KONSELING GENETIK M. Mansyur Romi Bag. Anatomi, Embriologi & Antropologi FK UGM Tim Genetika Klinik RSUP DR.SARDJITO YOGYAKARTA

Pertanyaan klasik: Peralatan lama: ? Kelamin janin ? ? Janin normal ? 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: Cairan amnion, 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 GENETIK KELAINAN 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) Hypercholesterolemia Sickle cell anemia Cystic fibrosis Tay-Sachs disease Huntington dss Phenylketonuria 1 in 500 1 in 600 (african ansestry) 1 in 1600 (european anst 1 in 3500 (ashkenazi jew 1 in 5000 1 in 10.000

Common conditions that are gene-influenced (Seashore & Weppner, 1996) Childhood Adulthood Cleft lip and palate Spina bifida Congenital heart dss Juvenile diabetes mell Cancer Pyloric stenosis Coronary artery dss Diabetes mellitus Schizophrenia Hypertension Alcoholism

Features of medical history that raise genetic concerns (Seashore & Weppner, 1996) 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 Cause of death Newcastle London Chromosomal Single gene Polygenic Nongenetic/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 Chromosomal Single gene Polygenic Nongenetic 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