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Review
. 2013 Feb;6(1):118-31.
doi: 10.1161/CIRCGENETICS.110.959387.

A clinical approach to inherited hypertrophy: the use of family history in diagnosis, risk assessment, and management

Kyla E Dunn  1 , Colleen Caleshu, Allison L Cirino, Carolyn Y Ho, Euan A Ashley
Affiliations
Review

A clinical approach to inherited hypertrophy: the use of family history in diagnosis, risk assessment, and management

Kyla E Dunn et al. Circ Cardiovasc Genet. 2013 Feb.
No abstract available

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Figures

Figure 1
Figure 1
Published in 1960, this family pedigree was the first to show autosomal dominant inheritance of hypertrophic cardiomyopathy (HCM). Females are represented by the symbol for Venus (♀), males by the symbol for Mars (♂). Filled shapes indicate verified disease. Adapted with permission from Hollman et al.
Figure 2
Figure 2
Strategic clinical assessment of a patient’s close family members aids diagnosis by adding valuable information to the family history. A, When 18-year-old Patient A (arrow) presented with mild left ventricular (LV) hypertrophy, his family history of sudden cardiac death (I-3 and II-7) raised suspicion for HCM. B, Clinical cardiology evaluation of the patient’s mother (III-2) and sisters (IV-2 and IV-3) provided the evidence needed for diagnosis. Circles indicate females; squares, males; slash, deceased. HCM = hypertrophic cardiomyopathy.
Figure 3
Figure 3
An uneventful family history lowers suspicion for HCM, prompting more thorough investigation of alternative etiologies. For 18-year-old Patient B (arrow) with mild left ventricular (LV) hypertrophy, 24-hour blood pressure monitoring revealed occult hypertension as the underlying cause. Circles indicate females; squares, males; slash, deceased. HCM = hypertrophic cardiomyopathy.
Figure 4
Figure 4
Screening recommendations for families with HCM. The frequency of screening is based on the age of the at-risk family member, due to the age-dependent penetrance of left ventricular (LV) hypertrophy. HCM = hypertrophic cardiomyopathy. Adapted with permission from Ho. Data from Gersh et al.
Figure 5
Figure 5
An evolving HCM family history, and careful pedigree assessment, shifts cardiology screening needs. A, Relatives needing screening based on initial diagnosis. Diagnosis of this 15-year-old patient (III-5, thick arrow) with HCM means his first-degree relatives (father II-3, mother II-4, and brother III-6; thin arrows) are each at 50% risk. B, Relatives needing screening based on initial plus a second diagnosis. When a second HCM diagnosis (II-6) is discovered in the patient’s maternal family history, this individual’s first-degree relatives (I-5, II-7, III-7, III-8, and III-9) also require cardiac screening. The patient’s father (II-3), not on the affected side of the family, is no longer considered at risk. C, Additional relatives need screening based on obligate carriers. Pedigree analysis identifies three obligate carriers (I-3, I-5, and II-4; marked with vertical line) connecting the individuals with HCM, including the patient’s mother. Each is at known risk for disease. Immediate family members of an obligate carrier are at 50% risk and also require screening (arrows added to I-6 and II-5). D, Genetic testing helps target screening to relatives definitively predisposed to HCM. In this family, several family members at 50% risk (II-7, III-6, III-7, and III-9) did not inherit the disease-causing variant; they and their descendants can be excused from further screening. By contrast, II-5 and I-6 test positive, newly revealing their children (II-8,9) to be at 50% risk. Circles indicate females; squares, males; slash, deceased; +, genetic variant present; –, genetic variant absent. HCM = hypertrophic cardiomyopathy. Adapted with permission from Ho.
Figure 6
Figure 6
The cardiac sarcomere, highlighting protein products of genes involved in hypertrophic cardiomyopathy. Disease-causing variants in cardiac myosin-binding protein C (MYBPC3) and beta-myosin heavy chain (MYH7) are most common, accounting for 20-45% and 15-20% of the disease respectively. Cardiac troponin T type 2 (TNNT2) and troponin I type 3 (TNNI3) each account for ~5%. Variation in other sarcomere genes is less frequent. Data from Ackerman et al.
Figure 7
Figure 7
Robust segregation analysis can help to determine whether a specific genetic variant is responsible for disease. In this HCM family, genetic testing of our patient (arrow) revealed a variant of uncertain significance (VUS) in the MYH7 gene. The VUS was present in all affected family members (III-2, III-4, III-5, and IV-3) and obligate carriers (II-4) tested, increasing confidence in its pathogenicity. Circles indicate females; squares, males; slash, deceased; ?, genotype unknown; +, VUS present; −, VUS absent. HCM = hypertrophic cardiomyopathy.
Figure 8
Figure 8
Constructing a family history is a dynamic process that unfolds over time. A, At diagnosis, this patient (arrow) had no known history of HCM but reported suspicious cardiac features in three family members (III-2, III-4, and IV-3). B, Review of family medical records dramatically altered the original history, showing those three family members to have HCM and the patient’s unaffected sister (III-1) to be an obligate carrier (vertical line). C, The patient’s mother then reported that her sister (II-9) carried a diagnosis of HCM. This definitively localized the disease to the maternal side of the family, revealing the patient’s mother (II-4) as another obligate carrier. Circles indicate females; squares, males; slash, deceased. HCM = hypertrophic cardiomyopathy.
See this image and copyright information in PMC

References

    1. Teare D. Asymmetrical hypertrophy of the heart in young adults. Br Heart J. 1958;20:1–8. - PMC - PubMed
    1. Hollman A, Goodwin JF, Teare D, Renwick JW. A family with obstructive cardiomyopathy (asymmetrical hypertrophy) Br Heart J. 1960;22:449–456. - PMC - PubMed
    1. Watson JD, Crick FH. Molecular structure of nucleic acids; a structure for deoxyribose nucleic acid. Nature. 1953;171:737–738. - PubMed
    1. Hershberger RE, Lindenfeld J, Mestroni L, Seidman CE, Taylor MR, Towbin JA. Genetic evaluation of cardiomyopathy—a Heart Failure Society of America practice guideline. J Card Fail. 2009;15:83–97. - PubMed
    1. Maron BJ. Sudden death in young athletes. N Engl J Med. 2003;349:1064–1075. - PubMed