Cardiovascular Journal of Africa: Vol 26 No 2 (March/April 2015)

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 26, No 2, March/April 2015

AFRICA

pattern (transmitral pulse-wave E/A ratio of 2.7 and E-wave

deceleration time of 111 ms) supported by an E/e

′

lateral of

almost 10.

The distribution of hypertrophy in/between the family

members varied. The proband showed a focal area of significant

hypertrophy involving the left ventricular apex and mid- to

apical segments of the right ventricular free wall [maximal

wall thickness (MWT) 14 mm]. In the younger brother (1.III.2,

Fig. 1) the pattern of hypertrophy involved the right ventricle

exclusively. The mid- to basal right ventricular free wall

demonstrated significant focal hypertrophy of up to 10 mm,

causing the bulging right ventricular free wall to almost ‘kiss’

the interventricular septum in systole – associated with a small

intra-cavitary right ventricular gradient and prominent systolic

flow turbulence on colour Doppler. The elder brother of the

proband (1.III.1, Fig. 1) showed a focal area of hypertrophy

with a MWT of 13 mm at the mid-septal region associated with

mid-left ventricular cavity obliteration.

In pedigree 2, the proband (2.II.3, Fig. 3) was the only affected

person from the family and showed systolic impairment with

poor EF of 31%. In line with this, systolic left ventricular long-

axis function and right ventricular long-axis systolic function,

as assessed by a TAPSE of 6 mm, was severely impaired. Tissue

Doppler indices demonstrated an individual with severe left

ventricular diastolic early relaxation impairment and high filling

pressures, reflected by a restrictive transmitral filling pattern

(E/A; E-wave deceleration time and E/e

′

lateral measuring

13) (Table 2). Significantly more hypertrophy was observed in

the MWT (21 mm) and mid-right ventricular free wall (9 mm).

Furthermore, the right heart flow was sluggish as highlighted

by marked spontaneous echo contrast present in both the right

atrium and right ventricle.

Molecular analysis

Molecular analysis of the cohort identified 14 genetic variants,

of which six were exonic variants and eight were intronic variants

(Table 3). In total, four novel variants were identified, of which

one was an exonic variant (p.Leu144His) and three were intronic

variants (c. –47C

T, c.109–17C

A, c.*35C

T). The remaining

variants have previously been documented, and all exonic

variants that resulted in an amino acid change (p.Pro82Ser,

9,10

p.Arg162Gln

9,11,12

p.Arg170Gln

) were tested for by restriction

enzyme analysis in available family members.

The mutation found in pedigree 1 (p.Leu144His) is novel, and

together with the exonic variant (p.Arg170Gln) found in pedigree

2, have not been observed in the South African population

before; these will be discussed in more detail. The remaining two

identified exonic variants, namely p.Arg162Gln and p.Pro82Ser,

were observed in two patients diagnosed with HCM. One patient

presented with symptoms of atrial fibrillation (male, 61 years)

and the other, an unexpected death, was diagnosed post mortem

(male, 41 years, ventricular hypertrophy). Both mutations had

previously been associated with HCM. Other family members

were either unaffected by HCM or not available for further

testing.

Identification of a novel cardiac troponin I gene

mutation

Bcc

I restriction enzyme digest was performed to confirm the

presence of the p.Leu144His mutation in the three siblings in

pedigree 1. Furthermore, this mutation was absent in a healthy,

Table 3. List of genetic variants identified in

TNNI3

Fragment

Sequence v

ariants

Amino acid

effect

Documented

Exon 1

c.-148A

G None

rs73935313

c.-47C

None

Novel

c.-35C

A None

rs3729707

Exon 2

c.25-8T

A None

rs3729836

c.108

21G

A None

rs3729837

Exon 4

c.109-17C

A None

Novel

c.150

13G

A None

rs73617692

Exon 5

c.198G

A p.Glu66

rs3729710

c.204G

T p.Arg68

rs3729711

c.244C

T p.Pro82Ser

rs77615401

Exon 7

c.432TG

AT p.Leu144His

Novel

c.485G

A p.Arg162Gln Previously described

12,14,15

c.509G

A p.Arg170Gln Previously described

Exon 8

c.*35C

T None

Novel

Arg: arginine; Glu: glutamine; His: histadine; Leu: leucine;

TNNI3

cardiac troponin I; Pro: proline.

*Novel mutation caused by two adjacent sequence changes; c.432T

(synonymous), which has been reported before,

and a novel

c.433G

T (non-synonymous) variant.

Fig. 3.

Diagram of the pedigree of the family carrying the

familial HCM-causing p.Arg170Gln mutation (pedi-

gree 2). The arrow indicates the proband. Solid

symbols indicate documented affected individuals,

open symbols indicate unaffected individuals. The

mutation carrier is indicated by

sign, and individuals

without mutations are indicated by a – sign. Slashed

symbols indicate deceased members. The arrow in the

chromatogram indicate the point of variation for the

p.Arg170Gln (c.509G

A) mutation. Individual alleles

of four microsatellite markers (D19S926, D19S418,

D19S880, D19S605) are shown for pedigree 2.