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Genetic Disorder Hesty Wahyuningsih  Sasaran Belajar 1. Ketepatan dalam menguraikan dan menyebutkan contoh Genes and human disease. 2. Ketepatan dalam menguraikan dan menyebutkan contoh Mendelian disorder. 3. Ketepatan dalam menguraikan dan menyebutkan contoh Complex multigenic di...

Genetic Disorder Hesty Wahyuningsih  Sasaran Belajar 1. Ketepatan dalam menguraikan dan menyebutkan contoh Genes and human disease. 2. Ketepatan dalam menguraikan dan menyebutkan contoh Mendelian disorder. 3. Ketepatan dalam menguraikan dan menyebutkan contoh Complex multigenic disorder. 4. Ketepatan dalam menguraikan dan menyebutkan contoh Chromosomal disorder. 5. Ketepatan dalam menguraikan dan menyebutkan contoh Non-Mendelian  Contoh gene-huma n disease  Burden of genetic disease in humans Type of genetic disease Prevalence (%) Monogenic 1 Chromosomal aberrations 0.5 Multifactorial, congenital / juvenile onset 4 Multifactorial, adult onset 60  Categories of genetic disorder Monogenic → mendelian Chromosomal (numerical, structural) → non mendelian Multifactorial → non menedelian Pewarisan Mendelian Autosomal: - autosomal dominan - autosomal resesif Sex-link - X-linked dominan - X-linked resesif - Y-linked PEDIGREE - Jenis kelamin - Hubungan antar individu dalam keluarga - Status penyakit - Garis horizontal: satu generasi - Garis vertikal: keturunan (sebelum → orangtua, atau sesudahnya → anak)  Monogenic 1. Autosomal Dominan 11  Autosomal Dominan Dd dd boy girl boy girl Dd Dd dd dd Tanda-tanda autosomal dominan Laki dan perempuan mempunyai kesempatan yang sama menjadi penderita Penderita terdapat dalam >1 generasi Transmisi oleh kedua jenis kelamin Muncul dalam keadaan heterozigot Homozigot lebih berat kondisinya Contoh: achondroplasia, retinitis pigmentosa, neurofibromatosis, penyakit neurodegeneratif Huntington. 13 Pedigree autosomal dominan  Monogenic 2. Autosomal Resesif 15  Tanda-tanda autosomal resesif Laki dan perempuan mempunyai kesempatan yang sama menjadi penderita Penderita biasanya hanya pada 1 generasi Orang tua seringnya ada hubungan keluarga (consanguineous) Muncul dalam keadaan homosigot Contoh penyakit: Thalassemia, Congenital adrenal hyperplasia, phenylketonuria (PKU) 16  Autosomal resesif Carrier Carrier Rr Rr RR Rr Rr rr Normal Carrier Carrier Affected Pedigree autosomal resesif PHENYL KETONURIA  PHENYL KETONURIA Mousy odour of urine Immediate dark green color appeared that faded within a few minutes when a few drops of 10% aqueous FeCl3 sol was added to urine Diaper test to screen young infants (< 2 months) with PKU. Adding a drop of clear yellow 10% aqueous ferric chloride solution to a wet diaper allows immediate appearance of green spot.  Monogenic 3. X-linked (X-terangkai) 21 Tanda-tanda X-linked (X-terangkai) ▪ Kebanyakan penderitanya adalah laki-laki ▪ Terdapat penderita pada beberapa generasi ▪ Ibu penderita adalah karier yang sehat ▪ Tidak ada penurunan dari bapak ke anak laki-lakinya Contohnya: Sindrom Fragile X, AIS, Buta warna, Duchene Muscular Dystrophy, Hemofilia, Riketsia 22  X- Linked XY XX XX XX XY XY Normal Carrier Normal Affected Pedigree of X-linked NON MENDELIAN  Non-Mendelian inheritance ▪ Reduced penetrance ▪ Anticipation ▪ Genomic imprinting ▪ Mitochondrial inheritance ▪ Multifactorial and polygenic inheritance  Non-Mendelian inheritance ▪ Reduced penetrance ▪ Anticipation ▪ Genomic imprinting ▪ Mitochondrial inheritance ▪ Multifactorial and polygenic inheritance  Reduced penetrance + + + - + + not all persons with a mutation develop the disease Examples: Hereditary cancer Spastic paraplegia  Non-Mendelian inheritance ▪ Reduced penetrance ▪ Anticipation ▪ Genomic imprinting ▪ Mitochondrial inheritance ▪ Multifactorial and polygenic inheritance  Anticipation ▪ The severity of the disease increases and the age of onset decreases in subsequent generations ▪ The underlying mutation is a triplet repeat that expands with every generation ▪ Examples: Fragile X- Syndrome  Non-Mendelian inheritance ▪ Reduced penetrance ▪ Anticipation ▪ Genomic imprinting ▪ Mitochondrial inheritance ▪ Multifactorial and polygenic inheritance  Genomic imprinting + + + + + + + + + + + + + + Disease only if inherited from the mother Girls and boys are equally affected  Imprinting ▪“Parent of origin effect” ▪Only one of the paternal chromosomes is active, the other is inactivated by imprinting ▪Examples: ❖ Angelman syndrome ❖ Prader-Willi syndrome ❖ Beckwitt-Wiedemann syndrome 15q11-q13 ▪ No paternal contribution: Prader-Willi syndrome ▪ No maternal contribution: Angelman syndrome  PRADER WILLI SYNDROME Hypotonia, obesity, small hands and feet, mild intellectual dissability, hypogonadism Etiology: a loss of expression of the paternally expressed genes on chromosome 15q11.2-q13. Labial Hypoplasia Hypotonia Obesity Small hand and feet  Prader-Willi syndrome ▪ Paternal deletion 70% ▪ Maternal uniparental disomy 30% ▪ Imprinting centre mutations G mutation in mitochondrial DNA Encephalopathy, lactic acidosis, stroke-like episodes Diabetes mellitus Pewarisan Mitokondrial Proses konsepsi: kepala sperma (tidak terdapat mitokondria) yg masuk ke sel telur ibu. DNA mitokondria --> 100% diwariskan dari Ibu  Pewarisan Mitochondrial Laki-laki tidak dapat mewariskan penyakit (mutasi) Kedua jenis kelamin dapat menjadi penderita – Laki-laki lebih sering menjadi penderita – Wanita mungkin dengan gejala yang lebih ringan Semua anak perempuan mempunyai risiko meneruskan mutasi Semua anak laki-laki mempunyai risiko untuk menjadi penderita Proporsi penderita laki dan perempuan sangat bervariasi – In LHON (Leber Hereditary Optic Neuropathy)50% anak laki, 30% anak perempuan Pedigree of Mitochondrial Inheritance  Mitochondrial inheritance Heteroplasmy: The percentage of the mutated DNA determines the severity of the disease The tissue specific distribution can influence the clinical picture Examples: ❖LHON Leber Hereditary Optic Neuropathy ❖MELAS Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes ❖MERRF Myoclonic Epilepsy associated with Ragged-Red Fibers Homoplasmy/Heteroplasmy Downloaded from: StudentConsult (on 28 December 2009 04:12 PM) © 2005 Elsevier  Non-Mendelian inheritance ▪ Reduced penetrance ▪ Anticipation ▪ Genomic imprinting ▪ Mitochondrial inheritance ▪ Multifactorial and polygenic inheritance → complex multigenic disorder Multifactorial disease  Multifactorial inheritance No clear pattern of inheritance Common diseases Examples: ❖ Diabetes mellitus ❖ Spina bifida ❖ Cleft/lip palate ❖ Autism / Bipolar disorders / Schizophrenia ❖ Dementia  Pewarisan Multifaktorial Tidak menunjukkan suatu bentuk kelainan gen tunggal Diagnosis klinik berdasarkan penyebab yang heterogen Risiko utk menjadi penderita/pembawa sifat berdasarkan data empiris: – Teliti risiko rekurensi berdasrkan studi keluarga – Tidak dgn kalkulasi yang teoritis – Hanya berlaku pada populasi yang diteliti – Contoh: risiko rekurensi NTD (Neural Tube Defect)/cleft lips/palate berdasar keluarga/populasi yang diteliti 51 Polygenic disease Simultaneous presence of mutations in different genes result in the phenotype Mutation in gene A and B and C -> disease Multifactorial disease Combination of genetic heterogeneity and polygenic inheritance and the effect of adverse environmental influences Mutations in (A AND B AND C) + ⇒ disease  5 + + 2 8 + 2 +  FOLATE DEFICIENCY Spina Bifida Meningoencephalocele Chromosomal Disorder  ABERASI KROMOSOM Struktural: Translokasi (t) Delesi (del) Duplikasi (dup) Derivasi (der) Inversi (inv) Ring (r) Isochromosome (i) Numerikal: Trisomy monosomy Triploidy Polyploidy/hyperdiploidy 57 Translocation Contoh: sindrom down translokasi robetsonian - ibu/bapak secara fisik normal, tapi kromosomnya ada translokasi di kromosom 14 dan 21 Inversi Pericentric Invertion Paracentric invertion  Contoh kelainan kromosom - down syndrome (trisomi 21) - klinefelter syndrome (47, XXY) - turner syndrome (45, X) - patau syndrome (trisomi 13) - edward syndrome (trisomi 18)  References Turnpenny P.D, Ellard S. Emery’s Elements of Medical Genetics. Elsevier. 2017 Aster. Robbins Pathologic Pathology. Ninth edition. Philadelphia, PA: Elsevier/Saunders, 2015. Thank You