Dataset Information

MYL2-associated congenital fiber-type disproportion and cardiomyopathy with variants in additional neuromuscular disease genes; the dilemma of panel testing.

ABSTRACT: Next-generation sequencing has led to transformative advances in our ability to diagnose rare diseases by simultaneously sequencing dozens, hundreds, or even entire genomes worth of genes to efficiently identify pathogenic mutations. These studies amount to multiple hypothesis testing on a massive scale and not infrequently lead to discovery of multiple genetic variants whose relative contributions to a patient's disease are unclear. Panel testing, in particular, can be problematic because each of the many genes being sequenced might represent a plausible explanation for a given case. We performed targeted gene panel analysis of 43 established neuromuscular disease genes in a patient with congenital fiber-type disproportion (CFTD) and fatal infantile cardiomyopathy. Initial review of variants identified changes in four genes that could be considered relevant candidates to cause this child's disease. Further analysis revealed that two of these are likely benign, but a homozygous frameshift variant in the myosin light chain 2 gene, MYL2, and a heterozygous nonsense mutation in the nebulin gene, NEB, met criteria to be classified as likely pathogenic or pathogenic. Recessive MYL2 mutations are a rare cause of CFTD associated with both skeletal and cardiomyopathy, whereas recessive NEB mutations cause nemaline myopathy. Although the proband's phenotype is likely largely explained by the MYL2 variant, the heterozygous pathogenic NEB variant cannot be ruled out as a contributing factor. This case illustrates the complexity when analyzing large numbers of variants from targeted gene panels in which each of the genes might plausibly contribute to the patient's clinical presentation.

SUBMITTER: Marttila M

PROVIDER: S-EPMC6672024 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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<i>MYL2</i>-associated congenital fiber-type disproportion and cardiomyopathy with variants in additional neuromuscular disease genes; the dilemma of panel testing.

Marttila Minttu M Win Wathone W Al-Ghamdi Fouad F Abdel-Hamid Hoda Z HZ Lacomis David D Beggs Alan H AH

Cold Spring Harbor molecular case studies 20190801 4

Next-generation sequencing has led to transformative advances in our ability to diagnose rare diseases by simultaneously sequencing dozens, hundreds, or even entire genomes worth of genes to efficiently identify pathogenic mutations. These studies amount to multiple hypothesis testing on a massive scale and not infrequently lead to discovery of multiple genetic variants whose relative contributions to a patient's disease are unclear. Panel testing, in particular, can be problematic because each ...[more]

PMID: 31127036

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Project description:BACKGROUND:As DNA sequencing costs decline, genetic testing options have expanded. Whole exome sequencing and whole genome sequencing (WGS) are entering clinical use, posing questions about their incremental value compared with disease-specific multigene panels that have been the cornerstone of genetic testing. METHODS AND RESULTS:Forty-one patients with hypertrophic cardiomyopathy who had undergone targeted hypertrophic cardiomyopathy genetic testing (either multigene panel or familial variant test) were recruited into the MedSeq Project, a clinical trial of WGS. Results from panel genetic testing and WGS were compared. In 20 of 41 participants, panel genetic testing identified variants classified as pathogenic, likely pathogenic, or uncertain significance. WGS identified 19 of these 20 variants, but the variant detection algorithm missed a pathogenic 18 bp duplication in myosin binding protein C (MYBPC3) because of low coverage. In 3 individuals, WGS identified variants in genes implicated in cardiomyopathy but not included in prior panel testing: a pathogenic protein tyrosine phosphatase, non-receptor type 11 (PTPN11) variant and variants of uncertain significance in integrin-linked kinase (ILK) and filamin-C (FLNC). WGS also identified 84 secondary findings (mean=2 per person, range=0-6), which mostly defined carrier status for recessive conditions. CONCLUSIONS:WGS detected nearly all variants identified on panel testing, provided 1 new diagnostic finding, and allowed interrogation of posited disease genes. Several variants of uncertain clinical use and numerous secondary genetic findings were also identified. Whereas panel testing and WGS provided similar diagnostic yield, WGS offers the advantage of reanalysis over time to incorporate advances in knowledge, but requires expertise in genomic interpretation to appropriately incorporate WGS into clinical care. CLINICAL TRIAL REGISTRATION:URL: https://clinicaltrials.gov. Unique identifier: NCT01736566.

Project description:Hypertrophic cardiomyopathy (HCM) is characterized by thickening of the ventricular muscle without dilation and is often associated with dominant pathogenic variants in cardiac sarcomeric protein genes. Here, we report a family with two infants diagnosed with infantile-onset HCM and mitral valve dysplasia that led to death before one year of age. Using exome sequencing, we discovered that one of the affected children had a homozygous frameshift variant in Myosin light chain 2 (MYL2:NM_000432.3:c.431_432delCT: p.Pro144Argfs*57;MYL2-fs), which alters the last 20 amino acids of the protein and is predicted to impact the most C-terminal of the three EF-hand domains in MYL2. The parents are unaffected heterozygous carriers of the variant and the variant is absent in control cohorts from gnomAD. The absence of the phenotype in carriers and the infantile presentation of severe HCM is in contrast to HCM associated with dominant MYL2 variants. Immunohistochemical analysis of the ventricular muscle of the deceased patient with the MYL2-fs variant showed a marked reduction of MYL2 expression compared to an unaffected control. In vitro overexpression studies further indicate that the MYL2-fs variant is actively degraded. In contrast, an HCM-associated missense variant (MYL2:p.Gly162Arg) and three other MYL2 stop-gain variants (p.E22*, p.K62*, p.E97*) that result in loss of the EF domains are stably expressed but show impaired localization. The degradation of the MYL2-fs can be rescued by inhibiting the cell's proteasome function supporting a post-translational effect of the variant. In vivo rescue experiments with a Drosophila MYL2-homolog (Mlc2) knockdown model indicate that neither the MYL2-fs nor the MYL2:p.Gly162Arg variant supports normal cardiac function. The tools that we have generated provide a rapid screening platform for functional assessment of variants of unknown significance in MYL2. Our study supports an autosomal recessive model of inheritance for MYL2 loss-of-function variants in infantile HCM and highlights the variant-specific molecular differences found in MYL2-associated cardiomyopathy.

Project description:A 52-year-old man presented after one episode of effort angina, normal treadmill electrocardiogram (ECG), and clearly positive adenosine cardiac magnetic resonance (aCMR) for reversible perfusion defects in the left anterior descending (LAD) coronary artery territory. Contrast high-dose dipyridamole (0.84 mg/kg per 6 min) stress echocardiography (cSE) demonstrated normal myocardial perfusion (MP) and wall motion at rest, while perfusion defects were shown in the lateral and apical segments after dipyridamole. Wall motion at stress was completely normal and stress/rest Doppler diastolic velocity ratio on the LAD demonstrated reduced flow reserve. In this case, cSE was the provocative test detecting both the LAD and circumflex obstructive lesions, thanks to MP analysis, while wall motion assessment was negative, not different from treadmill ECG, and aCMR highlighted only the LAD disease.In spite of the low sensitivity of wall motion assessment during stress-echocardiography to detect coronary artery disease (CAD) in patients with multivessel disease and balanced ischemia, the addition of cSE with myocardial perfusion assessment, is not only able to overcome this limitation of false negative rate on a per-patient basis, but may also depict multivessel myocardial perfusion defects more efficiently than aCMR, as in the reported case, thanks to high spatial resolution.Myocardial perfusion assessment during cSE, although not always technically feasible, has a very high spatial and temporal resolution which can easily demonstrate multivessel subendocardial perfusion defects during maximal vasodilation, which is often the only detectable marker of multivessel, balanced CAD.It is known that wall motion analysis during pharmacologic stress may result in falsely negative multivessel disease; in these cases perfusion imaging or Doppler measurement of coronary flow reserve may be helpful to detect multivessel obstructive CAD, which is a significant and dismal prognostic finding. aCMR is assumed as the perfect imaging modality for CAD detection, but in selected cases, such as the one presented, an advanced echocardiographic method in experienced hands can provide even more comprehensive results.

Dataset Information

MYL2-associated congenital fiber-type disproportion and cardiomyopathy with variants in additional neuromuscular disease genes; the dilemma of panel testing.

Publications

<i>MYL2</i>-associated congenital fiber-type disproportion and cardiomyopathy with variants in additional neuromuscular disease genes; the dilemma of panel testing.

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