Table 2.
List of the Genetic Associations With Metabolic/Infiltrative Genocopies of HCM, Originally Demonstrated Through the Collation of Different Types of Evidence (See References and Notes), Alongside the Main Currently Available Treatment Options
| Gene | Protein | Disease | Year(s) | Reference No. | Inheritance | Main Treatment Options | Notes |
|---|---|---|---|---|---|---|---|
| GAA | Glucosidase alpha | Pompe disease | 1986–1990 | 24, 25, 26 | AR | Enzyme‐replacement therapy, noninvasive ventilation | a |
| GLA | Galactosidase alpha | Anderson‐Fabry disease | 1989–1994 | 27, 28, 29 | X | Antiplatelet/anticoagulant agents, enzyme‐replacement therapy, analgesic drugs to relieve neuropathic pain | b |
| LAMP2 | Lysosome‐associated membrane protein 2 | Danon disease | 2004–2007 | 30, 31, 32 | X | ICD implantation | c |
| PRKAG2 |
Protein kinase AMP‐activated Non‐catalytic subunit gamma 2 |
Wolff‐Parkinson‐White syndrome | 2001 | 33 | AD | Antiarrhythmic drugs, ablation | d |
| TTR | Transthyretin | Transthyrethin amyloidosis | 1991–2002 | 34, 35, 36, 37 | AD | Liver/kidney/heart transplantation | e |
Of note, 15 other genes (including RASopathy genes such as PTPN11 and RAF1) have been classified as with ≥ moderate evidence by ClinGen for syndromic conditions where HCM can be seen. RASopathy genes are not included in the “genocopies of HCM” category as diagnostic discrimination between RASopathies and HCM is usually easier, due to the systemic features of the former (although in rare cases they may still resemble isolated HCM). AD indicates autosomal dominant; AR, autosomal recessive; HCM, hypertrophic cardiomyopathy; ICD, implantable cardioverter‐defibrillator; and X, X‐linked.
Other reports38, 39, 40 determined the gene sequence and contributed to show that the disease was due to a lack of alpha‐glucosidase.
Other reports41, 42 determined the gene sequence and contributed to show that the disease was due to a lack of alpha‐galactosidase.
Reports by Danon et al43 and Nishino et al44 described Danon disease as a distinct lysosomal glycogen storage disease and showed that the cause was a deficiency of lysosome‐associated membrane protein 2.
The reported study (Gollob et al33) consisted of a linkage analysis on two pedigrees including 70 individuals, with a LOD score for co‐segregation of variants in PRKAG2 and disease of 9.82.