KONSELING GENETIK

M. Mansyur RomiBag. Anatomi, Embriologi & Antropologi FK UGM

Tim Genetika Klinik RSUP DR.SARDJITO YOGYAKARTA

Pertanyaan klasik: ? Kelamin janin ? ? Janin normal ?

Peralatan lama: Variabel ukuran uterus Kenaikan BB ibu Auskultasi jantung janin

Peralatan abad XX 1950an: analisis sel janin dr cairan amnion

utk keberadaan sex chromatin 1966: kultur sel dr cairan amnion 1972: USG utk diagnosis anencephaly Saat ini USG mampu menilai hampir

seluruh anatomi janin

Penafsiran diagnosis pranatal bergantung:

Sampel yg dapat diperoleh Teknik yg dapat dipakai Informasi yg dapat diolah

Ragam sampel: Serum maternal, untuk:

Penanda (marker) cerminan kesehatan janin Protein yg berasal dr janin

Cairan amnion, untuk: Bahan yg dpt dianalisis (analytes) Sel yg berasal dr janin

Villus chorion, untuk: sel trofoblast Sel darah janin: eritrosit & lekosit

Teknik yg dipakai

Sampling darah maternal Amniocentesis Chorionic villous sampling (CVS) Cordocentesis Ultrasonography (USG) Embryo biopsy

Penapisan (screening) serum maternal Alfa fetoprotein (AFP)

Produksi dlm hepar janin, puncak: mgg 10-13 Dlm darah maternal lewat placenta atau difusi

menembus membran Konsentrasi puncak : mgg 24-32

Some causes of increased maternal serum AFP concentration Undersestimated gestational age Threatened abortion Multiple pregnancy Fetal abnormality: anencephaly, open neural tube

defect, anterior abdominal wall defect, Turner’s syndrome, bowel atresias, skin defects

Placental hemangioma

Decreased matenal serum AFP concentration: Trisomy 21, 18

Triple screen: AFP Human chorionic gonadotropin (HCG)

Disekresi embryo baru implantasi Unconjugated estrogen (UE)

Amniocentesis Cairan amnion volume> dg usia: 15-350

ml berisi: urin janin + bahan maternal normal steril dan tahan infeksi perlakuan umumnya pd trimester dua dg

risiko kematian janin 0,5 % perlakuan dini: mgg 12-15 dg risiko 2-11%

amniocentesis

Indikasi Analisis kromosom dari sel amnion yang

dikultur: trisomi 21 dsb Estimasi konsentrasi AFP dan aktifitas

acetylcholin esterase (Ache): neural tube defects

Analisis biokimiawi cairan amnion dan sel kultur: inborn error of metabolism

CVS Sel trofoblas: cermin status genetik janin cepat berproliferasi, tak perlu kultur sumber utk:

karyotype pemeriksaan DNA pengukuran aktifitas enzim yg diekspresi derivat

fibroblast perlakuan mgg 9-11 dg risiko kematian janin 2-

13%

Chorionic Villus Sampling (CVS)

Indication for CVS Diagnosis of chromosomal disorders Increasing number of inborn error of

metabolism DNA analysis

Cordocentesis Dilakukan bila cara lain utk mdpt sel janin

takcukup atau serum fetal sangat perlu dikaji sel janin utk: karyotyping bila dg cara lain

tampak mosaicism darah janin utk: mengukur protein serum hanya di pusat sangat khusus, risiko kematian

janin 0-3%

USG

Informasi anatomis dan fungsional janin mengungkap struktur: kepala, thorax,

abdomen, skeleton dan pertumbuhan janin real time usg: struktur & aktifitas jantung modern usg utk rincian anatomi janin:

ukuran & posisi ruang jantung, ventriculus cerebri, aorta & a.pulmonalis

MENGAPA PERLU MEMPELAJARI GENETIKA? Pergeseran pola : penyakit ‘lingkungan

‘(malnutrisi & infeksi) menurun, penyakit degeneratif & genetik meningkat

Terungkapnya peran faktor genetik sebagai penyebab penyakit pada manusia

Turunnya angka kematian bayi: Indonesia: 142%o(71)67%o(91),DIY:62%o(‘80)26%o(‘92)15,5%o(‘00)

Meluasnya konsep keluarga kecil

Genetically determined diseases Chromosomal disorders Single gene disorders Polygenic or multifactorial diseases Somatic cell genetic disorders

Mitochondrial genetic disorders

RAGAM PENYAKIT GENETIKKELAINAN KROMOSOMAL Pada umumnya jarang Pola pewarisan tidak jelas Biasanya resiko kerabat rendah

KELAINAN GEN TUNGGAL/MONOGENIK Jumlah ragamnya banyak, masing-masing kasusnya sedikit Pola pewarisan jelas, ikuti hukum Mendel Resiko kerabat tinggi

PENYAKIT POLIGENIK/MULTIFAKTORIAL Banyak dijumpai Pola pewarisan tidak jelas Resiko kerabat rendah-sedang

KELAINAN MUTASI SEL SOMATIK Mungkin ada gambaran “mosaik” Menyebabkan neoplasia/keganasan

KELAINAN GEN MITOKHONDRIA Pola pewarisan”maternal”atau sporadic

Coiling of DNA

Incidence of some common single gene disorders (Seashore & Weppner, 1996)

Single gene disorder Incidence

HypercholesterolemiaSickle cell anemiaCystic fibrosisTay-Sachs diseaseHuntington dssPhenylketonuria

1 in 5001 in 600 (african ansestry)1 in 1600 (european anst1 in 3500 (ashkenazi jew1 in 50001 in 10.000

Common conditions that are gene-influenced (Seashore & Weppner, 1996)

Childhood Adulthood

Cleft lip and palateSpina bifidaCongenital heart dssJuvenile diabetes mellCancerPyloric stenosis

Coronary artery dssDiabetes mellitusSchizophreniaHypertensionCancerAlcoholism

Features of medical history that raise genetic concerns (Seashore & Weppner, 1996)

Feature Risk

Multiple affected family members

Single gene; multifactorial; chromosomal

Family history of known inherited disorder

Risk of being affected with same condition

Maternal age over 35 yrs at delivery

Chromosome abnormality in baby

Genetic components of childhood mortality in the UK (Gelehrter et al. 1998)

Cause of death Newcastle London

ChromosomalSingle genePolygenicNongenetic/unknown

Total deaths

2.5% 8.5% 31.0% 58.0%

1041

}12.0%

25.5% 62.5%

200

Frequency of genetic disorders among pediatric Hospital Admissions in North America (Gelehrter et al. 1998)

Cause Seattle Montreal

ChromosomalSingle genePolygenicNongenetic

No. of admissions

0.6% 3.9% 48.9% 46.9%

4,115

0.4% 6.9% 29.0% 63.7%

12,801

Suggested readings: Gelehrter TD, Collins FS, Ginsburg D. Principles of

Medical Genetics 2nd ed. Williams & Wilkins 1998 Mange AP, Mange EJ. Genetics: Human Aspects 2nd ed.

Sinauer Assoc. Inc. 1990 Seashore MR, Wappner RS. Genetics in Primary Care &

Clinical Medicine. Prentice-Hall 1996 Kingston HM. ABC of Clinical Genetics BMJ 1994 Hartono, Risanto, Suryadi E, Romi MM. Buku Genetika

Kedokteran, FK UGM 2004