Definition of chromosomal abnormalities by next generation sequencing

Johns Hopkins University, Baltimore MD

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Abstract

DESCRIPTION (provided by applicant): Historically, chromosomal rearrangements have been investigated by conventional karyotype followed by arduous positional-cloning projects. More recently, molecular cytogenetic characterizations using fluorescence in situ hybridization, array comparative genomic hybridization, and SNP genotyping together with molecular methods such as inverse PCR and quantitative PCR have allowed an increasingly more precise evaluation of chromosome abnormalities with the result that some presumably balanced rearrangements have been found to include deletions, duplications, insertions or inversions. I will test a new approach: targeted genomic capture followed by next generation sequencing to rapidly and precisely define the molecular abnormalities in a set of clinically interesting cases followed in the Genetics clinics of the Johns Hopkins Institute of Genetic Medicine. 3 cases with complex dysmorphic syndromes already known to have translocations: the first (family L982181) is segregating an apparently balanced t(2;3)(p15;q12) translocation over 3 generations associated with craniofacial abnormalities; the second (patient JHU2010) has a t(2;6)(q22;p12.3) translocation and a breakpoint in the region of RUNX2 on chromosome 6p, associated with cleidocranial dysplasia (OMIM 119600); and the third (patient L08-2709) has a t(5;17)(q23.2;q24) translocation, with a breakpoint in the region upstream of the SOX9 on chromosome 17q, associated with the clinical phenotype of acampomelic campomelic dysplasia (OMIM 114290). Additionally, I will study three cases with deletions in the 10q21-q23 region that have been collected by the Valle lab as part of their ongoing interest in identification of schizophrenia susceptibility genes in this region. They include the fourth patient in my series (JHU2020), who has a 10q23.1 deletion associated with multiple anomalies and development delay; the fifth and sixth involve 2 families (JHU2000 and JHU88293) with overlapping deletions both of which inactivate PCDH15 on 10q21.1 and are associated with schizophrenia. The delineation of these complex rearrangements will lead to a better understanding of the molecular bases of their clinical phenotypes. In cases 5 and 6, the study of PCDH15 as a candidate gene for psychiatric disease is of interest because it is the only annotated gene that is deleted in both families (JHU2000 and JHU88293). Recessive truncating mutations in PCDH15 cause Usher type 1F (OMIM 602083) characterized by congenital hearing loss, vestibular dysfunction and pigmentary retinopathy. Interestingly, an early report, pre-appreciation of locus heterogeneity, suggested nearly 20% of patients with Usher syndrome develop psychosis [4].