Table 1.
Breakdown of the Original Linkage Studies Demonstrating the Co‐Segregation of Genetic Variants and Hypertrophic Cardiomyopathy in Large Pedigrees and Incontrovertibly Associating Sarcomeric Genes With HCM
| Gene | Protein | Demonstrated Associations | Year | Reference No. | Inheritance | N Pedigrees—(Total Size) | Max LOD | Notes |
|---|---|---|---|---|---|---|---|---|
| MYH7 | Beta‐myosin heavy chain | Locus 14q1 | 1989 | 7 | AD | 1 (96) | 9.37 | ··· |
| Locus 14q11‐12 | 1990 | 8 | 1 (96) | 4.62 | ··· | |||
| Gene | 1990 | 9 | 1 (96) | 15.9 | ··· | |||
| Genetic heterogeneity of HCM | 1990 | 10 | 4 (173) | 10.85 | ··· | |||
| TNNT2 | Cardiac troponin T | Locus 1q3 | 1993 | 11 | AD | 3 (97) | 8.47 | ··· |
| Gene | 1994 | 12 | 1 (70) | 6.3 | ··· | |||
| MYBPC3 | Myosin‐binding protein C | Locus 11p13‐q13 | 1993 | 13 | AD | 1 (54) | 4.98 | ··· |
| Gene | 1995 | 14 | 2 (46) | 3.74 | ··· | |||
| TPM1 | Alpha tropomyosin | Locus 15q2 | 1993 | 15 | AD | 2 (87) | 6.02 | ··· |
| Gene | 1994 | 12 | 2 (87) | 6.94 | ··· | |||
| MYL3 | Essential myosin light chain 3 | Gene | 1996 | 16 | AD | 1 (53) | 6.2 | ··· |
| TNNI3 | Cardiac troponin I | Gene | 1997 | 17 | AD | 1 (18) | 3.1 | ··· |
| MYL2 | Regulatory myosin light chain 2 | Gene | 1998 | 18 | AD | 3 (47) | 2.41 (estimated) | a |
| ACTC1 | Alpha actin (cardiac muscle) 1 | Gene | 1999 | 19 | AD | 1 (22) | 3.6 | ··· |
AD indicates autosomal dominant; and HCM, hypertrophic cardiomyopathy.
a
Although an LOD score of 2.41 is below the universally accepted threshold of LOD=3 for co‐segregation to be considered unequivocal, in the years following this original association with HCM, further evidence about the gene's disease‐causing role in HCM gradually accumulated20, 21, 22, and collectively made the association incontrovertible. A larger family with HCM due to a pathogenic variant in MYL2 was reported recently, with a LOD score for co‐segregation of 4.51.23