Xp11.22 deletions encompassing CENPVL1, CENPVL2, MAGED1 and GSPT2 as a cause of syndromic X-linked intellectual disability

Grau, C. R.; Starkovich, Molly; Azamian, Mahshid S.; Xia, Fan; Cheung, Sau Wai; Evans, Patricia; Henderson, Alex; Lalani, Seema R.; Scott, Daryl A.

doi:10.1371/journal.pone.0175962

Cited by 14 publications

(13 citation statements)

References 57 publications

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“…To further narrow the list of candidate disease-causing genes, we considered the following factors: (1) the number of de novo CNVs determined for each gene (Additional files 1 and 2 ); (2) additional CNVs < 5 Mb in size found in our cohort; (3) LOF variants found in ~ 15,000 WES cases (from BG and BHCMG “disease cohorts”); (4) phenotypic overlap among patients; (5) literature records supporting disease association; (6) predictions of haploinsufficiency [ 51 ] and intolerance to LOF [ 50 ] of the identified variants. Using these criteria, we found evidence supporting the contention of recently published disease genes, including BPTF (OMIM* 601819) [ 59 ], NONO (OMIM* 300084) [ 60 ], PSMD12 (OMIM* 604450) [ 61 ], TANGO2 (OMIM* 616830) [ 62 , 63 ], TRIP12 (OMIM* 604506) [ 64 , 65 ], and likely MAGED1 (OMIM* 300224) [ 66 ]. Furthermore, we found genes recently reported as disease-associated, including TBR1 (OMIM* 604616) [ 67 ] and CLTCL1 (OMIM* 601273) [ 68 ], as well as genes not yet associated with diseases.…”

Section: Resultssupporting

confidence: 75%

Identification of novel candidate disease genes from de novo exonic copy number variants

Gambin¹,

Yuan²,

Bi³

et al. 2017

Genome Med

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BackgroundExon-targeted microarrays can detect small (<1000 bp) intragenic copy number variants (CNVs), including those that affect only a single exon. This genome-wide high-sensitivity approach increases the molecular diagnosis for conditions with known disease-associated genes, enables better genotype–phenotype correlations, and facilitates variant allele detection allowing novel disease gene discovery.MethodsWe retrospectively analyzed data from 63,127 patients referred for clinical chromosomal microarray analysis (CMA) at Baylor Genetics laboratories, including 46,755 individuals tested using exon-targeted arrays, from 2007 to 2017. Small CNVs harboring a single gene or two to five non-disease-associated genes were identified; the genes involved were evaluated for a potential disease association.ResultsIn this clinical population, among rare CNVs involving any single gene reported in 7200 patients (11%), we identified 145 de novo autosomal CNVs (117 losses and 28 intragenic gains), 257 X-linked deletion CNVs in males, and 1049 inherited autosomal CNVs (878 losses and 171 intragenic gains); 111 known disease genes were potentially disrupted by de novo autosomal or X-linked (in males) single-gene CNVs. Ninety-one genes, either recently proposed as candidate disease genes or not yet associated with diseases, were disrupted by 147 single-gene CNVs, including 37 de novo deletions and ten de novo intragenic duplications on autosomes and 100 X-linked CNVs in males. Clinical features in individuals with de novo or X-linked CNVs encompassing at most five genes (224 bp to 1.6 Mb in size) were compared to those in individuals with larger-sized deletions (up to 5 Mb in size) in the internal CMA database or loss-of-function single nucleotide variants (SNVs) detected by clinical or research whole-exome sequencing (WES). This enabled the identification of recently published genes (BPTF, NONO, PSMD12, TANGO2, and TRIP12), novel candidate disease genes (ARGLU1 and STK3), and further confirmation of disease association for two recently proposed disease genes (MEIS2 and PTCHD1). Notably, exon-targeted CMA detected several pathogenic single-exon CNVs missed by clinical WES analyses.ConclusionsTogether, these data document the efficacy of exon-targeted CMA for detection of genic and exonic CNVs, complementing and extending WES in clinical diagnostics, and the potential for discovery of novel disease genes by genome-wide assay.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-017-0472-7) contains supplementary material, which is available to authorized users.

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Section: Resultssupporting

confidence: 75%

Identification of novel candidate disease genes from de novo exonic copy number variants

Gambin¹,

Yuan²,

Bi³

et al. 2017

Genome Med

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“…To investigate the potential involvement of human 16p11.2 BP4-BP5 duplication in CVMs, we retrospectively reviewed the subjects with the 16p11.2 BP4-BP5 duplication from a large cohort of patients that were tested clinically by CMA due to various medical problems 46 47. The spinal X-ray images were available for seven 16p11.2 BP4-BP5 duplication carriers (figure 1A).…”

Section: Resultsmentioning

confidence: 99%

IncreasedTBX6gene dosages induce congenital cervical vertebral malformations in humans and mice

Ren

Yang

et al. 2019

J Med Genet

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BackgroundCongenital vertebral malformations (CVMs) manifest with abnormal vertebral morphology. Genetic factors have been implicated in CVM pathogenesis, but the underlying pathogenic mechanisms remain unclear in most subjects. We previously reported that the human 16p11.2 BP4-BP5 deletion and its associated TBX6 dosage reduction caused CVMs. We aim to investigate the reciprocal 16p11.2 BP4-BP5 duplication and its potential genetic contributions to CVMs.Methods and resultsPatients who were found to carry the 16p11.2 BP4-BP5 duplication by chromosomal microarray analysis were retrospectively analysed for their vertebral phenotypes. The spinal assessments in seven duplication carriers showed that four (57%) presented characteristics of CVMs, supporting the contention that increased TBX6 dosage could induce CVMs. For further in vivo functional investigation in a model organism, we conducted genome editing of the upstream regulatory region of mouse Tbx6 using CRISPR-Cas9 and obtained three mouse mutant alleles (Tbx6up1 to Tbx6up3) with elevated expression levels of Tbx6. Luciferase reporter assays showed that the Tbx6up3 allele presented with the 160% expression level of that observed in the reference (+) allele. Therefore, the homozygous Tbx6up3/up3 mice could functionally mimic the TBX6 dosage of heterozygous carriers of 16p11.2 BP4-BP5 duplication (approximately 150%, ie, 3/2 gene dosage of the normal level). Remarkably, 60% of the Tbx6up3/up3 mice manifested with CVMs. Consistent with our observations in humans, the CVMs induced by increased Tbx6 dosage in mice mainly affected the cervical vertebrae.ConclusionOur findings in humans and mice consistently support that an increased TBX6 dosage contributes to the risk of developing cervical CVMs.

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“…In our case, seven of the eight Chr X inversions analyzed are located in regions where additional disease-associated SVs have been described (Supplemental Table S13). These involve recurrent mutations mediated by repeats within the polymorphic inversions, like the hemophilia A inversion (Antonarakis et al 1995) or the deletion causing incontinentia pigmenti (Aradhya et al 2001), different duplication-inverted triplication-duplication (DUP-TRP/INV-DUP) rearrangements due to DNA polymerase stalling during IR replication that affect dose-sensitive genes such as MECP2 and PLP1 (Carvalho et al 2011;Beck et al 2015), or deletions with one breakpoint mapping within or nearby the inversion IRs involved in X-linked intellectual disability (Grau et al 2017). Specifically, within the 6-Mb Xq28 telomeric region, there are seven genomic disorders caused by rearrangements overlapping or in close proximity to four polymorphic inversions (Deeb et al 1992;Bondeson et al 1995;Small et al 1997;Aradhya et al 2001;Clapham et al 2012;Fusco et al 2012;Li et al 2015a), making this region a possible hotspot for genome reorganization (Fig.…”

Section: Discussionmentioning

confidence: 99%

Determining the impact of uncharacterized inversions in the human genome by droplet digital PCR

et al. 2020

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Despite the interest in characterizing genomic variation, the presence of large repeats at the breakpoints hinders the analysis of many structural variants. This is especially problematic for inversions, since there is typically no gain or loss of DNA. Here, we tested novel linkage-based droplet digital PCR (ddPCR) assays to study 20 inversions ranging from 3.1 to 742 kb flanked by inverted repeats (IRs) up to 134 kb long. Of those, we validated 13 inversions predicted by different genome-wide techniques. In addition, we obtained new experimental human population information across 95 African, European, and East Asian individuals for 16 inversions, including four already validated variants without high-throughput genotyping methods. Through comparison with previous data, independent replicates and both inversion breakpoints, we demonstrate that the technique is highly accurate and reproducible. Most studied inversions are widespread across continents, and their frequency is negatively correlated with genetic length. Moreover, all except two show clear signs of being recurrent, and we could better define the factors affecting recurrence levels and estimate the inversion rate across the genome. Finally, the generated genotypes have allowed us to check inversion functional effects, validating gene expression differences reported before for two inversions and finding new candidate associations. Therefore, the developed methodology makes it possible to screen these and other complex genomic variants quickly in a large number of samples for the first time, highlighting the importance of direct genotyping to assess their potential consequences and clinical implications.

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Xp11.22 deletions encompassing CENPVL1, CENPVL2, MAGED1 and GSPT2 as a cause of syndromic X-linked intellectual disability

Cited by 14 publications

References 57 publications

Identification of novel candidate disease genes from de novo exonic copy number variants

Identification of novel candidate disease genes from de novo exonic copy number variants

IncreasedTBX6gene dosages induce congenital cervical vertebral malformations in humans and mice

Determining the impact of uncharacterized inversions in the human genome by droplet digital PCR

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