Presentation on theme: "Patterns of Inheritance"— Presentation transcript:
1 Patterns of Inheritance Autosomal RecessiveAutosomal DominantMales and females are equally likely to be affected.On average, the recurrence risk to the unborn sibling of an affected individual is 1/4.The trait is characteristically found in siblings, not parents of affected or the offspring of affected. Parents of affected children may be related. The rarer the trait in the general population, the more likely a consanguineous mating is involved.There is no skipping of generations.Males and females have an equally likely chance of inheriting the mutant allele and being affected.The recurrence risk of each child of an affected parent is 1/2.Normal siblings of affected individuals do not transmit the trait to their offspring.The defective product of the gene is usually a structural protein, not an enzyme
2 GIVE AN EXAMPLE OF SPECIFIC X LINKED DOMINANT DISORDERS PseudohyperparathyroidismVitamin D resistant ricketsAicardi syndromeMissing corpus callosumAlport syndromeRenal diseaseSN hearing lossCataractsX-Linked DominantX-Linked RecessiveThe trait is never passed from father to sonAll daughters of an affected male and a normal female are affected. All sons of an affected male and a normal female are normal. Matings of affected females and normal males produce 1/2 the sons affected and 1/2 the daughters affected. Males are usually more severely affected than females. The trait may be lethal in males. In the general population, females are more likely to be affected than males, even if the disease is not lethal in males.As with any X-linked trait, the disease is never passed from father to son. Males are much more likely to be affected than females. If affected males cannot reproduce, only males will be affected. All affected males in a family are related through their mothers. Trait or disease is typically passed from an affected grandfather, through his carrier daughters, to half of his grandsons.
3 Remember Punnett Squares? Here’s the scenario:A teenage girl who’s brother has CF wants to know her risk for being a CF carrierMom Dad↓AaAAAaaaSo her risk of being a carrier is 2/3!
4 Question TimeAdvanced maternal age suggests what kind of genetic abnormality?ChromosomalAdvance paternal age suggests what kind of genetic abnormality?Autosomal dominant (mutation)
5 Is it a… Disruption Deformation Malformation Dysplasia Sequence AssociationClub footClefting, constriction bands and limb reduction defectsPotters faciesAchondroplasiaRequires surgical interventionCHARGEPierre Robin
6 Images Name the Dysmorphic Feature Brachydactyly Clinodactyly Low-set ears & flat occiputSimian creaseBrushfield spotsDown Syndrome
7 Sequence vs. Association Single localized anomalyIn early morphogenesisCluster of anomalies not explained by chanceSecondary anomaliesPattern of multiple anomaliesIn later morphogenesis
8 Mandibular development Posterior displacement Posterior cleft palate SequenceAssociationPierre Robin SequenceColobomaHeart defectAtresia (choanal)Retarded growth and developmentGenital anomaliesEar anomaliesPrimary anomaly inMandibular developmentPrior to 9 weeksPosterior displacementof the tongueVertebral anomalies,Anal atresiaCardiac defectsT-E fistula withEsophageal atresiaRadial dysplasiaRenal anomalyLimb abnormalitiesPosterior cleft palate
9 Clefting Cleft lip +/- palate Isolated cleft palate 1/700 M > F (2:1)Asian > white > AA (3:2:1)Isolated cleft palate1/1000M = FNo difference
10 Anomalies Diagnosis? Usually an isolated anomaly Associated anomalies? Undescended testesInguinal herniasAmbiguous genitalia
11 Hypospadias Is hypospadias a major or minor anomaly? Major anomalies are of functional significancePolydactylyMeningomyeloceleCleft liftMinor anomalies are of cosmetic significance onlyEpicanthal foldsSingle transverse palmar creasesSuper numerary nipples
12 Morphology Causes? Folic acid deficiency Maternal AED use Associated findingsNeuroFlaccid paralysisType II ChiariUrologic – incontinenceOrthoHip / sacral dysplasiaClubbed feet
13 About 75% of patients with achondroplasia represent new mutations InheritanceAutosomal dominantAbout 75% of patients with achondroplasia represent new mutationsin the fibroblast growth factor receptor-3 (FGFR-3) geneClinical FeaturesMacrocephalic/frontal bossing/small foramen magnaRhizomeliaProminent abdomen and buttocksrhizomelia: short femur, humerusmesomelia: short radius, ulna, tibia, fibulaacromelia: hands and feet affectedmicromelia: entire limb affected
14 This patient come to the office, with a history mild mental retardation, maternal uncles withsimilar behavior. You notice the long face,prominent ears, jaw, and forehead, unusualspeech pattern (fast, fluctuating rate andrepetition of sounds), and if you follow him intoAdolescence he will develop enlarged testiclesDiagnosis : Fragile X Syndrome (most common form of inheritedMental retardation.Etiology: Expansion of a trinucleotide repeat CGG in the promoterRegion of FMR1 gene in Chr Xq27.3Normal repeatsPremutation carriers repeatsAffected individuals >200 repeats
15 Fragile XYour best friend tells you her cousin’s little girl has Fragile X. Is this possible?YesWhy?Females can carry the repeat but there is no clinical effect in 70?Lyonization (X inactivation)
16 Marfan Syndrome What’s the pattern of inheritance? What’s the defect? Autosomal dominantWhat’s the defect?Abnormal fibrillin geneWhat is the major associated morbidity?Aortic dilatation
18 Her disorder is due to what metabolic defect? Cholesterol metabolismThis is Smith-Lemli-Opitz (in case you didn’t know!)This child has poor growth and developmental delay.She also has webbed toes!
19 Name the syndrome Her features: Heavy eyebrows Synophrys Cornelia de lange!Her features:Heavy eyebrowsSynophrysLong eyelashesSmall upturned noseLong, smooth philtrumCupid’s bow mouthSmall hands and feetPhocomelia
24 Neurofibromatosis Mode of inheritance? Autosomal Dominant Pathogenesis?Neurofibromin – abnormal neural crest migrationDiagnostic Criteria?*Café-au-lait macules*Two or more Neurofibromas or one Plexiform neurofibroma*Optic Glioma*Axillary or inguinal freckling*Two or more Lisch Nodules*Bone lesions – sphenoid dysplasia, thinning or long bones*Family History in a 1st degree relative
25 A word on diabetes… Things to know 8 times increased risk for major congenital anomalies including:CVAnencephalySpina bifidaSmall left colonCaudal regression/sacral dysgenesis *Macrosomia
26 Whew that was a lot of stuff!!!! Thank you to Regina Zambrano (and Jay Gardner) for their help with this
27 Next Board Review Topic: Hearts and Lungs!!!(so read cardiology & pulmonary chapters)Date: To Be announced!