Genomic disorders are conditions that result from DNA rearrangements due to regional genomic architecture as a result of non-allelic homologous recombination (NAHR) between segmental duplications. These rearrangements result in microdeletion or microduplication, and cause the loss, gain, or disruption of dosage-sensitive genes. One hundred and thirty rearrangement """"""""hotspots"""""""" of the genome have been identified with features that are common to all known genomic disorders - 50kb-5Mb of sequence flanked by large (>10kb) segmental duplications with >95% sequence identity. Although these genomic features suggest a predisposition to recurrent de novo rearrangement, many of the hotspot regions show no variation in a large series of normal controls or in 290 individuals with idiopathic mental retardation. The candidate hypothesizes that many of these """"""""silent"""""""" regions contain genes that are essential for normal development but are involved in pathways other than those critical for normal cognition, and that de novo deletions or duplications will be seen in individuals with congenital anomalies. She proposes a targeted approach to detect novel rearrangements associated (i) with congenital heart disease, and (ii) with pediatric renal abnormalities. By targeting """"""""hotspot"""""""" regions, the candidate will detect rearrangements that are likely to be recurrent. In the process, she will identify genes that are critical for developmental pathways and important for pediatric disease. In addition, she will investigate structural and copy number variation within hotspot regions to determine whether these features play a role in an individual's risk for de novo rearrangement during meiosis.
A main goal of this project is to identify new genetic causes of birth defects, with a focus on heart defects and kidney abnormalities. The results of this study will provide new insight into the basis of both normal and abnormal development. The identification of new syndromes will allow more accurate diagnosis of patients and better genetic counseling for families.
| Dibbens, Leanne M; Mullen, Saul; Helbig, Ingo et al. (2009) Familial and sporadic 15q13.3 microdeletions in idiopathic generalized epilepsy: precedent for disorders with complex inheritance. Hum Mol Genet 18:3626-31 |
