DEVELOPMENTAL GENETICS, BIRTH DEFECT & PRENATAL DIAGNOSIS

M. Mansyur RomiDepartemen Anatomi, FK UGM

Tim Genetika Klinik RSUP DR.SARDJITO YOGYAKARTA

The Genetic Basis of Development

How do cells with the same genes grow up to be so different?

Three Procceses of Development The transformation from a zygote into an

organism Results from three interrelated processes:

cell division, cell differentiation morphogenesis

Figure 21.3a, b(a) Fertilized eggs of a frog

(b) Tadpole hatching from egg

Through a succession of mitotic cell divisions The zygote gives rise to a large number of cells

In cell differentiation Cells become specialized in structure and function

Morphogenesis encompasses the processes That give shape to the organism and its various parts

Differential gene expression Nearly all the cells of an organism have genomic

equivalence, that is, they have the same genes

Differences between cells in a multicellular organism differences in gene expression not from differences in the cells’ genomes

yields a variety of cell types each expressing a different combination of genes multicellular eukaryotes

cells become specialized as a zygote develops into a mature organism

Cell Differentiation

Different types of cells Make different proteins because different combinations of

genes are active in each type

Muscle cell Pancreas cells Blood cells

Cell Diferentiation

may retain all of their genetic potential Most retain a complete set of genes May be totipotent

Differentiated cells

The Stem Cells of Animals A stem cell Is a relatively unspecialized cell Can reproduce itself indefinitely Can differentiate into specialized cells of one or

more types, given appropriate conditions

Totipotentcells

Liver cells Nerve cells

Early human embryoat blastocyst stage(mammalian equiva-lent of blastula) From bone marrow

in this example

PluripotentcellsCultured

stem cells

Differentcultureconditions

Differenttypes ofdifferentiatedcells

Blood cells

Embryonic stem cells

Adult stem cellsEmbryonic and Adult Stem Cells Stem cells can be isolated From

early embryos at the blastocyst stage

Adult stem cells pluripoten

t, able to give rise to multiple but not all cell types

Complex assemblies of proteins control eukaryotic transcription

A variety of regulatory proteins interact with DNA and with each other

To turn the transcription of eukaryotic genes on or off

Transcriptional Regulation of Gene Expression During Development

Assist in initiating eukaryotic transcriptionEnhancers Promoter

Gene

DNA Activatorproteins

Otherproteins

Transcriptionfactors

RNA polymerase

Bendingof DNA

Transcription

Transcription Factors

Cytoplasmic Determinants and Cell-Cell Signals in Cell Differentiation

Cytoplasmic determinants in the cytoplasm of the unfertilized egg Regulate the expression of genes in the zygote that affect

the developmental fate of embryonic cells

Sperm

Molecules of another cyto-plasmic deter-minant

Unfertilized egg cell

Molecules of a a cytoplasmicdeterminant Fertilization

Zygote(fertilized egg)

Mitotic cell division

Two-celledembryo

Nucleus

Sperm

Induction

Signal molecules from embryonic cells cause transcriptional changes in nearby target cells

Early embryo(32 cells)

NUCLEUS Signaltransductionpathway

Signalreceptor

Signalmolecule(inducer)

Induction by nearby cells. The cells at the bottom of the early embryo depicted here are releasing chemicals that signal nearby cells to change their gene expression.

(b)

Pattern Formation

Pattern formation in animals and plants results from similar genetic and cellular mechanisms

Pattern formation Is the development of a spatial organization of tissues and

organs Occurs continually in plants Is mostly limited to embryos and juveniles in animals

Cell Positioning Positional information

Consists of molecular cues that control pattern formation

Tells a cell its location relative to the body’s axes and to other cells

Cascades of gene expression and cell-to-cell signaling direct the development of an animal

Early understanding of the relationship between gene expression and embryonic development

Came from studies of mutants of the fruit fly Drosophila melanogaster

THE GENETIC CONTROL OF EMBRYONIC DEVELOPMENT

Eye

Antenna

LegS

EM

50

Head of a normal fruit fly Head of a developmental mutant

What Are Birth Defects?

Birth defects are defined as abnormalities of structure, function, or body metabolism that are present at birth. These abnormalities lead to mental or physical disabilities or are fatal.

There are more than 4,000 different known birth defects ranging from minor to serious, and although many of them can be treated or cured, they are the leading cause of death in the first year of life.

What Are Birth Defects?

Birth defects are defined as abnormalities of structure, function, or body metabolism that are present at birth. These abnormalities lead to mental or physical disabilities or are fatal.

There are more than 4,000 different known birth defects ranging from minor to serious, and although many of them can be treated or cured, they are the leading cause of death in the first year of life.

Birth Defects Some babies survive the pregnancy but are born with

serious problems called birth defects. 3% of all live-born infants have an major

anomaly Additional anomalies are detected during

postnatal live – about 6% at 2 year-olds, 8% in 5year-olds, other 2% later

Single minor anomalies are present in about 14% of newborns

Birth defects Major anomalies are more common in early embryos

(up to 15%) than they are in newborns (3%). Most severely malformed embryos are spontaneously aborted during first 6 to 8 weeks.

Some birth defects include: Cerebral Palsy Cleft Lift and/or palate Down Syndrome Muscular Dystrophy Sickle Cell Anemia Spina Bifida and more!

Causes of Birth Defects Some causes are environmental because it is during

the first few weeks that a baby develops all the bodily systems needed for survival The mother’s diet Any diseases or infections the mother has Harmful substances Some medicines Exposure to hazards (such as chemicals, X-rays,

etc.) Some causes are hereditary

Sometimes a child inherits a defective gene that is dominant such as Huntington's

Some conditions affect only one sex and usually it’s the males Hemophilia Color blindness and more

More Causes of Birth defects

Errors in chromosomes Such as when a baby has too many

or too few chromosomes or has broken or rearranged chromosomes

This usually leads to Down Syndrome

Problems in Prenatal Development

Sometimes a pregnancy begins, but a baby doesn’t develop normally If the baby dies before the 20th

week it is called a miscarriage If the baby dies after that time, it

is called a stillbirth. 15-20% of recognized pregnancies

end in miscarriage 2% ends in stillbirth

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

Birth defects Major anomalies are more common in early embryos

(up to 15%) than they are in newborns (3%). Most severely malformed embryos are spontaneously aborted during first 6 to 8 weeks.

Some birth defects include: Cerebral Palsy Cleft Lift and/or palate Down Syndrome Muscular Dystrophy Sickle Cell Anemia Spina Bifida and more!