Chromoanasynthesis as a Cause of Jacobsen Syndrome

Jacobsen syndrome (OMIM #147791) is a rare multisystem genomic disorder involving craniofacial abnormalities, intellectual disability, other neurodevelopmental defects and terminal truncation of chromosome 11q, typically deleting ~170 to >340 genes. We describe the first case of Jacobsen syndrome caused by congenital chromoanasynthesis, an extreme form of complex chromosomal rearrangement. Six duplications and five deletions occurred on one copy of chromosome 11q with microhomology signatures in the breakpoint junctions, indicating an all-at-once replication-based rearrangement mechanism in a gametocyte or early post-zygotic cell. Eighteen genes were deleted from the Jacobsen region, including KIRREL3, which is associated with intellectual disability. Patients of any age with abnormal immune function who have recurrent or unusual infections, whose blood tests show evidence of immune dysfunction, or who have GVHD, XSCID, CGD or LAD may be eligible for this study. Patients' parents, siblings, grandparents, children, aunts, uncles and first cousins of any age also may be included. Healthy normal volunteers between 18 and 85 years of age are recruited as controls. ]]>
Jacobsen Syndrome Study Time Line Age 2 years, 7 month - first visit, received developmental assessment using the Vineland Adaptive Behavior Scales and Mullen Scales of Early Learning Age 3 years, 3 months - implementation of Bayley Scales of Infant Development at Children's National Medical Center Age 4 years, 4 months - received second neurodevelopmental assessment at NIH. Received brain computerized tomography study one month later Age 5 years, 7 months - received third neurodevelopmental assessment at NIH Blood draw and buccal swab acquired for genetics study February, 2017 - performed whole genome sequencing at NIH November, 2018 - Chromosome microarray analysis performed by Children's National Medical Center FISH analysis performed ]]>