Pathogenic intronic splice-affecting variants in MYBPC3 in three patients with hypertrophic cardiomyopathyCitation formats

  • External authors:
  • Katherine Wood
  • Huw Thomas
  • James Eden

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Pathogenic intronic splice-affecting variants in MYBPC3 in three patients with hypertrophic cardiomyopathy. / Newman, William; Wood, Katherine; Thomas, Huw; Ellingford, Jamie; O'Keefe, Raymond; Hopton, Claire; Eden, James.

In: Cardiogenetics, Vol. 11, No. 2, 02.06.2021, p. 73-83.

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@article{bc050dfbe2e943ca9da04b280f3c4172,
title = "Pathogenic intronic splice-affecting variants in MYBPC3 in three patients with hypertrophic cardiomyopathy",
abstract = "Genetic variants in MYBPC3 are one of the most common causes of hypertrophic cardiomyopathy (HCM). While variants in MYBPC3 affecting canonical splice site dinucleotides are a well-characterised cause of HCM, only recently has work begun to investigate the pathogenicity of more deeply intronic variants. Here, we present three patients with HCM and intronic splice-affecting MYBPC3 variants and analyse the impact of variants on splicing using in vitro minigene assays. We show that the three variants, a novel c.927-8G>A variant and the previously reported c.1624+4A>T and c.3815-10T>G variants, result in MYBPC3 splicing errors. Analysis of blood-derived patient RNA for the c.3815-10T>G variant revealed only wild type spliced product, indicating that mis-spliced transcripts from the mutant allele are degraded. These data indicate that the c.927-8G>A variant of uncertain significance and likely benign c.3815-10T>G should be reclassified as likely pathogenic. Furthermore, we find shortcomings in commonly applied bioinformatics strategies to prioritize variants impacting MYBPC3 splicing and re-emphasize the need for functional assessment of variants of uncertain significance in diagnostic testing.",
author = "William Newman and Katherine Wood and Huw Thomas and Jamie Ellingford and Raymond O'Keefe and Claire Hopton and James Eden",
year = "2021",
month = jun,
day = "2",
doi = "10.3390/cardiogenetics11020009",
language = "English",
volume = "11",
pages = "73--83",
journal = "Cardiogenetics",
issn = "2035-8253",
publisher = "PAGEpress",
number = "2",

}

RIS

TY - JOUR

T1 - Pathogenic intronic splice-affecting variants in MYBPC3 in three patients with hypertrophic cardiomyopathy

AU - Newman, William

AU - Wood, Katherine

AU - Thomas, Huw

AU - Ellingford, Jamie

AU - O'Keefe, Raymond

AU - Hopton, Claire

AU - Eden, James

PY - 2021/6/2

Y1 - 2021/6/2

N2 - Genetic variants in MYBPC3 are one of the most common causes of hypertrophic cardiomyopathy (HCM). While variants in MYBPC3 affecting canonical splice site dinucleotides are a well-characterised cause of HCM, only recently has work begun to investigate the pathogenicity of more deeply intronic variants. Here, we present three patients with HCM and intronic splice-affecting MYBPC3 variants and analyse the impact of variants on splicing using in vitro minigene assays. We show that the three variants, a novel c.927-8G>A variant and the previously reported c.1624+4A>T and c.3815-10T>G variants, result in MYBPC3 splicing errors. Analysis of blood-derived patient RNA for the c.3815-10T>G variant revealed only wild type spliced product, indicating that mis-spliced transcripts from the mutant allele are degraded. These data indicate that the c.927-8G>A variant of uncertain significance and likely benign c.3815-10T>G should be reclassified as likely pathogenic. Furthermore, we find shortcomings in commonly applied bioinformatics strategies to prioritize variants impacting MYBPC3 splicing and re-emphasize the need for functional assessment of variants of uncertain significance in diagnostic testing.

AB - Genetic variants in MYBPC3 are one of the most common causes of hypertrophic cardiomyopathy (HCM). While variants in MYBPC3 affecting canonical splice site dinucleotides are a well-characterised cause of HCM, only recently has work begun to investigate the pathogenicity of more deeply intronic variants. Here, we present three patients with HCM and intronic splice-affecting MYBPC3 variants and analyse the impact of variants on splicing using in vitro minigene assays. We show that the three variants, a novel c.927-8G>A variant and the previously reported c.1624+4A>T and c.3815-10T>G variants, result in MYBPC3 splicing errors. Analysis of blood-derived patient RNA for the c.3815-10T>G variant revealed only wild type spliced product, indicating that mis-spliced transcripts from the mutant allele are degraded. These data indicate that the c.927-8G>A variant of uncertain significance and likely benign c.3815-10T>G should be reclassified as likely pathogenic. Furthermore, we find shortcomings in commonly applied bioinformatics strategies to prioritize variants impacting MYBPC3 splicing and re-emphasize the need for functional assessment of variants of uncertain significance in diagnostic testing.

U2 - 10.3390/cardiogenetics11020009

DO - 10.3390/cardiogenetics11020009

M3 - Article

VL - 11

SP - 73

EP - 83

JO - Cardiogenetics

JF - Cardiogenetics

SN - 2035-8253

IS - 2

ER -