

...

Keyword(s):

Intellectual Disability ◽

De Novo ◽

De Novo Mutations

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IL1RAPL1 Gene Deletion in a Female Patient with Developmental Delay and Continuous Spike-Wave during Sleep

Journal of Pediatric Epilepsy ◽

10.1055/s-0041-1731816 ◽

2021 ◽

Author(s):

Evan Jiang ◽

Mark P. Fitzgerald ◽

Katherine L. Helbig ◽

Ethan M. Goldberg

Keyword(s):

Intellectual Disability ◽

Developmental Delay ◽

Synapse Formation ◽

De Novo ◽

Interleukin 1 ◽

Autism Spectrum ◽

Neurological Dysfunction ◽

Behavioral Disorder ◽

Clinical Genetic ◽

Severe Intellectual Disability

AbstractInterleukin-1 receptor accessory protein-like 1 (IL1RAPL1) encodes a protein that is highly expressed in neurons and has been shown to regulate neurite outgrowth as well as synapse formation and synaptic transmission. Clinically, mutations in or deletions of IL1RAPL1 have been associated with a spectrum of neurological dysfunction including autism spectrum disorder and nonsyndromic X-linked developmental delay/intellectual disability of varying severity. Nearly all reported cases are in males; in the few reported cases involving females, the clinical presentation was mild or the deletion was identified in phenotypically normal carriers in accordance with X-linked inheritance. Using genome-wide microarray analysis, we identified a novel de novo 373 kb interstitial deletion of the X chromosome (Xp21.1-p21.2) that includes exons 4 to 6 of the IL1RAPL1 gene in an 8-year-old girl with severe intellectual disability and behavioral disorder with a history of developmental regression. Overnight continuous video electroencephalography revealed electrical status epilepticus in sleep (ESES). This case expands the clinical genetic spectrum of IL1RAPL1-related neurodevelopmental disorders and highlights a new genetic association of ESES.

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Trio deep-sequencing does not reveal unexpected off-target and on-target mutations in Cas9-edited rhesus monkeys

Nature Communications ◽

10.1038/s41467-019-13481-y ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 8

Author(s):

Xin Luo ◽

Yaoxi He ◽

Chao Zhang ◽

Xiechao He ◽

Lanzhen Yan ◽

...

Keyword(s):

Rhesus Monkeys ◽

De Novo ◽

Preclinical Model ◽

Structural Variants ◽

Sequencing Data ◽

De Novo Mutations ◽

Target Region ◽

Long Read ◽

Target Effect

AbstractCRISPR-Cas9 is a widely-used genome editing tool, but its off-target effect and on-target complex mutations remain a concern, especially in view of future clinical applications. Non-human primates (NHPs) share close genetic and physiological similarities with humans, making them an ideal preclinical model for developing Cas9-based therapies. However, to our knowledge no comprehensive in vivo off-target and on-target assessment has been conducted in NHPs. Here, we perform whole genome trio sequencing of Cas9-treated rhesus monkeys. We only find a small number of de novo mutations that can be explained by expected spontaneous mutations, and no unexpected off-target mutations (OTMs) were detected. Furthermore, the long-read sequencing data does not detect large structural variants in the target region.

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Three intellectual disability-associated de novo mutations in MECP2 identified by trio-WES analysis

BMC Medical Genetics ◽

10.1186/s12881-020-01042-w ◽

2020 ◽

Vol 21 (1) ◽

Author(s):

Yi Gu ◽

Bingwu Xiang ◽

Lina Zhu ◽

Xiuwei Ma ◽

Xiang Chen ◽

...

Keyword(s):

Intellectual Disability ◽

De Novo ◽

De Novo Mutations

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De novo mutations in the SET nuclear proto-oncogene, encoding a component of the inhibitor of histone acetyltransferases (INHAT) complex in patients with nonsyndromic intellectual disability

Human Mutation ◽

10.1002/humu.23541 ◽

2018 ◽

Vol 39 (7) ◽

pp. 1014-1023 ◽

Cited By ~ 5

Author(s):

Servi J.C. Stevens ◽

Vyne van der Schoot ◽

Magalie S. Leduc ◽

Tuula Rinne ◽

Seema R. Lalani ◽

...

Keyword(s):

Intellectual Disability ◽

De Novo ◽

Histone Acetyltransferases ◽

De Novo Mutations

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A Novel SETBP1 Gene Disruption by a De Novo Balanced Translocation in a Patient with Speech Impairment, Intellectual, and Behavioral Disorder

Journal of Pediatric Genetics ◽

10.1055/s-0040-1715639 ◽

2020 ◽

Author(s):

Ivona Vrkić Boban ◽

Futoshi Sekiguchi ◽

Mirela Lozić ◽

Noriko Miyake ◽

Naomichi Matsumoto ◽

...

Keyword(s):

Intellectual Disability ◽

Autosomal Dominant ◽

De Novo ◽

Chromosomal Abnormalities ◽

Chromosome Translocation ◽

Behavioral Disorder ◽

Behavioral Difficulties ◽

Speech Impairment ◽

Balanced Translocation ◽

Severe Intellectual Disability

AbstractBalanced chromosomal abnormalities (BCAs) can disrupt gene function resulting in disease. To date, BCA disrupting the SET binding protein 1 (SETBP1) gene has not been reported. On the other hand, de novo heterozygous variants in the highly conserved 11-bp region in SETBP1 can result in the Schinzel–Giedion syndrome. This condition is characterized by severe intellectual disability, a characteristic face, and multiple-system anomalies. Further other types of mutations involving SETBP1 are associated with a different phenotype, mental retardation, autosomal dominant 29 (MRD29), which has mild dysmorphic features, developmental delay, and behavioral disorders. Here we report a male patient who has moderate intellectual disability, mild behavioral difficulties, and severe expressive speech impairment resulting from a de novo balanced chromosome translocation, t(12;18)(q22;q12.3). By whole genome sequencing, we determined the breakpoints at the nucleotide level. The 18q12.3 breakpoint was located between exons 2 and 3 of SETBP1. Phenotypic features of our patient are compatible with those with MRD29. This is the first reported BCA disrupting SETBP1.

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Computational Approaches for Transcriptome Assembly Based on Sequencing Technologies

Current Bioinformatics ◽

10.2174/1574893614666190410155603 ◽

2020 ◽

Vol 15 (1) ◽

pp. 2-16

Author(s):

Yuwen Luo ◽

Xingyu Liao ◽

Fang-Xiang Wu ◽

Jianxin Wang

Keyword(s):

De Novo ◽

Transcriptome Assembly ◽

Critical Role ◽

High Sensitivity ◽

Biological Properties ◽

Sequencing Data ◽

Sequencing Technologies ◽

Long Reads ◽

Massive Sequencing ◽

Generation Sequencing

Transcriptome assembly plays a critical role in studying biological properties and examining the expression levels of genomes in specific cells. It is also the basis of many downstream analyses. With the increase of speed and the decrease in cost, massive sequencing data continues to accumulate. A large number of assembly strategies based on different computational methods and experiments have been developed. How to efficiently perform transcriptome assembly with high sensitivity and accuracy becomes a key issue. In this work, the issues with transcriptome assembly are explored based on different sequencing technologies. Specifically, transcriptome assemblies with next-generation sequencing reads are divided into reference-based assemblies and de novo assemblies. The examples of different species are used to illustrate that long reads produced by the third-generation sequencing technologies can cover fulllength transcripts without assemblies. In addition, different transcriptome assemblies using the Hybrid-seq methods and other tools are also summarized. Finally, we discuss the future directions of transcriptome assemblies.

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