Pediatric Genetics Lecture Presentation PDF

Pediatric Genetics ‫ هيفاء الضياني‬.‫د‬ Disorders of chromosome structure  Deletions  Duplications  Inversion  Insertion  Translocations  Duplication  Gain of structural material can also lead to congenital malformations and intellectual impairment.  Duplications...

Pediatric Genetics ‫ هيفاء الضياني‬.‫د‬ Disorders of chromosome structure  Deletions  Duplications  Inversion  Insertion  Translocations  Duplication  Gain of structural material can also lead to congenital malformations and intellectual impairment.  Duplications are often better tolerated – and less likely to cause clinically important changes – than deletions.  Duplications and deletions are also described as gene copy number variation (CNV).  Example: Charcot–Marie–Tooth disease  The duplication can range from being submicroscopic to being large enough to be visible on a karyotype.  Deletion Deletions involve loss of part of a chromosome and usually result in physical abnormalities and cognitive impairment. It is now possible to specify the genes involved in chromosomal deletions as molecular methods are replacing standard cytogenetic investigations. A variety of microdeletion syndromes are known  Translocations  An exchange of material between two different chromosomes.  When this exchange involves no loss or gain of chromosomal material, the translocation is ‘balanced’ and usually has no phenotypic effect.  Balanced reciprocal translocations are relatively common, occurring in 1 in 500 of the general population.  A translocation that appears balanced on conventional chromosome analysis may still involve the loss of a few genes or the disruption of a single gene at one of the chromosomal break points, resulting in an abnormal phenotype.  Unbalanced reciprocal translocations involve a loss or gain of the overall amount of chromosomal material and often impair both physical and cognitive development, leading to dysmorphic features, congenital malformations, developmental delay, and learning difficulties. Mendelian inheritance Mendelian inheritance  Autosomal dominant inheritance  Autosomal recessive inheritance  X-linked inheritance  X-linked recessive inheritance  X-linked dominant disorders  Y-linked inheritance  Pedigree Drawing  To identify specific patterns of inheritance, geneticists construct and analyze pedigrees, pictorial representations of a family history.  Males are represented by squares and females by circles.  Mattings are connected with a solid line between each partner's symbols.  Children from a couple are represented below their parents and are the next generation.  To be useful, pedigrees should include representatives of at least three generations of family members.  Autosomal dominant inheritance  Most common mode of Mendelian inheritance.  Affected individual carries the abnormal gene on one of a pair of autosomes.  There is 1 in 2 chance of inheriting the abnormal gene from affected parent  There may be variation in expression, non- penetrance, no family history.  Traits generally involve mutations in genes that code for regulatory or structural proteins  Autosomal dominant inheritance  Achondroplasia  Familial hypercholesterolaemia (almost all cases)  Marfan syndrome  Myotonic dystrophy  Neurofibromatosis  Noonan syndrome  Osteogenesis imperfecta (most forms)  Otosclerosis  Tuberous sclerosis Autosomal Recessive Disorders  Children affected with AR disorders are usually born to unaffected parents, each of whom carries one copy of the mutation.  If both members of a couple are carriers (or heterozygotes) for this mutation, each of their offspring has a 25% chance of being affected  A normal sibling of an affected individual has a two-thirds chance of being a carrier (heterozygote)  Males and females are likely to be affected equally  Rare traits are likely to be associated with parental consanguinity  Traits generally involve mutations in genes that code for enzymes Autosomal Recessive Disorders  Congenital adrenal hyperplasia  Cystic fibrosis  Friedreich ataxia  Galactosaemia  Glycogen storage diseases  Hurler syndrome  Oculocutaneous albinism  Phenylketonuria  Sickle cell disease  Thalassaemia  Werdnig–Hoffmann disease (SMA1)  X-Linked Recessive disorders  Males are affected.  Female carriers are usually healthy, though occasionally a female carrier shows features of the disease.  Each son of a female carrier has a 1 in 2 (50%) risk of being affected.  Each daughter of a female carrier has a 1 in 2 (50%) risk of being a carrier.  All daughters of affected males will all be carriers.  Sons of affected males will not be affected, because a man passes a Y chromosome to his sons.  Because the trait can be passed through multiple carrier females, it may skip generations X-Linked Recessive disorders  Colour blindness (red–green)  Duchenne and Becker muscular dystrophies  Fragile X syndrome  Glucose-6-phosphate dehydrogenase deficiency  Haemophilia A and B  Hunter syndrome (mucopolysaccharidosis II)  X-linked dominant disorders  Both males and females are affected.  An example is hypophosphataemic (vitamin D-resistant) rickets.  In some X-linked dominant disorders, a female carrying the mutation will be affected while the mutation-carrying males have an even more serious condition. Thus, a mutation that causes Rett syndrome (a neurodegenerative disorder) in a girl will cause a lethal, neonatal-onset encephalopathy in males. Y-linked inheritance  Y-linked traits are extremely rare.  Y-linked inheritance would result in only males being affected, with transmission from an affected father to all his sons.  Y-linked genes determine sexual differentiation and spermatogenesis, and mutations are associated with infertility and so are rarely transmitted.