s 359 estimated to occur in 2% to 3% of cancers. Rather than producing disease, we present a case in which chromothripsis resulted in disease cure. A 59-year-old woman was troubled with the manifestations of WHIM syndrome until she experienced spontaneous resolution of symptoms in her 30s. WHIMS, an autosomal dominant immunodeficiency disorder caused by gain of function mutations in the chemokine receptor CXCR4 gene, is characterized by warts, hypogammaglobulinemia, recurrent infections and myelokathexis (impaired egress of mature neutrophils from bone marrow [BM] causing neutropenia). The patient, who now had leukocytosis, had the PCR-RFLP detected mutant CXCR4 allele of her affecteddaughters in her skin fibroblasts, but not in her blood. BM evaluation revealed an acrocentric chromosome 2. FISH demonstrated a centromeric inversion, deletion of NMYC, and ALK in the long arm. Oligo-SNP microarray revealed 7 deletions of chromosome 2 resulting in hemizygous loss of 163 genes including CXCR4 at 2q22.1. Next generation sequencing showed the abnormal chromosome 2 was composed of 18 segments arranged in random order and orientation. Competitive mouse BM transplantation experiments demonstrated that Cxcr4 haploinsufficiency is sufficient to confer a strong long-term engraftment advantage of donor BM over BM from wild-type or WHIMSmice, suggesting amechanism for the patient’s cure after a hematopoietic stem cell (HSC) underwent chromothripsis. These findings suggest partial inactivation of CXCR4 may be a strategy to promote HSC engraftment in transplantation. Conflict of Interest: A provisional patent on CXCR4 knock down as a method to enhance HSC engraftment has been filed by the US government with D.H.M., Q.L., M.S., J.G., H.L.M., and P.M.M. as inventors. The authors confirm that there are no other conflicts of interest. Congenital Heart Defects in Neonates: Determining the Incidence of Genetic Testing and Follow-up Consultation at UCLA Sibel Kantarci , Claire Baldauf , Elena Minakova , Joanna Parga , Isabell Purdy , Jeffrey Petersen , Meena Garg , Udaykumar Devaskar b Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA, USA; Department of Pediatrics, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA, USA Congenital heart defects (CHDs) are among the most common birth defects (8 per 1,000 live births), and are the leading cause of infant mortality and morbidity. CHD may occur as an isolated malformation or may be part of a syndrome. The etiology for the majority of cardiac birth defects is unknown but genetic factors including chromosomal abnormalities and single gene mutations play an important role. The aim of this study is to determine which genetic tests have been performed for the NICU patients with CHD between 2009 and 2015. Conventional chromosome analysis (n Z 51), FISH for DGS/VCFS region of 22q11.2 (n Z 29), and/or chromosomal microarray analysis (CMA) (nZ 104), were performed on 106 infants (F:45 andM:61) (isolated:59 and syndromic:47). Additionally clinical exome sequencing (CES) was performed on 3 infants with CHD. Aneuploidies (nZ 6) and structural aberrations (nZ 5) were detected in syndromic patients. However, only 1 structural and 1 numerical aberrations were observed in isolated patients by chromosome analysis. The 22q11.2 FISH results were abnormal in 2 patients. CMA studies revealed normal findings (isolated:40 and syndromic:20), 22q11.21 deletions (isolated:3 and syndromic:2), abnormalities rather than 22q11.21 deletion (isolated:6 and syndromic:17), abnormalities of unknown significance (isolated:7 and syndromic:7), and regions of homozygosity (>5 Mb) (isolated:2). Currently, CES studies are in progress. Currently, there is no specific algorithm for which genetic test, if any, should be performed for which type of CHD. We plan to create of an appropriate algorithm for testing based on cardiac lesion and improving the rate of physician follow-up of genetic testing results. Y Chromosome Microdeletion Detection by Cytoscan HD Microarray Platform Maria C. Sederberg, Leslie R. Rowe, Allen N. Lamb ARUP Laboratories, Department of Pathology, University of Utah, Salt Lake City, UT, USA Male infertility has many causes, including microdeletions of specific regions on the long arm of the Y chromosome, leading to oligospermia and azoospermia. These azoospermia factor regions (AZF) are categorized as AZFa, b, and c. These may be deleted individually or in combination, and are detected by multiplex PCR. Many laboratories do not report Y microdeletions in studies of patients with DD/ID, autism, or dysmorphism. It is important to understand how well the Affymetrix Cytoscan HD detects AZF deletions, to recognize when mosaicism exist, and when a rearranged Y is present. Fourteen AZF deletion-positive patients by PCR were used: 4 AZFabc, 4 AZFbc, 2 AZFa, 2 AZFb, and 2 AZFc. Chromosomes were examined for 3 cases. All samples showed concordance between the PCR and microarray results for the deletions. Deletions of AZFa or AZFb, or larger ones that include these regions, are generally easy to visually confirm due to good probe performance. The AZFc deletions are more difficult to visually detect, likely due to probe performance in this palindrome-rich region. The microarray provided additional information not available with PCR and AZFabc and bc deletions are not always simple deletions as mosaicism was observed. With information from pseudoautosomal regions, structural rearrangements were implied for some cases. Sex was called female for large AZFabc deletions and was based on a ratio of X:Y probe calls, rather than presence of SRY or short arm sequences, requiring visual examination of the sex chromosomes. International Breakpoint Mapping Consortium (IBMC). Systematic Mapping of Chromosomal Breakpoints in the Context of Phenotypes and Nuclear Genome Organization Niels Tommerup , Malene B. Rasmussen , Mana M. Mehrjouy , Iben Bache , Allan Lind-Thomsen , Ana Carolina dos Santos Fonseca , Christina Halgren , Mads Bak , Peter Jacky c University of Copenhagen, Department of Cellular and Molecular Medicine, Copenhagen, Denmark; Universidade de S~ ao Paulo, Departamento de Gen etica e Biologia Evolutiva, S~ ao Paulo, Brazil; Northwest Permanente, PC, Emeritus, OR, USA We still lack genotype-phenotype-information for approximately 80% to 90% of our protein-coding genes, and for almost
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Aug 31, 2023
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