Autosomal dominant inheritance Sperm Sperm Sperm Sperm A a A= normal(major) allele Eggs AA Aa Eggs AA aA a= mutated(minor) allele A A Eggs AA Aa Eggs aa A 1/2 of offspring 3/4 of offspring affected affected Sperm Sperm Sperm Sperm perm Spe a Eggs aA aA Eggs aA aA Eggs aa A A Eggs aA aA ggs aa Eggs aa aa A all offspring all offspring all offspring affected affected ffected
Autosomal dominant inheritance Sperm A Sperm a Eggs A AA Aa Eggs A AA Aa A = normal (major) allele a = mutated (minor) allele 1/2 of offspring affected Sperm A Sperm a Eggs A AA aA Eggs a Aa aa 3/4 of offspring affected Sperm a Sperm a Eggs A aA aA Eggs a aa aa all offspring affected Sperm a Sperm a Eggs a aa aa Eggs a aa aa all offspring affected Sperm a Sperm a Eggs A aA aA Eggs A aA aA all offspring affected
Example: Neurofibromatosis type 1(NF 1) An autosomal dominant disorder caused by inactivation of one copy of the neurofibromin gene (NF 1)located at 17q112 Incidence of NF 1 =+1/3500 births; 80% of mutations are paternal in origin Sperm Sperm A EggsAA A A III 口口○ Eggs AA A de novo mutation A inherited from father 1/2 of offspring 1/2 of offspring affected affected A= normal(major) allele a= mutated(minor) allele
Sperm A Sperm a Eggs A AA Aa Eggs A AA Aa de novo mutation inherited from father 1/2 of offspring affected 1/2 of offspring affected A = normal (major) allele a = mutated (minor) allele Example: Neurofibromatosis type 1 (NF1) An autosomal dominant disorder caused by inactivation of one copy of the neurofibromin gene (NF1) located at 17q11.2. Incidence of NF1 = ~1/3500 births; 80% of mutations are paternal in origin. Aa AA Aa AA AA Aa
Penetrance and expressivity Penetrance: the probability that a genetic variant will have a detectable phenotype(this is an all-or-nothing classification) Variable penetrance: describes variants with less than 100% penetrance Expressivity: the severity of expression of the phenotype Variable expressivity: describes phenotypes that vary among individuals with the same genotype Expressivity of neurofibromatosis type 1 phenotype Cafe-au-lait spots (black arrows) Disseminated Lisch nodules Distended eye due to And cutaneous cutaneous and (iris hamartomas) pressure from tumor neurofibroma subcutaneous on optic nerve white arrow neurofibromas
Penetrance and expressivity Penetrance: the probability that a genetic variant will have a detectable phenotype (this is an all-or-nothing classification): Variable penetrance: describes variants with less than 100% penetrance Expressivity: the severity of expression of the phenotype Variable expressivity: describes phenotypes that vary among individuals with the same genotype Lisch nodules (iris hamartomas) Café-au-lait spots (black arrows) And cutaneous neurofibroma (white arrow) Disseminated cutaneous and subcuntaneous neurofibromas Distended eye due to pressure from tumor on optic nerve Expressivity of neurofibromatosis type 1 phenotype
Autosomal recessive inheritance 四百O A=normal(major) allele a= mutated(minor) allele Sperm Sperm Sperm Sperm Sperm Sperm A Eggs AA aA Eggs aa E g gs aa aa EggsAa aa EggsAa aa Eggs aa a a a 1/4 of offs pring 1/2 of offspring all offspring affected affected affected
Autosomal recessive inheritance Sperm A Sperm a Eggs A AA aA Eggs a Aa aa A = normal (major) allele a = mutated (minor) allele 1/4 of offspring affected Sperm A Sperm a Eggs a Aa aa Eggs a Aa aa 1/2 of offspring affected Sperm a Sperm a Eggs a aa aa Eggs a aa aa all offspring affected Aa Aa aa aa
Example: Cystic fibrosis(CF) An autosomal recessive disorder caused by mutations in the CF transmembrane regulator gene(CFTR)located at 7q31.2 Large differences in frequency of CFTR mutations in different populations -1/25 among Northern Europeans; 17500 in Asian populations Symptoms include: abnormal chloride ion transport in exocrine tissues leading to the accumulation of mucus in lungs, sinuses, intestines pancreas and male reproductive tract. Accompanying bacterial infections and inflammation cause tissue damage and organ failure. Expression of CF symptoms is highly variable Pathway from Gene CYSTIC FIBROSIS Mutation to Syndrome INFECTION, INFLAMMATION BLOCKED DUCTS SYMPTOMS IMPAIRED MUCOSAL DEFENSE Salty sweat Intestinal block ALTERED SECRETIONS ION TRANSPOR Recreat bacteral Is intections CFTR PROTEIN CBAVD CFTR DNA Gallbladder, liver CBAVD E Lung from cystic congenital absence of vas defere Fibrosis patient
Example: Cystic fibrosis (CF) An autosomal recessive disorder caused by mutations in the CF transmembrane regulator gene (CFTR) located at 7q31.2. Large differences in frequency of CFTR mutations in different populations: ~1/25 among Northern Europeans; ~1/500 in Asian populations Symptoms include: abnormal chloride ion transport in exocrine tissues leading to the accumulation of mucus in lungs, sinuses, intestines, pancreas and male reproductive tract. Accompanying bacterial infections and inflammation cause tissue damage and organ failure. Expression of CF symptoms is highly variable. Lung from cystic Fibrosis patient CBAVD = congenital absence of vas deferens