We very much enjoyed reading the review article by Gregory-Evans et
al. on coloboma in the December issue of the Journal of Medical Genetics.
The authors should be commended on the most thorough treatment of the
subject in the clinical genetics literature to date. In reading it,
however, we thought there were a few additional points that required
clarification.
We very much enjoyed reading the review article by Gregory-Evans et
al. on coloboma in the December issue of the Journal of Medical Genetics.
The authors should be commended on the most thorough treatment of the
subject in the clinical genetics literature to date. In reading it,
however, we thought there were a few additional points that required
clarification.
The first is the use of the word “coloboma.” As the authors point
out, this term has been used somewhat imprecisely in the past. We would
propose the term “uveal coloboma” be used for those ocular malformations
that appear to be due to faulty optic fissure closure—including what is
listed as iris coloboma, chorioretinal coloboma, and some of the disorders
listed as “optic nerve colobomas.” The lattermost term is particularly
troublesome to use as it alternatively may mean a uveal coloboma that
extends posteriorly to the optic nerve or some other form of anomalous
nerve (e.g., the anomalous nerve in papillo-renal syndrome (PAX2
mutations) or the morning glory disc anomaly.[1]) They correctly point
out that these latter anomalies may have a different genetic and
embryologic basis. To avoid confusion, it might be appropriate to speak
of these conditions as “uveal coloboma with optic nerve involvement” and
“congenital optic nerve anomlies.”
Our second comment concerns the mechanism of uveal coloboma
formation. The authors do an excellent job at discussing the genes
involved in ocular development that may cause uveal coloboma. However, it
should be born in mind that non-closure of the optic fissure is the
“default state” of the developing optic cup and that failure to close
could result from either direct or indirect causes. The former are those
specific genes that mediate closure of the fissure; the latter are those
genes necessary to “set the stage” for fissure closure. An example of
such a gene is MITF, which, when mutated in mouse can produce an optic cup
with retarded growth such that the two edges of the optic fissure are not
in the right place at the right time to join.[2] An even more indirect
mechanism might result from toxicity from environmental agents.
Lastly, we want to underline the point made at the end of the paper
that we do not have good candidate genes to test on a wholesale basis for
a patient that presents with coloboma. We believe that it is premature to
offer testing for PAX6, CHX10 or SHH, for instance, on all patients, as
the yield would likely be very low and results might be difficult to
interpret.
Congratulations again on an overall superb article.
References
1. Sanyanusin P, Schimmenti LA, McNoe LA, et al. Mutation of the PAX2
gene in a family with optic nerve colobomas, renal anomalies and
vesicoureteral reflux. Nat Genet 1995;9:358-64.
2. Hero I, Farjah M, Scholtz CL. The prenatal development of the
optic fissure in colobomatous microphthalmia. Invest Ophthalmol Vis Sci
1991;32:2622-35.
We thank the authors for their comments on our Letter to the Editor
describing a novel locus for autosomal dominant keratoconus on chromosome 3 [1].
We thoroughly agree with the author’s opinion that simple astigmatism should not
be considered a diagnostic criteria for forme fruste KC. However, none of our 4
patients diagnosed with forme fruste KC had simple astigmatism. In these
patients, t...
We thank the authors for their comments on our Letter to the Editor
describing a novel locus for autosomal dominant keratoconus on chromosome 3 [1].
We thoroughly agree with the author’s opinion that simple astigmatism should not
be considered a diagnostic criteria for forme fruste KC. However, none of our 4
patients diagnosed with forme fruste KC had simple astigmatism. In these
patients, the clinical diagnosis of KC was based on a 1,5 Dioptre (D) increment
scale videokeratographic analysis. In particular, in patient III:9 (whose
videokeratographic picture is shown in the middle panel of figure 2) astigmatism
was irregular on the right eye and regular on the left. A superior-inferior
difference was recorded in both eyes, while in the right the corneal apex was
dislocated in the inferior temporal quadrant of the cornea. Thus, this patient
fulfil the diagnostic criteria for forme fruste KC [2]. Figure 2 showed these
findings, although some details could have been lost in the printed version. We
confirmed these data in patient III:9 with a more sensitive quantitative
evaluation of the same videokeratography using a colorcoded map with 0,45 D
increments. This analysis showed that the highest keratometric values in dioptre
were 42,70 D on the superior and 43,60 D on the inferior cornea of the right eye
and 43,60 D in the superior and 45,0 D on the inferior cornea of the left eye.
Taken together these data point out the role of videokeratography in the
diagnosis of subtle corneal abnormalities such as forme fruste KC, in agreement
with Levy and coworkers who recommend to achieve a detection rate of at least
0.5 D increment scale for forme fruste KC [3].
Finally, the Hudson-Stahli’s line, described in two KC patients in table 2
was not considered as a sign of the disease but an occasional finding on
slit-lamp examination.
References
(1) Liskova P. Diagnostic criteria of forme fruste keratoconus [electronic
response to Brancati F et al. A locus for autosomal dominant
keratoconus maps to human chromosome 3p14–q13]
(2). Brancati F, Valente EM, Sarkozy A, Feher J, Castori M, Del Duca P, Mingarelli
R, Pizzuti A, Dallapiccola B. A locus for autosomal dominant keratoconus maps to
human chromosome 3p14-q13. J Med Genet 2004;41:188- 192.
(3). Rabinowitz YS.
Videokeratographic indices to aid in screening for keratoconus. J Refract Surg
1995;11:371-379. 4. Levy D, Hutchings H, Rouland JF, Guell J, Burillon C, Arne
JL, Colin J, Laroche L, Montard M, Delbosc B, Aptel I, Ginisty H, Grandjean H,
Malecaze F. Videokeratographic anomalies in familial keratoconus. Ophthalmology
2004;111:867-874.
The authors: Francesco Brancati1,2, Enza Maria Valente1, Anna Sarkozy1,2,
Jànos Fehèr3, Marco Castori1,2, Pietro Del Duca4, Rita Mingarelli1, Antonio
Pizzuti1,2 and Bruno Dallapiccola1,2
1 CSS Hospital, IRCCS, San Giovanni Rotondo
and CSS-Mendel Institute, Rome;
2 Department of Experimental Medicine and
Pathology, University “La Sapienza”, Rome;
3 Department of Ophthalmology,
University "La Sapienza", Rome;
Chen et al. identified R1193Q, a single nucleotide polymorphism (SNP) in the
cardiac sodium channel gene SCN5A, in a group of Han Chinese individuals. The
frequency of SNP R1193Q in this Chinese population is high, reaching 12% (11/94)
[1]. The results confirm our earlier report that SNP R1193Q is present in the
general population [2]. SNP R1193Q occurs within the context of a CpG dimer.
Because the major...
Chen et al. identified R1193Q, a single nucleotide polymorphism (SNP) in the
cardiac sodium channel gene SCN5A, in a group of Han Chinese individuals. The
frequency of SNP R1193Q in this Chinese population is high, reaching 12% (11/94)
[1]. The results confirm our earlier report that SNP R1193Q is present in the
general population [2]. SNP R1193Q occurs within the context of a CpG dimer.
Because the majority of methylation in human DNA occurs at the C in the CpG
dimer, it will interfere with efficient correction of C to T transitions
resulting from 5-methyl cytosine deamination, making this a potential hotspot
for mutation [3].
SCN5A is one of the disease-causing genes for long QT syndrome (LQTS), a cardiac
disorder characterized by the prolonged QT interval on electrocardiograms (ECG)
[4, 5]. LQTS patients have a high risk of syncope and sudden death due to a
specific ventricular tachyarrhythmia, torsade de pointes. LQTS can be classified
into two types, congenital LQTS vs. acquired LQTS. Congenital LQTS is uncommon,
however, acquired LQTS is common, and may account for more than 8% of the
general population [2].
Congenital LQTS is caused by genetic defects. To date, more than 250 different
disease-causing mutations in six genes, KvLQT1 (or KCNQ1), HERG (or KCNH2),
SCN5A, ANKB, KCNE1, and KCNE2 have been identified in LQTS patients and
families, and mutations in these genes may account for approximately 50% to 75%
of congenital LQTS cases [6]. Mutations in KvLQT1, KCNE1, KCNJ2, and HCN4 were
also identified in congenital LQTS patients associated with other symptoms,
including deafness (KvLQT1, KCNE1), periodic paralysis (KCNJ2), and sinus node
dysfunction (HCN4) [6, 7]. Acquired LQTS is caused by drugs and other
environmental factors [2]. To be accurate, the pathogenesis of acquired LQTS is
caused by the interaction between genetic factors (e.g. mutations) and
environmental factors (e.g. drugs). Acquired LQTS is mostly sporadic, which
makes it challenging to identify its genetic factors using classical linkage
analysis and positional cloning. Thus, several studies used the candidate gene
approach, focusing on the genes responsible for congenital LQTS. This approach
appears to be effective. Multiple SNPs in KvLQT1, HERG, SCN5A, KCNE1, and KCNE2
have been identified in patients with acquired LQTS (Table 1). These studies
provide evidence for the hypothesis that acquired and congenital LQTS may share
the same genetic basis, and acquired LQTS may represent a latent form of
congenital LQTS.
Chen et al. reported that one of the nine carriers with SNP R1193Q is affected
with congenital LQTS (QTc = 472 ms) [1]. This finding is consistent with our
results from electrophysiological studies of mutant R1193Q sodium channels. We
studied seven patients with acquired LQTS and identified SNP R1193Q of SCN5A in
one of the patients [2]. As with any other reported studies on acquired LQTS, it
is difficult to provide definitive genetic evidence that R1193 is a cause of
acquired LQTS. An alternative was to provide functional or physiological
evidence to support the hypothesis that R1193Q is a cause of acquired LQTS. We
performed detailed electrophysiological characterization of SNP R1193Q on the
whole-cell or single channel levels in both Xenopus oocytes and mammalian HEK293
cells. Distinct differences were observed between wild type and mutant R1193Q
sodium channels. Similar to two other well-characterized mutations, N1325S and
R1644H causing congenital LQTS, SNP R1193Q leads to the generation of a
late-phase persistent non-inactivating sodium current, and frequent dispersed
reopenings of the channels on the single channel level [2, 8, 9]. These results
predict that R1193Q is capable of causing congenital LQTS. This prediction is
now supported by the finding by Chen et al. that one R1193Q carrier from a
general population is affected with congenital LQTS [1]. Thus, R1193Q is
associated with both congenital and acquired LQTS. Three other mutations, KvLQT1
R555C, SCN5A S1103Y, and SCN5A V1667I are also associated with both congenital
and acquired LQTS (Table 1).
How to explain the finding that several carriers with SNP R1193Q have normal QTc
or borderline QT interval prolongation? The penetrance of mutations associated
with LQTS is highly variable. Many individuals with LQTS mutations display a
normal QT interval or borderline QTc [4, 10]. These individuals are, however, at
a risk of developing LQTS, ventricular arrhythmias and sudden death when exposed
to drugs or other environmental stimuli. It will be interesting to test whether
the individuals who have a normal phenotype, but carry SCN5A SNP R1193Q will
display LQTS when exposed to quinidine or sotalol. Furthermore, if the allele
frequency of Q1193 is 6% in the Chinese population, a case-control association
study can be designed to estimate the risk of this variant to acquired
arrhythmias in this population (note that a case-control study is unrealistic
with an allele frequency of 0.1% in the Caucasian population).
The low frequency of 0.2% in a mostly Caucasian population and a high 12% rate
of SNP R1193Q in a Chinese population may reflect an ethnic difference. It is
important, however, to note that Xie et al. sequenced the SCN5A gene in 120
unrelated Han Chinese individuals, but did not report the identification of
R1193Q in their samples [11]. SNP R1193Q was also identified in a normal
Japanese population (1/48 = 2%) [12], which contradicts with the report by Vatta
et al. that the variant was not present in 100 Japanese controls (please note
that the variant was mislabeled in Vatta et al. report) [13]. Therefore, more
studies with much larger sample sizes are required to obtain the accurate
estimate of the true frequency of SNP R1193Q in the Chinese and Japanese
populations.
In summary, SNP R1193Q of the cardiac sodium channel gene SCN5A is present in
several general populations, although its prevalence rate varies with different
ethnic background, ranging from 0.2% to 12%. Electrophysiological
characteristics of R1193Q predict that individuals carrying R1193Q are at an
increased risk of developing LQTS. Genetic studies provide supportive evidence
for the prediction, however, more studies are clearly warranted to estimate the
relative risk or risk ratio for this variant.
Correspondence to:
Dr Qing Wang
Center for Molecular Genetics/ND4-38, the Cleveland Clinic Foundation,
Cleveland, OH 44195, USA Telephone #: (216) 445-0570; Fax #: (216) 444-2682;
E-mail: wangq2@ccf.org.
References
(1) Chen Y-T, Hwang HW, Niu DM, Hwang BT, Chen JJ, Lin YJ, Shieh RC, Lee MT,
Hung SI, Wu JY. R1193Q of SCN5A, a Brugada and long QT mutation, is a common
polymorphism in Han Chinese. J Med Genet 2004;this issue.
(2) Wang Q, Chen S, Chen Q, Wan X, Shen J, Hoeltge GA, Timur AA, Keating MT,
Kirsch GE. The common SCN5A mutation R1193Q causes LQTS-type
electrophysiological alterations of the cardiac sodium channel. J Med Genet
2004;41(5):e66.
(3) Barker D, Schafer M, White R. Restriction sites containing CpG show a higher
frequency of polymorphism in human DNA. Cell 1984;36(1):131-8.
(4) Chen S, Zhang L, Bryant RM, Vincent GM, Flippin M, Lee JC, Brown E,
Zimmerman F, Rozich R, Szafranski P, Oberti C, Sterba R, Marangi D, Tchou PJ,
Chung MK, Wang Q. KCNQ1 mutations in patients with a family history of lethal
cardiac arrhythmias and sudden death. Clin Genet 2003;63(4):273-82.
(5) Wang Q, Pyeritz RE, Seidman C E, Basson CT. Genetic studies of myocardial
and vascular disease. In: Topol EJ, editor. Textbook of Cardiovascular Medicine.
2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2002. p. 1967-89.
(6) Yong S, Tian X, Wang Q. LQT4 gene: the missing ankyrin. Molecular
Interventions 2003;3(3):131-6.
(7) Ueda K, Nakamura K, Hayashi T, Inagaki N, Takahashi M, Arimura T, Morita H,
Higashiuesato Y, Hirano Y, Yasunami M, Takishita S, Yamashina A, Ohe T, Sunamori
M, Hiraoka M, Kimura A. Functional characterization of a trafficking-defective
HCN4 mutation, D553N, associated with cardiac arrhythmia. J Biol Chem
2004;279(26):27194-8.
(8) Dumaine R, Wang Q, Keating MT, Hartmann HA, Schwartz PJ, Brown AM, Kirsch
GE. Multiple mechanisms of Na+ channel--linked long-QT syndrome. Circ Res
1996;78(5):916-24.
(9) Wang Q, Shen J, Li Z, Timothy K, Vincent GM, Priori SG, Schwartz PJ, Keating
MT. Cardiac sodium channel mutations in patients with long QT syndrome, an
inherited cardiac arrhythmia. Hum Mol Genet 1995;4(9):1603-7.
(10) Vincent GM, Timothy KW, Leppert M, Keating M. The spectrum of symptoms and
QT intervals in carriers of the gene for the long-QT syndrome [see comments]. N
Engl J Med 1992;327(12):846-52.
(11) Xie XD, Wang XX, Chen JZ, Tao M, Shang YP, Guo XG, Zheng LR. [Single
nucleotide polymorphism in SCN5A and the distribution in Chinese Han ethnic
group]. Sheng Li Xue Bao 2004;56(1):36-40.
(12) Takahata T, Yasui-Furukori N, Sasaki S, Igarashi T, Okumura K, Munakata A,
Tateishi T. Nucleotide changes in the translated region of SCN5A from Japanese
patients with Brugada syndrome and control subjects. Life Sci
2003;72(21):2391-9.
(13) Vatta M, Dumaine R, Varghese G, Richard TA, Shimizu W, Aihara N, Nademanee
K, Brugada R, Brugada J, Veerakul G, Li H, Bowles NE, Brugada P, Antzelevitch C,
Towbin JA. Genetic and biophysical basis of sudden unexplained nocturnal death
syndrome (SUNDS), a disease allelic to Brugada syndrome. Hum Mol Genet
2002;11(3):337-45.
(14) Donger C, Denjoy I, Berthet M, Neyroud N, Cruaud C, Bennaceur M, Chivoret
G, Schwartz K, Coumel P, Guicheney P. KVLQT1 C-terminal missense mutation causes
a forme fruste long-QT syndrome. Circulation 1997;96(9):2778-81.
(15) Napolitano C, Schwartz PJ, Brown AM, Ronchetti E, Bianchi L, Pinnavaia A,
Acquaro G, Priori SG. Evidence for a cardiac ion channel mutation underlying
drug-induced QT prolongation and life-threatening arrhythmias. J Cardiovasc
Electrophysiol 2000;11(6):691-6.
(16) Yang P, Kanki H, Drolet B, Yang T, Wei J, Viswanathan PC, Hohnloser SH,
Shimizu W, Schwartz PJ, Stanton M, Murray KT, Norris K, George AL, Jr., Roden
DM. Allelic variants in long-QT disease genes in patients with drug- associated
torsades de pointes. Circulation 2002;105(16):1943-8.
(17) Chevalier P, Rodriguez C, Bontemps L, Miquel M, Kirkorian G, Rousson R,
Potet F, Schott JJ, Baro I, Touboul P. Non-invasive testing of acquired long QT
syndrome: evidence for multiple arrhythmogenic substrates. Cardiovasc Res
2001;50(2):386-98.
(18) Piquette RK. Torsade de pointes induced by cisapride/clarithromycin
interaction. Ann Pharmacother 1999;33(1):22-6.
(19) Paulussen AD, Gilissen RA, Armstrong M, Doevendans PA, Verhasselt P, Smeets
HJ, Schulze-Bahr E, Haverkamp W, Breithardt G, Cohen N, Aerssens J. Genetic
variations of KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 in drug-induced long QT
syndrome patients. J Mol Med 2004;82(3):182-8.
(20) Chen S, Chung MK, Martin D, Rozich R, Tchou PJ, Wang Q. SNP S1103Y in the
cardiac sodium channel gene SCN5A is associated with cardiac arrhythmias and
sudden death in a white family. J Med Genet 2002;39(12):913-5.
(21) Splawski I, Timothy K, Tateyama M, Clancy CE, Malhotra A, Beggs AH,
Cappuccio FP, Sagnella GA, Kass R, Keating M. Variant of SCN5A sodium channel
implicated in risk of cardaic arrhythmia. Science 2002;297:1333-6.
(22) Piippo K, Holmstrom S, Swan H, Viitasalo M, Raatikka M, Toivonen L, Kontula
K. Effect of the antimalarial drug halofantrine in the long QT syndrome due to a
mutation of the cardiac sodium channel gene SCN5A. Am J Cardiol
2001;87(7):909-11.
(23) Makita N, Horie M, Nakamura T, Ai T, Sasaki K, Yokoi H, Sakurai M, Sakuma
I, Otani H, Sawa H, Kitabatake A. Drug-induced long-QT syndrome associated with
a subclinical SCN5A mutation. Circulation 2002;106(10):1269-74.
(24) Abbott GW, Sesti F, Splawski I, Buck ME, Lehmann MH, Timothy KW, Keating
MT, Goldstein SA. MiRP1 forms IKr potassium channels with HERG and is associated
with cardiac arrhythmia. Cell 1999;97(2):175-87.
(25) Sesti F, Abbott GW, Wei J, Murray KT, Saksena S, Schwartz PJ, Priori SG,
Roden DM, George AL, Jr., Goldstein SA. A common polymorphism associated with
antibiotic-induced cardiac arrhythmia. Proc Natl Acad Sci U S A 2000
12;97(19):10613-8.
We would like to comment on the letter describing linkage analysis in
autosomal dominant keratoconus presented by Brancati et al. in the March
issue of JMG [1]. The pedigree includes 4 patients with forme fruste
keratoconus and Figure 2 shows the videokeratography of patient III:9 to support
this diagnosis. However, from the data presented this patient appears to have
unilateral simple astigmatism, whi...
We would like to comment on the letter describing linkage analysis in
autosomal dominant keratoconus presented by Brancati et al. in the March
issue of JMG [1]. The pedigree includes 4 patients with forme fruste
keratoconus and Figure 2 shows the videokeratography of patient III:9 to support
this diagnosis. However, from the data presented this patient appears to have
unilateral simple astigmatism, which does not fulfil the diagnostic criteria
defined in the reference provided [2]. Futhermore, there
is little evidence of inferior corneal steepening and the keratometry
values are not unusually high [2,3] Corneal thickness measurements, which
may be reduced in keratoconus, were not presented.
The authors point out that large pedigrees with clinically evident
keratoconus are rare and videokeratography has been used to identify
asymptomatic family members who have early changes of keratoconus. These
patients with forme fruste keratoconus allow pedigrees to be expanded [4,5].
Levy et al. (2004) identified specific parameters that may characterise forme fruste keratoconus
[6]. However it has yet to be shown that these
abnormalities inevitably progress to clinical keratoconus .We consider
that the diagnostic criteria for forme fruste keratoconus should not be
expanded to include patients with simple astigmatism until a link between
the two conditions can be established. The exclusion of patient III:9 from
the study would inevitably result in a reduction in the significance of
the calculated LOD score.
In addition, we would also like to point out that the clinical sign
of a Hudson Stahli line used to describe the clinical features of the
disease in affected patients (Table 2) is usually accepted to be a sign of
a normal cornea. A circular Fleischer ring is the clinical sign that
accompanies the central corneal steepening of keratoconus
Although this letter raises the interesting possibility of a new
locus for familial keratoconus the points that we have highlighted should
be addressed to clarify the diagnosis of the early stages of the disease.
References
(1) Brancati F, Valente EM, Sarkozy A, et al. A locus for autosomal
dominant keratoconus maps to human chromosome 3p14-q13. J Med Genet
2004;41(3):188-92.
(2) Rabinowitz YS. Videokeratographic indices to aid in screening for
keratoconus. J Refract Surg 1995;11(5):371-9.
(3) Rabinowitz YS. The genetics of keratoconus. Ophthalmol Clin North
Am 2003;16(4):607-20, vii.
Recently, Wang
et al. [1] reported R1193Q mutation of SCN5A in one of the 7 patients with
acquired long QT syndrome (LQTS) and suggested that R1193Q is a functional
mutation that can increase the susceptibility to LQTS. The authors fo...
Recently, Wang
et al. [1] reported R1193Q mutation of SCN5A in one of the 7 patients with
acquired long QT syndrome (LQTS) and suggested that R1193Q is a functional
mutation that can increase the susceptibility to LQTS. The authors found 0.2%
(4 of 2087) of the control subjects (in which more than 90% were whites and
only 0.4% were Asians) also carried the mutation and suggested that it may be a
risk factor for LQTS in the general population. The same mutation has been
reported in a Japanese infant with Brugada syndrome having frequent ventricular
fibrillation episodes [2]. They found none of the 100 control subjects of Asian
descent carried the variant.
We have identified the same R1193Q
mutation by direct DNA sequencing of SCN5A in a four-generation family of
Chinese descent with cardiac conduction abnormalities and several instances of
sudden death. However, the mutation is not associated with the disease or any
ECG abnormalities in this family.
We then screened for the presence
of R1193Q mutation in randomly selected control subjects consisting of Han
Chinese by direct DNA sequencing and SNP genotyping using
high-throughput MALDI-TOF mass spectrometry. R1193Q mutation was present
in 12% (11/94) of the subjects with allele frequency of 6%. One of the carriers
was homozygous for the mutation, and all the others were heterozygous. Clinical
studies were available in nine of the 11 carriers (Table 1). Two of them had
abnormal electrocardiograms (ECGs). No known associated risk factors were
identified in subject no.1 for her frequent ventricular premature complexes
(VPCs). Drug-induced prolonged QT-interval was ruled out in subject no.7.
Table 1. Summary of clinical findings in the
R1193Q carriers
1
2
3
4
5
6
7
8
9
Genotype
R/Q
R/Q
R/Q
R/Q
R/Q
R/Q
R/Q
R/Q
Q/Q
Age/Gender
35, F
32, M
45, F
40, F
71, M
26, M
75, F
46, M
76, M
History
of syncope or arrhythmia
¡V*
¡V
¡V
¡V
¡V
¡V
¡V
¡V
¡V
Family
history of sudden death or arrhythmia
¡V
¡V
¡V
¡V
¡V
¡V
¡V
¡V
¡V
ECG findings
Brugada
sign#
¡V
¡V
¡V
¡V
¡V
¡V
¡V
¡V
¡V
Prolonged
QTc
¡V
¡V
¡V
¡V
¡V
¡V
+¡±
¡V
¡V
Others
Frequent VPCs
¡V
¡V
¡V
¡V
¡V
¡V
¡V
¡V
*-
indicated negative findings
#
Type 1~3 ST-segment abnormalities in leads V1-V3 (3)
To
investigate whether sequence variants other than R1193Q had effects on the
clinical presentations, we sequenced all the coding regions of SCN5A in all
carriers and compared the sequences to 4 control subjects. Fifteen SNPs
including six novel ones were identified (Table 2). All novel SNPs were either
located within the introns or showed synonymous amino acid changes and thus
suggesting these SNPs are likely to be normal variants. There was no clear
association of any particular SNPs in the carriers with abnormal ECG as
compared to those with normal tracings; including H558R polymorphism which has
been reported to modify the expression of the arrhythmia causing mutation
[4].
Table 2.SNPs identified in the R1193Q carriers
and control subjects
In summary,
R1193Q, a Brugada and long QT mutation found in patients with other ethnic
background, is a common polymorphism in Han Chinese. Further studies will be
needed to determine whether this variant carries an increased risk for
arrhythmia in the Chinese population.
*Institute of Biomedical Sciences,
Academia Sinica, Taipei, Taiwan.
#Dept
Pediatrics, Taipei Veteran General Hospital, Taipei, Taiwan
¡±Department
of Pediatrics, Duke University Medical Center, Durham, NC, USA
Acknowledgements
The research project
was supported by grants from the National Science & Technology Program forGenomic Medicine, National Science Council, Taiwan (National Clinical
Core and National Genotyping Core),and the Genomics and Proteomics
Program, Academia Sinica.
References
(1)
Wang Q, Chen S, Chen Q, Wan X,
Shen J, Hoeltge GA, Timur AA, Keating MT, Kirsch GE. The common SCN5A mutation
R1193Q causes LQTS-type electrophysiological alterations of the cardiac sodium
channel. J Med Genet 2004; 41(5):e66.
(2) Vatta M, Dumaine R, Varghese G,
Richard TA, Shimizu W, Aihara N, Nademanee K, Brugada R, Brugada J, Veerakul G,
Li H, Bowles NE, Brugada P, Antzelevitch C, Towbin JA. Genetic and biophysical
basis of sudden unexplained nocturnal death syndrome (SUNDS), a disease allelic
to Brugada syndrome. Hum Mol Genet 2002; 11(3): 337-345.
We read with interest a recent report in your journal by
Jakkula et al.[1] on two families of multiple epiphyseal
dysplasia (MED) with the recurrent R718W mutation in COMP.
Key points of the report are: 1) In a family (family 1),
two children presented with muscular weakness and all four
family members with R718W showed moderate rise in plasma
creatine kinase...
We read with interest a recent report in your journal by
Jakkula et al.[1] on two families of multiple epiphyseal
dysplasia (MED) with the recurrent R718W mutation in COMP.
Key points of the report are: 1) In a family (family 1),
two children presented with muscular weakness and all four
family members with R718W showed moderate rise in plasma
creatine kinase (CK), indicating possible association of
myopathy; 2) In both families, the skeletal change is more
severe in the knee joint than in the hip joint. This
observation contradicts to the previous assumption of
genotype-phenotype association, i.e. presence of
dysplastic capital femoral epiphyses and severely irregular
acetabuli is suggestive of COMP mutations, while dysplastic
changes in patients with collagen IX mutation are mainly
seen in the knees and the hips are relatively spared.[2,3]
We previously experienced a MED family with three affected
individuals harboring the same R718W mutation.[4] Here we
describe their clinical and radiographic features for
comparison and further discussion.
The proband was a 64-year-old factory laborer who presented
with bilateral coxalgia at aged 56 years that had started 2
years. His height was 152 cm (nearly Ð3 SD), and his
weight 53.5 kg. He had no history of muscle weakness.
Physical examination had no indication of myopathy. His CK
was 67 (normal range: 50-170) U/L, and was kept within the
normal range during the follow-up period. Radiographic
examination showed severe osteoarthritic (OA) changes in
both hip joints (Figure 1A). The OA changes were minimal in
knee, ankle, foot, shoulder, elbow, hand and wrist joints
(Figure 1B and C). Only an episode of transient pain in the left
knee was noted as well as transient pain in the right
elbow, the right shoulder and the left hand. The hip pain
could not be controlled by medication, and he underwent
bilateral total hip replacement at aged 57 years.
Figure 1 Radiographs of the proband aged 56 years.
A) Hip. Terminal
osteoartritic (OA) changes.
B) The left knee. Mild
dysplasia with flattend femoral chondyle and tibial spine.
C) The right hand. Advanced OA of the MP (metacarpo-
phalangeal) and CM (carpo-metacarpal) joints.
The daughter of the proband, a 37-year-old housewife, had
the bilateral knee pain; the right since the age 32 years
and the left since the age 35 years, respectively. She had
no symptom in other joints. Physical examination revealed
no remarkable findings. Her height was 156 cm, and her
weight 51 kg. The son of the proband was a 33-year-old
factory worker. His height was 161 cm, and his weight 57
kg. He was found to have MED when he visited us because of
the injury of the anterior cruciate ligament of the right
knee. He had occasional vague pain in the right knee on
climbing stairs, but had no symptom in other joints. Both
individuals had no sign and symptom of myopathy. Their CK
levels were normal (80 and 123 U/L). Radiographic
examination identified dysplasia of the hip, knee, and the
1st and 2nd metatarsal joints in both patients (Fig. 2).
Hip dysplasias were marked in the son, but minimal in the
daughter, while knee changes were similar and mild.
Figure 2 Radiographs of the affected family members.
A) and C) The
daughter at aged 37 years.
B) D) and E) The son at aged
33 years.
A) and B) FHip joints. Dysplasia was marked in B,
but minimal in A.
C) and D) Knee joints. Dysplasias of the
knee joints were both mild.
Thus, myopathy was clearly absent in our cases. We consider
the association of myopathy with R718W in the JakkulaÕs
case is fortuitous. Although more than 50 COMP mutations
have been reported, they present MED or more severe
pseudoachondroplasia (PSACH) phenotype, but not myopathy.
The family 1 of the JakkulaÕs a report [1] is the only
exception. COMP is expressed in skeletal muscle, but not
abundant. Even the closely-situated mutation, G719D, did
not present myopathy, though it showed severe PSACH
phenotype.[5]
In our family, the skeletal changes were more severe in the
hip joint, which is consistent with the previous assumption
for the phenotype of the COMP mutation.[2,3] Hip changes
in patients with COMP mutations progress with age as
typically seen in PSACH. It is also true in the cases of
Jakkula et al.[1] The inconsistency of their cases with
the previous assumption may result from the patients' age
at observation. Two affected individuals in the family did
develop severe hip OA in adulthood. Alternatively, it may
be another example of phenotypic variation of the same
mutation.
References
1) Jakkula E, Lohiniva J, Capone A, et al. A recurrent
R718W mutation in COMP results in multiple epiphyseal
dysplasia with mild myopathy: clinical and pathogenetic
overlap with collagen IX mutations. J Med Genet 2003;
40:942-8.
3) Briggs MD, Chapman KL. Pseudoachondroplasia and multiple
epiphyseal dysplasia: mutation review, molecular
interactions, and genotype to phenotype correlations. Hum
Mutat 2002; 19:465-78.
4) Mabuchi A, Manabe N, Haga N, et al. Novel types of COMP
mutations and genotype-phenotype association in
pseudoachondroplasia and multiple epiphyseal dysplasia. Hum
Genet 2003; 112:84-90.
5) Mabuchi A, Haga N, Ikeda T, et al. A novel mutation in
exon 18 of the cartilage oligomeric matrix protein gene
causes a severe pseudoachondroplasia. Am J Med Genet 2001;
104:135-9.
We thank Dr Selvan for his comments [1] on our paper.[2] Cyrillic 3 does indeed use the BRCAPRO and MENDEL models. With regards to our use of BRCAPRO, we would like to draw his attention to the official Cyrillic 3 homepage [3] where it states clearly that the BRCAPRO plug-in calculates risk
based on the “Bayes’ rules of determination of the probability of a mutation, given family history. An estimate of th...
We thank Dr Selvan for his comments [1] on our paper.[2] Cyrillic 3 does indeed use the BRCAPRO and MENDEL models. With regards to our use of BRCAPRO, we would like to draw his attention to the official Cyrillic 3 homepage [3] where it states clearly that the BRCAPRO plug-in calculates risk
based on the “Bayes’ rules of determination of the probability of a mutation, given family history. An estimate of the mutation frequencies in the normal population [4,5] and among Ashkenazi Jews [6] provides the probability of the mutation in the proband, prior to the ascertainment of family history.” In summary, the BRCAPRO software included in Cyrillic 3 gives the option of using three population models on which it bases its results - Claus et al 1994, Ford et al 1998 and Streuwing et al 1997. The guidelines for using BRCAPRO within Cyrillic 3 were followed and we generated results for
unaffected family members using both the Ford and Claus results. As was clearly stated in our paper "Claus and Ford risks were calculated using a plug-in for the Cyrillic 3 package, a software package designed to display family pedigrees for use in clinical genetics and genetic counselling." All results were subsequently described as Claus or Ford. Having to state that they had been derived from a BRCAPRO plug-in every time would have been unwieldy.
In the Study tools section we clearly state: "Computerized risk assessment packages Gail, BRCAPRO (Claus and Ford) and Tyrer-Cuzick were tested on this population". While we were a little ambiguous in the paragraphs before this, we think this sentence is perfectly clear in explaining what we were doing and as the correspondent acknowledges, he is not familiar with Cyrillic 3. We are not sure how much clearer we could have been.
With regard to the rest of the correspondence this appears to be an advert to use the CancerGene software programme. Although Dr Selvan does distinguish between models that merely predict the likelihood of a mutation being present (Myriad I and II, [7]), those that just predict breast cancer risk over time [8,9] and those that purport to do both (BRCAPRO) our paper was only addressing breast cancer risk. Although we did not use a direct download of the BRCAPRO, we have no reason to
believe that the results would have been any different if we had. BRCAPRO appears to underestimate breast cancer risk over time because it assumes that all inherited breast cancer is due to mutations in BRCA1 or BRCA2. The Ford element of this involves the use of the Ford et al [5] penetrance figures in the BRCAPRO algorithm as opposed to those of Claus [8].
References
1. Selvan, M. Breast cancer risk prediction models. Rapid Respone, www.jmedgenet.com.
2. Amir E, Evans DG, Shenton A, Lalloo F, Moran A, Boggis C, Wilson M,
Howell A. Evaluation of breast cancer risk assessment packages in the family history evaluation and screening programme. J Med Genet. 2003 Nov;40(11):807-14.
3. About BRCAPro in Cyrillic 3. Accessed on: 14th April 2004. Details available at:
http://www.cyrillicsoftware.com/support/cy3brca.htm
4. Claus EB, Schildkraut JM, Thompson WD, Risch NJ. The genetic
attributable risk of breast and ovarian cancer. Cancer. 1996;77(11):2318-
24.
5. Ford D, Easton DF, Stratton M, Narod S, Goldgar D, Devilee P, Bishop
DT, Weber B, Lenoir G, Chang-Claude J, Sobol H, Teare MD, Struewing J,
Arason A, Scherneck S, Peto J, Rebbeck TR, Tonin P, Neuhausen S,
Barkardottir R, Eyfjord J, Lynch H, Ponder BA, Gayther SA, Zelada-Hedman M
and the Breast Cancer Linkage Consortium. Genetic Heterogeneity and
Penetrance Analysis of the BRCA1 and BRCA2 genes in breast cancer
families. Am J Hum Genet 1998;62:676-89
6. Struewing JP, Hartge P, Wacholder S, Baker SM, Berlin M, McAdams M,
Timmerman MM, Brody LC, Tucker MA (1997) The risk of cancer associated
with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. New
England Journal of Medicine 336:1401-1408
7. Couch FJ, DeShano ML, Blackwood MA, et al. BRCA1 mutations in women
attending clinics that evaluate the risk of breast cancer. N Engl J Med
1997; 336:1409-1415.
8. Claus EB, Risch N, Thompson WD. Autosomal dominant inheritance of
early onset breast cancer:implications for risk prediction. Cancer
1994;73:643-51
9. Gail MH, Brinton LA, Byar DP, et al.: Projecting individualized
probabilities of developing breast cancer for white females who are being
examined annually. J Natl Cancer Inst 1989; 81(24):1879-1886.
Berry DA, Parmigiani G, Sanchez J, et al. Probability of carrying a
mutation of breast-ovarian cancer gene BRCA1 based on family history. J
Natl Cancer Inst 1997; 89(3):227-238.
Cyrillic 3.0 pedigree software. Accessed on: March 30th, 2004.
Details available at:
http://www.exetersoftware.com/cat/cyrillic/cyrillic.html
Frank TS, Manley SA, Olopade OI et al. Sequence analysis of BRCA1 and
BRCA2: Correlation of mutations with family history and ovarian cancer
risk. J Clin Oncol 1998; 16:2417-2425.
Parmigiani G, Berry D, Aguilar O. Determining carrier probabilities
for breast cancer-susceptibility genes BRCA1 and BRCA2. Am J Hum Genet
1998; 62(1): 145-158.
Shattuck-Eidens D, Oliphant A, McClure M et al. BRCA1 sequence
analysis in women at high risk for susceptibility mutations. Risk factor
analysis and implications for genetic testing. JAMA 1997; 278:1242-1250.
The University of Texas Southwestern Medical Center at Dallas.
CancerGene. Available at
http://www3.utsouthwestern.edu/cancergene/index.ht
I would like to bring to your attention an error with respect to the
original article by Amir et al.[1]
The paper validated a few available breast cancer risk
prediction models and compared them to the Tyrer-Cuzick model.[2] From the paper by Amir et al., I understand that they used
the Cyrillic plug-in to estimate breast cancer risk (Cyrillic 3.1
Version). Although, I am only fa...
I would like to bring to your attention an error with respect to the
original article by Amir et al.[1]
The paper validated a few available breast cancer risk
prediction models and compared them to the Tyrer-Cuzick model.[2] From the paper by Amir et al., I understand that they used
the Cyrillic plug-in to estimate breast cancer risk (Cyrillic 3.1
Version). Although, I am only familiar with Cyrillic version 2.1,
according to the home page for Cyrillic 3.1, it calculates risk
assessments according to the BRCAPRO and Mendel models. In their paper,
the authors referred to the Ford model [3] and at times to
the Claus models as the BRCAPro model, which is not correct. It will be
good to clarify on this to the research community, as this paper is an
important reference in breast cancer research in perspectives of risk
estimation and model development. BRCAPRO [4,5] is one of the eight models available through the
CancerGene program [6,7] Amir et al.[1] consistently made this mistake in their paper: in the introduction, study
tools section, Table 4, Table 5, Table 9, and in Figure 1. Clarification
of what models were validated for their data is needed.
The risk models most widely used in breast cancer research, and in
clinical and genetic counseling are the Gail model,[8] the
Claus model, [9,10] BRCAPRO,[4,5] Myriad I, also called the Shattuck-Eidens model,[11] Myriad II, also called the Frank model,[12] the Couch model,[13] also known as
the UPenn model, the NCI model,[14] and the Family
History Assessment Tool.[15] Among them, BRCAPRO
estimates the probability of an individual being a carrier of a
deleterious BRCA-1 or -2 mutation, along with estimating the predicted
breast cancer risk, while the Gail and Claus models are empirical models
developed prior to the identification of the BRCA genes. The Myriad and
Couch models are empirical models to estimate the probability of BRCA1 or
BRCA2 mutations. CancerGene,[6,7] is a
software program that incorporates all the aforementioned models into a
single software package. After all the pedigree information and other
epidemiological risk factors required for each of these models have been
entered, CancerGene calculates the risk for each model separately. The
best feature of the program is its ability to calculate an individual
woman’s predicted risk values and outputs from all these models, allowing
an oncologist, genetic counselor, researcher, or physician to compare the
values of predicted risk.
References
1. Amir E, Evans DG, Shenton A, Lalloo F, Moran A, Boggis C, Wilson M,
Howell A. Evaluation of breast cancer risk assessment packages in the
family history evaluation and screening programme. J Med Genet. 2003
Nov;40(11):807-14.
2. Tyrer JP, Duffy SW, Cuzick J. A breast cancer prediction model
incorporating familial and personal risk factors. Statist. Med. 2004;
23:1111–1130
3. Ford D, Easton DF, Bishop DT, Narod SA, Goldgar DE, the Breast Cancer
Linkage Consortium. Risk of cancer in BRCA-1 mutation carriers. Lancet
1994;343:692–5.
4. Berry DA, Parmigiani G, Sanchez J, et al. Probability of carrying a
mutation of breast-ovarian cancer gene BRCA1 based on family history. J
Natl Cancer Inst 1997; 89(3):227-238.
5. Parmigiani G, Berry D, Aguilar O. Determining carrier probabilities
for breast cancer-susceptibility genes BRCA1 and BRCA2. Am J Hum Genet
1998; 62(1): 145-158.
6. Euhus DM. Understanding mathematical models for breast cancer risk
assessment and counseling. Breast J 2001; 7(4):224-232.
7. Euhus DM, Smith KC, Robinson L, Stucky A, Olopade OI, Cummings S,
Garber JE, Chittenden A, Mills GB, Rieger P, Esserman L, Crawford B,
Hughes KS, Roche CA, Ganz PA, Seldon J, Fabian CJ, Klemp J, Tomlinson G.
Pretest prediction of BRCA1 or BRCA2 mutation by risk counselors and the
computer model BRCAPRO. J Natl Cancer Inst 2002; 94(11):844-851.
8. Gail MH, Brinton LA, Byar DP, et al.: Projecting individualized
probabilities of developing breast cancer for white females who are being
examined annually. J Natl Cancer Inst 1989; 81(24):1879-1886.
9. Claus EB, Risch N, Thompson WD. Genetic analysis of breast cancer in the cancer and steroid hormone study.
Am J Hum Genet. 1991;48(2):232-42.
10. Claus EB, Risch N, Thompson WD. Autosomal dominant inheritance of early onset breast cancer:implications for risk prediction. Cancer 1994;73:643-51
11. Shattuck-Eidens D, Oliphant A, McClure M et al. BRCA1 sequence
analysis in women at high risk for susceptibility mutations. Risk factor
analysis and implications for genetic testing. JAMA 1997; 278:1242-1250.
12. Frank TS, Manley SA, Olopade OI et al. Sequence analysis of BRCA1 and
BRCA2: Correlation of mutations with family history and ovarian cancer
risk. J Clin Oncol 1998; 16:2417-2425.
13. Couch FJ, DeShano ML, Blackwood MA, et al. BRCA1 mutations in women
attending clinics that evaluate the risk of breast cancer. N Engl J Med
1997; 336:1409-1415.
14. Hartge P, Struewing JP, Wacholder S, Brody LC, Tucker MA. The
prevalence of common BRCA1 and BRCA2 mutations among Ashkenazi Jews. Am J
Hum Genet. 1999 Apr;64(4):963-70.
15. Gilpin CA, Carson N, Hunter AG. A preliminary validation of a family
history assessment form to select women at risk for breast or ovarian
cancer for referral to a genetics center. Clin Genet 2000; 58(4):299-308.
Dear Editors
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The first is the use of t...
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Dear Editor
We read with interest a recent report in your journal by Jakkula et al.[1] on two families of multiple epiphyseal dysplasia (MED) with the recurrent R718W mutation in COMP.
Key points of the report are:
1) In a family (family 1), two children presented with muscular weakness and all four family members with R718W showed moderate rise in plasma creatine kinase...
Dear Editor
We thank Dr Selvan for his comments [1] on our paper.[2] Cyrillic 3 does indeed use the BRCAPRO and MENDEL models. With regards to our use of BRCAPRO, we would like to draw his attention to the official Cyrillic 3 homepage [3] where it states clearly that the BRCAPRO plug-in calculates risk based on the “Bayes’ rules of determination of the probability of a mutation, given family history. An estimate of th...
Dear Editor
I would like to bring to your attention an error with respect to the original article by Amir et al.[1]
The paper validated a few available breast cancer risk prediction models and compared them to the Tyrer-Cuzick model.[2] From the paper by Amir et al., I understand that they used the Cyrillic plug-in to estimate breast cancer risk (Cyrillic 3.1 Version). Although, I am only fa...
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