Functional testing for variant prioritization in a family with long QT syndrome

Beidokhti, Maliheh Najari; Bertalovitz, Alexander C.; Ji, Weizhen; McCormack, Jorge; Jeffries, Lauren; Sempou, Emily; Khokha, Mustafa K.; McDonald, Thomas V.; Lakhani, Saquib A.

doi:10.1007/s00438-021-01780-3

Cited by 3 publications

(2 citation statements)

References 46 publications

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“…In the families described, it is noteworthy that multiple, severely affected patients carry additional genetic variants or have additional cardiovascular morbidities. This observation is in line with the notion that the KCNH2:p.(Ser906Leu) variant confers a risk towards developing LQTS2, which could be influenced by additional genetic variants as described in various studies [19][20][21].…”

Section: Genetic Heterogeneitysupporting

confidence: 90%

Reclassification of a likely pathogenic Dutch founder variant in KCNH2; implications of reduced penetrance

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Bootsma

et al. 2022

Preprint

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Background: Variants in KCNH2, encoding the hERG channel which is responsible for the rapid component of the cardiac delayed rectifier K+ current (IKr), are causal to Long QT Syndrome type 2 (LQTS2). We identified eight index patients with a new variant of unknown significance (VUS), KCNH2:c.2717C>T:p.(Ser906Leu). We aimed to elucidate the biophysiological effect of this variant, to enable reclassification and consequent clinical decision-making. Methods: A genotype-phenotype overview of the patients and relatives was created. The biophysiological effects were assessed by manual whole-cell patch-clamp using HEK293a cells expressing: (I) wild type (WT) KCNH2, (II) KCNH2-p.S906L alone (homozygous, Hm) or (III) KCNH2-p.S906L in combination with WT (1:1) (heterozygous, Hz). A calibrated automated patch-clamp assay using Flp-In HEK293 was used to follow up on the functional data. Results: Incomplete penetrance of LQTS2 in KCNH2:p.(Ser906Leu) carriers was observed. In addition, some patients were heterozygous for other VUSs in CACNA1C, PKP2, RYR2, or AKAP9. The phenotype of carriers of KCNH2:p.(Ser906Leu) ranged from asymptomatic to life-threatening arrhythmic events. Manual patch-clamp showed a reduced current density by 69.8%, and 60.4% in KCNH2-p.S906L-Hm and KCNH2-p.S906L-Hz, respectively. The time constant of activation was significantly increased with 80.1% in KCNH2-p.S906L-Hm compared to KCNH2-WT. Assessment of KCNH2-p.S906L-Hz, by calibrated automatic patch-clamp showed a reduction in current density by 35.6%. Conclusion: The reduced current density in the KCNH2-p.S906L-Hz indicates a moderate loss of function. Combined with the reduced penetrance and variable phenotype, we conclude that KCNH2:p.(Ser906Leu) is a low penetrant likely pathogenic variant for LQTS2.

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Section: Genetic Heterogeneitysupporting

confidence: 90%

Reclassification of a likely pathogenic Dutch founder variant in KCNH2; implications of reduced penetrance

Copier

Bootsma

et al. 2022

Preprint

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“…Approaches such as ours that focus on children with undiagnosed diseases and couple NGS with laboratory assessments of gene and variant function are adding to the genetic lexicon, thereby improving the clinical diagnostic utility of NGS. While the rate of novel gene discovery in our Diagnosed cohort was 8%, it is worth noting that 56% of Diagnosed patients contributed some novel element to the body of rare disease knowledge, whether through novel variants of known genes, novel modes of inheritance for a condition, or expansion of a given condition's phenotype (AbuBakr et al, 2020; Amabile et al, 2020; Elfar et al, 2019; Kiraly‐Borri et al, 2019; Landim‐Vieira et al, 2019; Marquez et al, 2020; Mis et al, 2020; Mis et al, 2021; Najari Beidokhti et al, 2021; Sega et al, 2019). In addition, the patient‐centered approach of investigating molecular mechanisms underlying a rare disease can shed light on not just that specific condition, but can potentially reveal unexpected insights into normal biology or even into other diseases (Del Viso et al, 2016; Griffin et al, 2018; Kulkarni et al, 2018; Kulkarni & Khokha, 2018; Sempou et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

A retrospective cohort analysis of the Yale pediatric genomics discovery program

Al‐Ali

Jeffries

Faustino

et al. 2022

American J of Med Genetics Pt A

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The Pediatric Genomics Discovery Program (PGDP) at Yale uses next-generation sequencing (NGS) and translational research to evaluate complex patients with a wide range of phenotypes suspected to have rare genetic diseases. We conducted a retrospective cohort analysis of 356 PGDP probands evaluated between June 2015 and July 2020, querying our database for participant demographics, clinical characteristics, NGS results, and diagnostic and research findings. The three most common phenotypes among the entire studied cohort (n = 356) were immune system abnormalities (n = 105, 29%), syndromic or multisystem disease (n = 103, 29%), and cardiovascular system abnormalities (n = 62, 17%). Of 216 patients with final classifications, 77 (36%) received new diagnoses and 139 (64%) were undiagnosed; the remaining 140 patients were still actively being investigated. Monogenetic diagnoses were found in 67 (89%); the largest group had variants in known disease genes but with new contributions such as novel variants (n = 31, 40%) or expanded phenotypes (n = 14, 18%). Finally, five PGDP diagnoses (8%) were suggestive of novel gene-to-phenotype relationships. A broad range of patients can benefit from single subject studies combining NGS and functional molecular analyses. All pediatric providers should consider further genetics evaluations for patients lacking precise molecular diagnoses.

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Reclassification of a likely pathogenic Dutch founder variant in KCNH2; implications of reduced penetrance

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Bootsma

et al. 2022

Human Molecular Genetics

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Background Variants in KCNH2, encoding the hERG channel which is responsible for the rapid component of the cardiac delayed rectifier K+ current (IKr), are causal to Long QT Syndrome type 2 (LQTS2). We identified eight index patients with a new variant of unknown significance (VUS), KCNH2:c.2717C > T:p.(Ser906Leu). We aimed to elucidate the biophysiological effect of this variant, to enable reclassification and consequent clinical decision-making. Methods A genotype–phenotype overview of the patients and relatives was created. The biophysiological effects were assessed independently by manual and automated calibrated patch-clamp. HEK293a cells expressing: (I) wild type (WT) KCNH2, (II) KCNH2-p.S906L alone (homozygous, Hm) or (III) KCNH2-p.S906L in combination with WT (1:1) (heterozygous, Hz), were used for manual patching. Automated patch-clamp measured the variants function against known benign and pathogenic variants, using Flp-In T-rex HEK293 KCNH2-variant cell lines. Results Incomplete penetrance of LQTS2 in KCNH2:p.(Ser906Leu) carriers was observed. In addition, some patients were heterozygous for other VUSs in CACNA1C, PKP2, RYR2, or AKAP9. The phenotype of carriers of KCNH2:p.(Ser906Leu) ranged from asymptomatic to life-threatening arrhythmic events. Manual patch-clamp showed a reduced current density by 69.8%, and 60.4% in KCNH2-p.S906L-Hm and KCNH2-p.S906L-Hz, respectively. The time constant of activation was significantly increased with 80.1% in KCNH2-p.S906L-Hm compared to KCNH2-WT. Assessment of KCNH2-p.S906L-Hz, by calibrated automatic patch-clamp assay showed a reduction in current density by 35.6%. Conclusion The reduced current density in the KCNH2-p.S906L-Hz indicates a moderate loss-of-function. Combined with the reduced penetrance and variable phenotype, we conclude that KCNH2:p.(Ser906Leu) is a low penetrant likely pathogenic variant for LQTS2.

show abstract

Functional testing for variant prioritization in a family with long QT syndrome

Cited by 3 publications

References 46 publications

Reclassification of a likely pathogenic Dutch founder variant in KCNH2; implications of reduced penetrance

Reclassification of a likely pathogenic Dutch founder variant in KCNH2; implications of reduced penetrance

A retrospective cohort analysis of the Yale pediatric genomics discovery program

Reclassification of a likely pathogenic Dutch founder variant in KCNH2; implications of reduced penetrance

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