Can tandem alternative splicing and evasion of premature termination codon surveillance contribute to attenuated <scp>Peutz–Jeghers</scp> syndrome?

Gazzaz, Nour; Frost, Frederick G.; Alderman, Emily; Richmond, Phillip A.; Dalmann, Joshua; Lin, Susan; Salman, Areesha; Bel, Kate L. Del; Lehman, Anna; Turvey, Stuart E.; Boerkoel, Cornelius F.; Cherukuri, Praveen F.

doi:10.1002/ajmg.a.62942

Cited by 3 publications

(3 citation statements)

References 20 publications

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“…In this context, it is not possible to predict whether the variant causes exon skipping, moves splicing to the natural alternative AG and is thus benign, or in the case of c.613‐2A>G, creates a new acceptor 1 bp upstream and thus encodes a frameshift variant. Tandem splice acceptor sites (NAGN n AG) are a mechanism of alternative splicing; clinical reporting often fails to note the creation of NAGN n AG tandem splice acceptor sites or to contextualize variants altering them (Bradley et al, 2012; Gazzaz et al, 2022). We hypothesize that the integration of transcript‐aware variant reporting and classification and empiric assessment of splicing variants enables genetic dissection, that is, acts as a forward genetic screen, of complex loci such as PHF21A .…”

Section: Discussionmentioning

confidence: 99%

Naturally occurring splice variants dissect the functional domains of BHC80 and emphasize the need for RNA analysis

Hejla,

Huynh,

Samra

et al. 2024

American J of Med Genetics Pt A

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Pathogenic PHF21A variation causes PHF21A‐related neurodevelopmental disorders (NDDs). Although amorphic alleles, including haploinsufficiency, have been established as a disease mechanism, increasing evidence suggests that missense variants as well as frameshift variants extending the BHC80 carboxyl terminus also cause disease. Expanding on these, we report a proposita with intellectual disability and overgrowth and a novel de novo heterozygous PHF21A splice variant (NM_001352027.3:c.[153+1G>C];[=]) causing skipping of exon 6, which encodes an in‐frame BHC80 deletion (p.(Asn30_Gln51del)). This deletion disrupts a predicted leucine zipper domain and implicates this domain in BHC80 function and as a target of variation causing PHF21A‐related NDDs. This extension of understanding emphasizes the application of RNA analysis in precision genomic medicine practice.

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Section: Discussionmentioning

confidence: 99%

Naturally occurring splice variants dissect the functional domains of BHC80 and emphasize the need for RNA analysis

Hejla,

Huynh,

Samra

et al. 2024

American J of Med Genetics Pt A

Self Cite

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“…Transcriptomic data enables expression analyses and assesses mRNA quality control and splicing, particularly for variants with the potential to alter splicing. Of particular interest are variants that alter splicing without disrupting the canonical or natural splice donor or acceptor (Gazzaz et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

“…Tandem splice acceptor sites (NAGN n AG) are a mechanism of alternative splicing, although clinical reporting often fails to note the creation of NAGN n AG tandem splice acceptor sites or to contextualize them (Gazzaz et al, 2022). The AG splice acceptor site used within an intron is context dependent; often the AG proximate to the polypyrimidine tract is used preferentially, whereas in other situations the choice is stochastic (Bradley et al, 2012; Smith et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

Generation of tandem alternative splice acceptor sites and CLTC haploinsufficiency: A cause of CLTC‐related disorder

Sage,

Lee,

Dalmann

et al. 2023

American J of Med Genetics Pt A

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Tandem splice acceptors (NAGN n AG) are a common mechanism of alternative splicing, but variants that are likely to generate or to disrupt tandem splice sites have rarely been reported as disease causing. We identify a pathogenic intron ];[=]) in a propositus with intellectual disability and behavioral problems. By RNAseq analysis of peripheral blood mRNA, this variant generates transcripts using cryptic proximal splice acceptors (NM_004859.4: r.3765_3766insTTCACAGAAAGGAACTAG, and NM_004859.4: r.3765_3766insAAAGGAACTAG). Given that the propositus expresses 38% the level of CLTC transcripts as unaffected controls, these variant transcripts, which encode premature termination codons, likely undergo nonsense mediated mRNA decay (NMD). This is the first functional evidence for CLTC haploinsufficiency as a cause of CLTC-related disorder and the first evidence that the generation of tandem alternative splice sites causes CLTC-related disorder. We suggest that variants creating tandem alternative splice sites are an underreported disease mechanism and that transcriptome-level analysis should be routinely pursued to define the pathogenicity of such variants.

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A Novel Frameshift Variant of the ELF4 Gene in a Patient with Autoinflammatory Disease: Clinical Features, Transcriptomic Profiling and Functional Studies

Sun,

Han,

et al. 2024

J Clin Immunol

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Can tandem alternative splicing and evasion of premature termination codon surveillance contribute to attenuated Peutz–Jeghers syndrome?

Cited by 3 publications

References 20 publications

Naturally occurring splice variants dissect the functional domains of BHC80 and emphasize the need for RNA analysis

Naturally occurring splice variants dissect the functional domains of BHC80 and emphasize the need for RNA analysis

Generation of tandem alternative splice acceptor sites and CLTC haploinsufficiency: A cause of CLTC‐related disorder

A Novel Frameshift Variant of the ELF4 Gene in a Patient with Autoinflammatory Disease: Clinical Features, Transcriptomic Profiling and Functional Studies

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