Deteksi Mutasi Gen NKX2.5, TBXS, GATA4, dan MYH6 pada Defek Septum Atrium Sekundum Sporadik.
Deteksi Mutasi Gen NKX2.5, TBXS,
GATA4, dan MYH6 pada llefek Septum
Atrium Sekundum Sporadik
Sri Endah Rahayuningsih
Bagian llmu Kesehatan Anak, Falrultas Kedoktercn Unil'ersitas Padiadiaran
Abstruk: Mutasi gen NKX2.5, TBXS, GAU4, dan MYH6 telah ditemukan pada DSA.familial,
tetapi sarnpai saat ini belum ada penelitian tentang mutasi gen GATA4 dan MYH6 pada DSA
sporadik. Tujuan penelitian irci untuk mengetahui apakah ada hubungan mutasi gen NKX2.5,
TEXI GATA4, dan MYI76 dengan DSA sekundum sporadik Subjek penelitian ini adalah pasien
DSA sekundum dan kontrol adalah pasien tanpa penyakit jantung bawsan yang memenuhi
kriteria inklusi. Penelitian merupckan penelitian epidemiologi genetik dengan rancangaft
kasus kontrcl. Untuk lneftgu1i hipotesis adanya hubungan fftatxsi gen NKX2.5, TBXS, GAIA4,
MYH6 dengan DSA sekundum sporadik digunakan perhitungan Rasio Odds. Jumlah sampel
dihitung berdasarkan prevalensi. Deteksi mutasi gen NKX2.5, TBX1, GATA4, don MYH6
dan
dilalq4kan dengan pemeriksaan sekuensingterhadap isolasi DNA- Hasil penelitian menunjukkan
tempat mutasi NKX2.5, GAU4, dan MYH6yang berbeda dercgan penelitian terdahulu. Terdapat
hubungan mutasi gen NKX2.5, GAU4, dan MYH6 dengan DSA sekundum sporadik {Rasio
Odds: ]6,01; IK-13,97-18,05. Tidak ditemukan mutosi TBXS. Ditemukan tujuh anak DSA
sekundum sporadik dengan mutasi gen NKX2.5, GAU4, dan MYE6 yang terdiri dari satu
mhsense mutdion gen NKX2.5, satu frameshifi mutalion dengan denovo mutMion, satu missense matffiion gen GATA4, dan empat missense mutstinns gen MYH6. Kesimpulan tempat
mutasi gen NKX2.5, GATA4, dan MYH6 pada penelitian
ini berbeda
dengan penelitian
sebelumnya, terdapat hubungan bermakna mutasi gen NKX2.5, CI'4TA4, dan MYH6 dengan DSA
sekundum sporadik Ditemukan satuframehifi matdions gen GATA4 yang merupakan de nwo
mutations.
Kata kunci : D SA sporadik, NKX2, 5, GAU4, TBXS, MYH6.
Maj Kedokt Indon, Volum: 59, Nomor: 7, Juli 2009
De teksi
Mutasi Gen NKX2. 5, TBX5,
GATA 4, dan
MYH6
Detection of NKX2.5, TBX5, GATA4, and II{YH6 Gene Mutations
in Finding an Association with Sporadic Secundum Atrial Septal Defect
Sri Endah Rahayuningsih
Pediatric Depqrtfient, Faculty of Medicine Padjadjaran University
Abstrac't: Mutations of NKX2.5, TBX1, GATA4, and MIH6 gene had been identified infamilial
ASD, butuntilrecentlyreports onGAA4 andMYH6 genemutationsin sporadicASDwas stillnot
available. Tbe aimof this studytiasto detttuihe the associtTtionbefueetNKX2.S, TBX5, GAA4,
and MYH6 gene mutations and sporadic secundum ASD. The subjects of this study were patients
with secundurn ASD and the control group were patimk without cangmital heart disease. A
genetic epidemiologt study was conducted with case control design to determine the association
betwem NKX2.5, TBX1, GATA4, and MYH6 gene mutations and sporadic secundum ASD. Hypothesis whether there was an association between NKX2.5, TBX1, GATA4, and MIH6 gene
rnutations and sporadic secundum ASD was tested by Odds Ratio celculation. The sample size
wasealculatedbasedonprevalence. SequeTrcingafDNAisolatiqnwasperfC(p.Glu1 354Gln)
'lA>T(p.Glu1354Val)
c. a7 7 I
Gambar
8,
(v.Gln 1 593 Le u)
I
Perbandingan Tempat Mutasi MYH6 pada Penelltian ini, yang Merupakan Missense Mutations,
dengan Penelitian
SebelumnYa
Kesimpulan
D[ penyunting. Moss asd Adam's heart disease in infants; children, dnd ail6lesisnts, edisi ke-6. Philadelphia: William & Wilkins;
Ditemukan sebelas tempat mutasi NKX2.5, GATA4 dan
20at.h.603-17.
Ivm{6 yang berbeda dengan penelitian terdahulu' Mutasi
gen NKX2.5, dan MYH6 berhubungan dengan terjadinya
3.
DSA sekundum qporadik, karern mutasi yang terjadi adalah
missense mutation yangtidak menimbulkan premature stop
codon, sedangkan mutasi gen GATA4 pada penelitian ini
adalah penyebab terjadinya DSA sekundum qporadik karena
4.
320
A{
Vick GW. Defects of the atrial septum including atrioventricular
septal defects, Dalam; Garson 4 Brieker JI, Fisher DJr Neish S&
penyunting. The sCience and praiiice of pediatric cardiology,
edisi ke-2. Baltimore: Williams & Wilkins; 1998' h. 1141-80.
Okubo A" Miyoshi O, Baba K. A novel GAIA4 nrutation completely segregated w.ith atrial septal defect in a large Japanese
family. J Med Genet. 20A4;41:97-102.
Maj Kedokt Indon, Volum: 59, Nomor: 7' Juli
2O09
DeteksiMutasi Gen NKX2.5, TBX1, GAA4, danMYH6
5.
6.
7.
8.
Dinas Kesehatan Provinsi Jawa Barat. Profil kesehatan provinsi
Jawa Barat. Bandrurg: Departemen Kesehatan Provinsi Jawa Baral;
14.
2404.
15.
Park MK Pediatric cardiology for practitioners, edisi ke-5. Philadelphia: Mosby; 2007.
Kdnig K, Will JC, Berger F. Familial congenital heart disease,
progressive atrioventricular block and the cardiac homeobox
transcription factor gene NKX2.5: identifrcation of a novel
mutation. Clin Res Cardiol. 2006;95:l-5.
Khalid Y, Ghina M, Fadi B, Fadi C, May K Joseph R, dkk.
Consanguineous marriage and congenital heart defects: a case-
control study in the neonatal period. Am J Med
9.
Genet.
l1
42.
Forrester MB, Merz RD. Descriptive epidemiology of selected
coageirital heart defects, Havtaii,L986-1999. Paed Periaat Epid.
17.
Morales-Suaiez-Yarcla MM,
Bille C, Christensen K, Olsen
J.
liam & Wilkins; 2001.h.64-79.
Maj Kedold Indon, Volum: 59, Nomor: 7, Juli 2009
Reamon-Buettner SM, Borlak J. Somatic NKX2-5 mutations as a
novol mechanism ofdisease in complex congenital heart disease.
J Med Genet. 2004;4L:684-90.
Reamon-Buettner SM, Borlak J. TBX5 mutations in non-HoltOram syndrome (HOS) malformed hearts. Hum Mutat.
2004;24(l):218-22.
18.
Carniel E, Taylor MRQ Sinagra G Lenarda d Ku L, Fain PR.
aMyosin heavy chain a sarcomeric gene associated with dilated
aad hypertrophic phenotypes of cardiomyopathy. Circulations.
2405;lL2:54-9.
19. Gruber
20.
2l
.
2004;18:415-24.
Smoking habits, nicotine use, and congenital malformations.
Obstet & Gynec. 20A6j07 :5 l-7.
Clark EB. Etiology of congenital cardiovascular malformations:
epidemiology and genetics. Dalam: Allen HD, Gutgesell HR Clark
EB, Driscoll DJ, penyunting. Moss and Adam's heart disease in
infanls, childreq aad adolescents, edisi ke-6. Philadelphia: Wil-
1 97 6;5 3 :7 0 1 -2.
Schott JJ, Berxon DW, Basson CT. Congenital heart disease caused
by mutations in the transcription factors NKX2-5. Science.
1998;281:108-11
16.
2006;140 A:1524-30 .
Cedergren MI, Kallen BAJ. Maternal obesity and infant heart
defects, Obes Res. 2003;1 l:123-8.
10. Botto LD, Cornea A, Erickson JD. Racial and temporal variations in the prevalence ofheart disease. Pediatrios. 2001;107:32-
Nora JJ, Nora AH. Recurrence risks in children having one parerf
with a congenit al heart disease. Circulat ions.
22.
23.
PJ, Epstein JA Development gone awry: congenital heart
disease. Circ Res. 2004;94:273-83.
Ching YH, Ghosh TK, Cross SJ. Mutation in myosin heavy
chain 6 causes atrial septal defect. Nat Genet.2005;31(4):423-8.
Strachan T, Read AP. Human molecular genetics, edisi ke-3. New
York: Garland Science; 2004.
Lewin B. Genes VIL USA: Odord University Press; 1999.
Jackson FLC. Human genetic variation and health: new assessment approaches based on ethnogenetic layering. Brit Med 8u11.
2004',69:215-35.
@r"
32t
GATA4, dan MYH6 pada llefek Septum
Atrium Sekundum Sporadik
Sri Endah Rahayuningsih
Bagian llmu Kesehatan Anak, Falrultas Kedoktercn Unil'ersitas Padiadiaran
Abstruk: Mutasi gen NKX2.5, TBXS, GAU4, dan MYH6 telah ditemukan pada DSA.familial,
tetapi sarnpai saat ini belum ada penelitian tentang mutasi gen GATA4 dan MYH6 pada DSA
sporadik. Tujuan penelitian irci untuk mengetahui apakah ada hubungan mutasi gen NKX2.5,
TEXI GATA4, dan MYI76 dengan DSA sekundum sporadik Subjek penelitian ini adalah pasien
DSA sekundum dan kontrol adalah pasien tanpa penyakit jantung bawsan yang memenuhi
kriteria inklusi. Penelitian merupckan penelitian epidemiologi genetik dengan rancangaft
kasus kontrcl. Untuk lneftgu1i hipotesis adanya hubungan fftatxsi gen NKX2.5, TBXS, GAIA4,
MYH6 dengan DSA sekundum sporadik digunakan perhitungan Rasio Odds. Jumlah sampel
dihitung berdasarkan prevalensi. Deteksi mutasi gen NKX2.5, TBX1, GATA4, don MYH6
dan
dilalq4kan dengan pemeriksaan sekuensingterhadap isolasi DNA- Hasil penelitian menunjukkan
tempat mutasi NKX2.5, GAU4, dan MYH6yang berbeda dercgan penelitian terdahulu. Terdapat
hubungan mutasi gen NKX2.5, GAU4, dan MYH6 dengan DSA sekundum sporadik {Rasio
Odds: ]6,01; IK-13,97-18,05. Tidak ditemukan mutosi TBXS. Ditemukan tujuh anak DSA
sekundum sporadik dengan mutasi gen NKX2.5, GAU4, dan MYE6 yang terdiri dari satu
mhsense mutdion gen NKX2.5, satu frameshifi mutalion dengan denovo mutMion, satu missense matffiion gen GATA4, dan empat missense mutstinns gen MYH6. Kesimpulan tempat
mutasi gen NKX2.5, GATA4, dan MYH6 pada penelitian
ini berbeda
dengan penelitian
sebelumnya, terdapat hubungan bermakna mutasi gen NKX2.5, CI'4TA4, dan MYH6 dengan DSA
sekundum sporadik Ditemukan satuframehifi matdions gen GATA4 yang merupakan de nwo
mutations.
Kata kunci : D SA sporadik, NKX2, 5, GAU4, TBXS, MYH6.
Maj Kedokt Indon, Volum: 59, Nomor: 7, Juli 2009
De teksi
Mutasi Gen NKX2. 5, TBX5,
GATA 4, dan
MYH6
Detection of NKX2.5, TBX5, GATA4, and II{YH6 Gene Mutations
in Finding an Association with Sporadic Secundum Atrial Septal Defect
Sri Endah Rahayuningsih
Pediatric Depqrtfient, Faculty of Medicine Padjadjaran University
Abstrac't: Mutations of NKX2.5, TBX1, GATA4, and MIH6 gene had been identified infamilial
ASD, butuntilrecentlyreports onGAA4 andMYH6 genemutationsin sporadicASDwas stillnot
available. Tbe aimof this studytiasto detttuihe the associtTtionbefueetNKX2.S, TBX5, GAA4,
and MYH6 gene mutations and sporadic secundum ASD. The subjects of this study were patients
with secundurn ASD and the control group were patimk without cangmital heart disease. A
genetic epidemiologt study was conducted with case control design to determine the association
betwem NKX2.5, TBX1, GATA4, and MYH6 gene mutations and sporadic secundum ASD. Hypothesis whether there was an association between NKX2.5, TBX1, GATA4, and MIH6 gene
rnutations and sporadic secundum ASD was tested by Odds Ratio celculation. The sample size
wasealculatedbasedonprevalence. SequeTrcingafDNAisolatiqnwasperfC(p.Glu1 354Gln)
'lA>T(p.Glu1354Val)
c. a7 7 I
Gambar
8,
(v.Gln 1 593 Le u)
I
Perbandingan Tempat Mutasi MYH6 pada Penelltian ini, yang Merupakan Missense Mutations,
dengan Penelitian
SebelumnYa
Kesimpulan
D[ penyunting. Moss asd Adam's heart disease in infants; children, dnd ail6lesisnts, edisi ke-6. Philadelphia: William & Wilkins;
Ditemukan sebelas tempat mutasi NKX2.5, GATA4 dan
20at.h.603-17.
Ivm{6 yang berbeda dengan penelitian terdahulu' Mutasi
gen NKX2.5, dan MYH6 berhubungan dengan terjadinya
3.
DSA sekundum qporadik, karern mutasi yang terjadi adalah
missense mutation yangtidak menimbulkan premature stop
codon, sedangkan mutasi gen GATA4 pada penelitian ini
adalah penyebab terjadinya DSA sekundum qporadik karena
4.
320
A{
Vick GW. Defects of the atrial septum including atrioventricular
septal defects, Dalam; Garson 4 Brieker JI, Fisher DJr Neish S&
penyunting. The sCience and praiiice of pediatric cardiology,
edisi ke-2. Baltimore: Williams & Wilkins; 1998' h. 1141-80.
Okubo A" Miyoshi O, Baba K. A novel GAIA4 nrutation completely segregated w.ith atrial septal defect in a large Japanese
family. J Med Genet. 20A4;41:97-102.
Maj Kedokt Indon, Volum: 59, Nomor: 7' Juli
2O09
DeteksiMutasi Gen NKX2.5, TBX1, GAA4, danMYH6
5.
6.
7.
8.
Dinas Kesehatan Provinsi Jawa Barat. Profil kesehatan provinsi
Jawa Barat. Bandrurg: Departemen Kesehatan Provinsi Jawa Baral;
14.
2404.
15.
Park MK Pediatric cardiology for practitioners, edisi ke-5. Philadelphia: Mosby; 2007.
Kdnig K, Will JC, Berger F. Familial congenital heart disease,
progressive atrioventricular block and the cardiac homeobox
transcription factor gene NKX2.5: identifrcation of a novel
mutation. Clin Res Cardiol. 2006;95:l-5.
Khalid Y, Ghina M, Fadi B, Fadi C, May K Joseph R, dkk.
Consanguineous marriage and congenital heart defects: a case-
control study in the neonatal period. Am J Med
9.
Genet.
l1
42.
Forrester MB, Merz RD. Descriptive epidemiology of selected
coageirital heart defects, Havtaii,L986-1999. Paed Periaat Epid.
17.
Morales-Suaiez-Yarcla MM,
Bille C, Christensen K, Olsen
J.
liam & Wilkins; 2001.h.64-79.
Maj Kedold Indon, Volum: 59, Nomor: 7, Juli 2009
Reamon-Buettner SM, Borlak J. Somatic NKX2-5 mutations as a
novol mechanism ofdisease in complex congenital heart disease.
J Med Genet. 2004;4L:684-90.
Reamon-Buettner SM, Borlak J. TBX5 mutations in non-HoltOram syndrome (HOS) malformed hearts. Hum Mutat.
2004;24(l):218-22.
18.
Carniel E, Taylor MRQ Sinagra G Lenarda d Ku L, Fain PR.
aMyosin heavy chain a sarcomeric gene associated with dilated
aad hypertrophic phenotypes of cardiomyopathy. Circulations.
2405;lL2:54-9.
19. Gruber
20.
2l
.
2004;18:415-24.
Smoking habits, nicotine use, and congenital malformations.
Obstet & Gynec. 20A6j07 :5 l-7.
Clark EB. Etiology of congenital cardiovascular malformations:
epidemiology and genetics. Dalam: Allen HD, Gutgesell HR Clark
EB, Driscoll DJ, penyunting. Moss and Adam's heart disease in
infanls, childreq aad adolescents, edisi ke-6. Philadelphia: Wil-
1 97 6;5 3 :7 0 1 -2.
Schott JJ, Berxon DW, Basson CT. Congenital heart disease caused
by mutations in the transcription factors NKX2-5. Science.
1998;281:108-11
16.
2006;140 A:1524-30 .
Cedergren MI, Kallen BAJ. Maternal obesity and infant heart
defects, Obes Res. 2003;1 l:123-8.
10. Botto LD, Cornea A, Erickson JD. Racial and temporal variations in the prevalence ofheart disease. Pediatrios. 2001;107:32-
Nora JJ, Nora AH. Recurrence risks in children having one parerf
with a congenit al heart disease. Circulat ions.
22.
23.
PJ, Epstein JA Development gone awry: congenital heart
disease. Circ Res. 2004;94:273-83.
Ching YH, Ghosh TK, Cross SJ. Mutation in myosin heavy
chain 6 causes atrial septal defect. Nat Genet.2005;31(4):423-8.
Strachan T, Read AP. Human molecular genetics, edisi ke-3. New
York: Garland Science; 2004.
Lewin B. Genes VIL USA: Odord University Press; 1999.
Jackson FLC. Human genetic variation and health: new assessment approaches based on ethnogenetic layering. Brit Med 8u11.
2004',69:215-35.
@r"
32t