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Patterns of Inheritance Autosomal Dominant There is no skipping of generations. Males and females have an equally likely chance of inheriting the mutant.

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Presentation on theme: "Patterns of Inheritance Autosomal Dominant There is no skipping of generations. Males and females have an equally likely chance of inheriting the mutant."— Presentation transcript:

1 Patterns of Inheritance Autosomal Dominant 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 Males 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. Autosomal Recessive

2 X-Linked Dominant X-Linked Recessive The trait is never passed from father to son All 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. GIVE AN EXAMPLE OF SPECIFIC X LINKED DOMINANT DISORDERS Pseudohyperparathyroidism Vitamin D resistant rickets Aicardi syndrome Missing corpus callosum Alport syndrome Renal disease SN hearing loss Cataracts

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 carrier Mom  Dad ↓ Aa AAAAa a aa So her risk of being a carrier is 2/3!

4 Question Time Advanced maternal age suggests what kind of genetic abnormality? – Chromosomal Advance paternal age suggests what kind of genetic abnormality? – Autosomal dominant (mutation)

5 Is it a… Disruption Deformation Malformation Dysplasia Sequence Association Club foot Clefting, constriction bands and limb reduction defects Potters facies Achondroplasia Requires surgical intervention CHARGE Pierre Robin

6 Images Brachydactyly Clinodactyly Low-set ears & flat occiput Simian crease Brushfield spots Down Syndrome Name the Dysmorphic Feature

7 Sequence vs. Association Sequence Association Single localized anomaly In early morphogenesis Secondary anomalies Pattern of multiple anomalies In later morphogenesis Cluster of anomalies not explained by chance

8 SequenceAssociation Coloboma Heart defect Atresia (choanal) Retarded growth and development Genital anomalies Ear anomalies Vertebral anomalies, Anal atresia Cardiac defects T-E fistula with Esophageal atresia Radial dysplasia Renal anomaly Limb abnormalities Primary anomaly in Mandibular development Prior to 9 weeks Posterior displacement of the tongue Posterior cleft palate Pierre Robin Sequence

9 Clefting Cleft lip +/- palate – 1/700 – M > F (2:1) – Asian > white > AA (3:2:1) Isolated cleft palate – 1/1000 – M = F – No difference

10 Anomalies Diagnosis? Usually an isolated anomaly Associated anomalies? –Undescended testes –Inguinal hernias –Ambiguous genitalia

11 Hypospadias Is hypospadias a major or minor anomaly? – MAJOR! Major anomalies are of functional significance – Polydactyly – Meningomyelocele – Cleft lift Minor anomalies are of cosmetic significance only – Epicanthal folds – Single transverse palmar creases – Super numerary nipples

12 Morphology Causes? – Folic acid deficiency – Maternal AED use Associated findings – Neuro Flaccid paralysis Type II Chiari – Urologic – incontinence – Ortho Hip / sacral dysplasia Clubbed feet

13 Inheritance Autosomal dominant About 75% of patients with achondroplasia represent new mutations in the fibroblast growth factor receptor-3 (FGFR-3) gene Achondroplasia rhizomelia: short femur, humerus mesomelia: short radius, ulna, tibia, fibula acromelia: hands and feet affected micromelia: entire limb affected Clinical Features Macrocephalic/frontal bossing/small foramen magna Rhizomelia Prominent abdomen and buttocks

14 This patient come to the office, with a history mild mental retardation, maternal uncles with similar behavior. You notice the long face, prominent ears, jaw, and forehead, unusual speech pattern (fast, fluctuating rate and repetition of sounds), and if you follow him into Adolescence he will develop enlarged testicles Diagnosis : Fragile X Syndrome (most common form of inherited Mental retardation. Etiology: Expansion of a trinucleotide repeat CGG in the promoter Region of FMR1 gene in Chr Xq27.3 Normal 6-54 repeats Premutation carriers 54-200 repeats Affected individuals >200 repeats

15 Fragile X Your best friend tells you her cousin’s little girl has Fragile X. Is this possible? – Yes – Why? Females can carry the repeat but there is no clinical effect in 70? Why? – Lyonization (X inactivation)

16 Marfan Syndrome What’s the pattern of inheritance? – Autosomal dominant What’s the defect? – Abnormal fibrillin gene What is the major associated morbidity? – Aortic dilatation

17 Associated anomalies? Cardiac – Aortic aneurysms – Aortic & mitral regurge Orthopedic – Ligament laxity – Pectus excavatum or carinatum Ophthalmologic – Lens dislocation – myopia

18 This child has poor growth and developmental delay. She also has webbed toes! Her disorder is due to what metabolic defect? – Cholesterol metabolism – This is Smith-Lemli-Opitz (in case you didn’t know!)

19 Name the syndrome Her features: Heavy eyebrows Synophrys Long eyelashes Small upturned nose Long, smooth philtrum Cupid’s bow mouth Small hands and feet Phocomelia Cornelia de lange!

20 Diagnosis? Chvostek’s sign Tetany Mental Retardation Diagnosis? Albright’s Hereditary Osteodystrophy

21 Genetics Pathogenesis Characteristics 20q13.2 – Auto Dom Defect of G proteins Unresponsive to PTH Short stature Obesity Hypocalcemia Shortened 3 rd thru 5 th metacarpals

22 What anomalies? Urologic? – Cryptorchidism – Dilated ureters, GU reflux Renal? – Hydronephrosis – Cystic dysplasia Abdomen? – Absent abd wall musculature Pulmonary? – hypoplasia PRUNE BELLY

23 Diagnosis? Neurofibromatosis (Von Recklinghausen Disease)

24 Neurofibromatosis Mode of inheritance? – Autosomal Dominant Pathogenesis? – Neurofibromin – abnormal neural crest migration Diagnostic 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 1 st degree relative

25 A word on diabetes… Things to know – 8 times increased risk for major congenital anomalies including: CV Anencephaly Spina bifida Small left colon Caudal 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!

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