Patient accounts of diagnostic testing for familial hypercholesterolaemia: comparing responses to genetic and non-genetic testing methods

Introduction: Both hereditary (hATTR) and wild-type (wtATTR) transthyretin amyloidosis are under-recognized causes of cardiomyopathy (CM) and heart failure. Certain findings on Transthoracic Echocardiography (TTE) and cardiac Magnetic Resonance Imaging (cMRI) are suggestive but not diagnostic of ATTR. Although biopsy historically has been the gold standard for diagnosis, patients can be diagnosed with the highly sensitive and specific technetium-99m pyrophosphate scan (Tc-99m PYP). Genetic testing is recommended to confirm hATTR in patients diagnosed with ATTR cardiac amyloidosis. Despite growing awareness of this condition, many cases remain undiagnosed. This study evaluated if patients with TTEs concerning for infiltrative CM received appropriate diagnostic testing for ATTR-CM. Methods: Our echocardiography registry was queried from January 2011 to March 2020 for patients with our echo lab’s embedded infiltrative CM code. Data on demographics, comorbidities, TTE variables, cMRI results, PYP scans, genetic testing and biopsy results were retrieved from electronic medical records. Thorough manual chart review excluded other causes of CM. Data was expressed as mean ± SD and n (%). Results: We retrieved 510 patients (mean age 64 ± 16 years; 43% female) with TTEs suspicious for infiltrative CM revealing a mean interventricular septal diameter (IVSd) of 1.6 ± 0.3 cm. Only 67 (13%) patients underwent cMRI with 11 (16%) suggestive of cardiac amyloidosis. Of the patients with suspicious TTEs, 16 (3.1%) had PYP scans and 24 (4.7%) had tissue biopsy, with positive results in 7 (44%) and 11 (46%), respectively. Genetic testing in 31 (6%) patients revealed known hATTR mutations in 2 (6.5%) patients. Cardiac amyloidosis was diagnosed in 23 (4.5%) with 11 ATTR (2 hATTR), 5 amyloid light chain, and 7 unknown subtype. Conclusion: Despite clinical and TTE findings suspicious for ATTR-CM, many patients did not undergo appropriate confirmatory testing (see Figure 1).

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A comparison of Simon Broome and welsh criteria for selecting patients for familial hypercholesterolaemia (FH) genetic testing

Atherosclerosis ◽

10.1016/j.atherosclerosis.2018.06.552 ◽

2018 ◽

Vol 275 ◽

pp. e181

Author(s):

P. Ashfield-watt ◽

L. Gritzmacher ◽

I. McDowell ◽

G. Bayly ◽

K. Haralambos

Keyword(s):

Genetic Testing ◽

Familial Hypercholesterolaemia

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Development of a Genomic DNA Reference Material Panel for Thalassemia Genetic Testing

10.1101/676015 ◽

2019 ◽

Author(s):

Zhen-Zhen Yin ◽

Shou-Fang Qu ◽

Chuan-Feng Huang ◽

Fang Chen ◽

Jian-Biao Li ◽

...

Keyword(s):

Quality Assurance ◽

Genetic Testing ◽

Cell Lines ◽

Reference Materials ◽

Genomic Dna ◽

Southern China ◽

Testing Methods ◽

Clinical Genetic ◽

Clinical Genetic Testing ◽

Technology Platforms

AbstractThalassemia is one of the most common autosomal recessive inherited diseases worldwide, and it is also highly prevalent and variable in Southern China. Various types of genetic testing technologies have been developed for diagnosis and screening of thalassemia. Characterized genomic DNA reference materials are necessary for assay development, validation, proficiency testing and quality assurance. However, there is no publicly available reference materials for thalassemia genetic testing as yet. To address the need for these materials, the National Institutes for Food and Drug Control and the China National Gene Bank established 31 new cell lines with 2 wild genotypes and 29 distinct genotypes of thalassemia which account for approximately 90% thalassemia carriers in China. The genomic DNA of 31 cell lines were characterized by four clinical genetic testing laboratories using different genetic testing methods and technology platforms. The genotyping results were concordant among four laboratories. In addition, the results of stability test demonstrated that the genotypes of these DNA samples were not influenced by preanalytical conditions such as long-term exposure to high temperature(37□) environment and repeated freeze-thawing. In conclusion, we developed the first national panel of 31 genomic DNA reference materials which are renewable and publicly available for the quality assurance of various genetic testing methods and will facilitate research and development in thalassemia genetic testing.

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Comparative analysis of the phenotypic predictors of mutations in familial hypercholesterolaemia: Standardizing diagnostic testing in the clinic

Atherosclerosis ◽

10.1016/j.atherosclerosis.2018.06.496 ◽

2018 ◽

Vol 275 ◽

pp. e165

Author(s):

D.C. Chan ◽

J. Pang ◽

A.J. Hooper ◽

D.A. Bell ◽

T.R. Bates ◽

...

Keyword(s):

Comparative Analysis ◽

Familial Hypercholesterolaemia ◽

Diagnostic Testing

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Decision letter for "Widening the spectrum of genetic testing in familial hypercholesterolaemia: Will it translate into better patient and population outcomes?"

10.1111/cge.13685/v1/decision1 ◽

2019 ◽

Keyword(s):

Genetic Testing ◽

Familial Hypercholesterolaemia

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Recent advances in the understanding and care of familial hypercholesterolaemia: significance of the biology and therapeutic regulation of proprotein convertase subtilisin/kexin type 9

Clinical Science ◽

10.1042/cs20140755 ◽

2015 ◽

Vol 129 (1) ◽

pp. 63-79 ◽

Cited By ~ 18

Author(s):

Michael M. Page ◽

Claudia Stefanutti ◽

Allan Sniderman ◽

Gerald F. Watts

Keyword(s):

Genetic Testing ◽

Familial Hypercholesterolaemia ◽

Lipoprotein Metabolism ◽

New Drugs ◽

High Density Lipoproteins ◽

Proprotein Convertase ◽

Pcsk9 Inhibitors ◽

Statin Intolerance ◽

Cascade Screening ◽

Recent Advances

Familial hypercholesterolaemia (FH) is an autosomal co-dominant disorder that markedly raises plasma low-density lipoprotein-cholesterol (LDL-C) concentration, causing premature atherosclerotic coronary artery disease (CAD). FH has recently come under intense focus and, although there is general consensus in recent international guidelines regarding diagnosis and treatment, there is debate about the value of genetic studies. Genetic testing can be cost-effective as part of cascade screening in dedicated centres, but the full mutation spectrum responsible for FH has not been established in many populations, and its use in primary care is not at present logistically feasible. Whether using genetic testing or not, cholesterol screening of family members of index patients with an abnormally raised LDL-C must be used to determine the need for early treatment to prevent the development of CAD. The metabolic defects in FH extend beyond LDL, and may affect triacylglycerol-rich and high-density lipoproteins, lipoprotein(a) and oxidative stress. Achievement of the recommended targets for LDL-C with current treatments is difficult, but this may be resolved by new drug therapies. Lipoprotein apheresis remains an effective treatment for severe FH and, although expensive, it costs less than the two recently introduced orphan drugs (lomitapide and mipomersen) for homozygous FH. Recent advances in understanding of the biology of proprotein convertase subtilisin/kexin type 9 (PCSK9) have further elucidated the regulation of lipoprotein metabolism and led to new drugs for effectively treating hypercholesterolaemia in FH and related conditions, as well as for treating many patients with statin intolerance. The mechanisms of action of PCSK9 inhibitors on lipoprotein metabolism and atherosclerosis, as well as their impact on cardiovascular outcomes and cost-effectiveness, remain to be established.

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