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Genes for CDH: Arrays, Mice and Humans Daryl A. Scott, MD

. Who Are We?. Physician/ScientistClinicalPediatricianClinical GeneticistTexas Children's HospitalHouston, TexasResearchLaboratoryBaylor College of MedicineIdentify genes that cause CDHDavid Pearson, clinical coordinator. . www.vesalius.com. . Our Presentation. Stories of our CDH childrenStudy of CDH started in 2003Focusing on individual patientsAnswers for familiesImprove medical careLearn about the causes of CDH .

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Genes for CDH: Arrays, Mice and Humans Daryl A. Scott, MD

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    4. Premature boy, outside hospital R-sided anterior CDH Clouded corneas, congenital glaucoma? Cryptorchidism Kidney anomalies Aniridia

    8. Premature boy, outside hospital R-sided anterior CDH Clouded corneas, congenital glaucoma? Cryptorchidism Kidney anomalies Aniridia PAX6 = Eyes

    9. Premature boy, outside hospital R-sided anterior CDH Clouded corneas, congenital glaucoma? (PAX6) Cryptorchidism Kidney anomalies Aniridia (PAX6) PAX6 = Eyes

    10. Premature boy, outside hospital R-sided anterior CDH Clouded corneas, congenital glaucoma? (PAX6) Cryptorchidism Kidney anomalies Aniridia (PAX6) PAX6 = Eyes WT1 = Genetalia and Kidneys

    11. Premature boy, outside hospital R-sided anterior CDH Clouded corneas, congenital glaucoma? (PAX6) Cryptorchidism (WT1) Kidney anomalies (WT1) Aniridia (PAX6) PAX6 = Eyes WT1 = Genetalia and Kidneys

    12. Premature boy, outside hospital R-sided anterior CDH Clouded corneas, congenital glaucoma? (PAX6) Cryptorchidism (WT1) Kidney anomalies (WT1) Aniridia (PAX6) PAX6 = Eyes WT1 = Genetalia and Kidneys WT1 = CDH?

    13. Two children chromosome 11 deletions and CDH Four children with mutations in WT1 with CDH Mouse without Wt1 have CDH

    14. Premature boy, outside hospital R-sided anterior CDH (WT1) Clouded corneas, congenital glaucoma? (PAX6) Cryptorchidism (WT1) Kidney anomalies (WT1) Aniridia (PAX6) PAX6 = Eyes WT1 = Genetalia,Kidneys,CDH

    15. Met with parents Diagnosis = Deletion of chromosome 11p De novo event, not inherited Risk to future siblings very low Risk to next generation = 50%

    16. Met with parents Diagnosis = Deletion of chromosome 11p De novo event, not inherited Risk to future siblings very low Risk to next generation = 50% High risk for kidney tumors

    18. Identified all published reports CDH with chromosomal anomaly Which areas had more than three cases? Made a map of CDH genes

    23. Array Comparative Genome Hybridization

    24. Array Comparative Genome Hybridization

    25. Array Comparative Genome Hybridization

    26. Array Comparative Genome Hybridization

    46. Met with parents Diagnosis: 46,XX,der(15)t(2;15)(q37.2;q26.2) Requested parental sample for evaluation Balanced translocation in one parent

    50. Met with parents again Diagnosis: 46,XX,der(15)t(2;15)(q37.2;q26.2) Balanced translocation in parent High risk for siblings Child at high risk for passing on change

    51. 2 year old male Radio-ulnar synostosis Intestinal malrotation Diaphragmatic eventration

    54. 2 year old male Radio-ulnar synostosis Intestinal malrotation Diaphragmatic eventration Chromosome analysis: 46,XY Clinical testing by aCGH Deletion on 8p Enrolled in our study

    56. Deletion unaffected father Diaphragmatic Eventration?

    57. One infant de novo R112X heterozygous mutation in FOG2 Diaphragmatic eventration Severe pulmonary hypoplasia Died in infancy Mice mutations in Fog2 mutation Diaphragmatic eventrations Pulmonary hypoplasia

    58. Met with family Diagnosis: FOG2 deletion 50% risk of passing to siblings 50% risk of son passing deletion to his children Incomplete penetrant No symptoms Severe symptoms Other factors: genetic, environmental Is unaffected sister at risk?

    59. Identical twin boy Prenatal Complex congenital heart disease Amniocentesis deletion on chromosome 8p Same findings in twin Birth Dysmorphic features Large anterior CDH Twin did not have CDH Enrolled in our study

    64. Humans GATA4 mutations in familial ASD Rare GATA4 mutations responsible for more serious defects Mice Heart defects Anterior CDH Doubts CDH? Severe heart defects Another gene?

    67. Serious commitment Very confident 1 year of your life $100,000 Process can fail at any time Convinced Diaphragm development Heart development Other roles in development

    71. Met with family Diagnosis: Deletion of 8p23.1 De novo change, not inherited Risk to siblings is very low 50% risk of passing on to next generation

    73. One year old boy Hospitalized since birth Anterior left-sided CDH Heart defects Omphalocele Entered our study

    76. Deletions of this region never described No mutation in FZD2 ever reported May often be lethal FZD2 is downstream of PORC Mutations in PORC Syndrome Goltz CDH Omphalocele

    77. Met with parents Diagnosis: FZD2 deletion De novo change, not inherited Risk to siblings is very low 50% risk of passing on to next generation

    79. Bright Many new CDH genes Many families will have answers

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