The era of individualized genetic medicine is fast approaching. Remarkable technical advances have brought the search for rare pathogenic variants to the fore in studies of complex disorders, redefining the focus of 'risk variant'from the population based cohort to the individual patient. Such studies have identified structural variations and complex genomic rearrangements as key variants associated with autism and other neuropsychiatric phenotypes, suggesting neurological pathways may be particularly sensitive to fusion genes and dosage effects. Yet current methods to map such variants remain imprecise, unable to detect balanced rearrangements and inversions, potentially bypassing a highly informative patient subgroup. This fellowship intends to address this significant deficit in our understanding of the impact of genomic rearrangements on neurodevelopmental abnormalities. The studies proposed herein will use """"""""next- generation"""""""" sequencing to identify genes disrupted by apparently balanced rearrangements. They will build upon innovations in cancer genetics, customizing them for analysis of abnormal germline karyotypes. A massively parallel paired-end strategy of sequencing jumping clones will be used to first map precise breakpoints in autism spectrum disorder (ASD) patients with known genomic rearrangements (Aim I), then conduct comprehensive molecular analysis of disrupted gene(s) and pathways (Aim 11). Relying on methodological optimization, Aim 111 will seek to screen a large independent cohort of patients diagnosed with ASD and other disorders to identify consistent rearrangements and/or novel rare mutations. These studies will thus sequentially build in both scope and sophistication to address an important and understudied patient cohort. Collectively, they could yield important progress in focusing genetic risk to the individual genome, potentially delivering genotype-based classification as a pragmatic diagnostic tool in pediatric clinical practice. Public Health Relevance: The heritability of autism and related neurodevelopmental disorders is high but contributing genetic risk factors remain uncertain. The true incidence of genomic rearrangements in these patient groups could be substantially underestimated due to technological limitations. Novel methods for rapid screening are therefore needed. These studies could facilitate new diagnostic classifications that account for individual genomic events, explain a meaningful proportion of disease variance that is currently unknown, and help elucidate causative pathways.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F08-G (20))
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Desmond, Nancy L
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Massachusetts General Hospital
United States
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Ordulu, Zehra; Wong, Kristen E; Currall, Benjamin B et al. (2014) Describing sequencing results of structural chromosome rearrangements with a suggested next-generation cytogenetic nomenclature. Am J Hum Genet 94:695-709
Chen, Xiaoli; Shen, Yiping; Zhang, Feng et al. (2013) Molecular analysis of a deletion hotspot in the NRXN1 region reveals the involvement of short inverted repeats in deletion CNVs. Am J Hum Genet 92:375-86
Chiang, Colby; Jacobsen, Jessie C; Ernst, Carl et al. (2012) Complex reorganization and predominant non-homologous repair following chromosomal breakage in karyotypically balanced germline rearrangements and transgenic integration. Nat Genet 44:390-7, S1
Talkowski, Michael E; Rosenfeld, Jill A; Blumenthal, Ian et al. (2012) Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries. Cell 149:525-37
Talkowski, Michael E; Ordulu, Zehra; Pillalamarri, Vamsee et al. (2012) Clinical diagnosis by whole-genome sequencing of a prenatal sample. N Engl J Med 367:2226-32
Lamb, Allen N; Rosenfeld, Jill A; Neill, Nicholas J et al. (2012) Haploinsufficiency of SOX5 at 12p12.1 is associated with developmental delays with prominent language delay, behavior problems, and mild dysmorphic features. Hum Mutat 33:728-40
Ernst, Carl; Marshall, Christian R; Shen, Yiping et al. (2012) Highly penetrant alterations of a critical region including BDNF in human psychopathology and obesity. Arch Gen Psychiatry 69:1238-46
Golzio, Christelle; Willer, Jason; Talkowski, Michael E et al. (2012) KCTD13 is a major driver of mirrored neuroanatomical phenotypes of the 16p11.2 copy number variant. Nature 485:363-7
Talkowski, Michael E; Mullegama, Sureni V; Rosenfeld, Jill A et al. (2011) Assessment of 2q23.1 microdeletion syndrome implicates MBD5 as a single causal locus of intellectual disability, epilepsy, and autism spectrum disorder. Am J Hum Genet 89:551-63
Talkowski, Michael E; Ernst, Carl; Heilbut, Adrian et al. (2011) Next-generation sequencing strategies enable routine detection of balanced chromosome rearrangements for clinical diagnostics and genetic research. Am J Hum Genet 88:469-81