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Feusier et al. J Transl Genet Genom 2021;5:189-99 Journal of Translational
DOI: 10.20517/jtgg.2021.05
Genetics and Genomics

Original Article Open Access

Shared genomic segment analysis in a large high-
risk chronic lymphocytic leukemia pedigree

implicates CXCR4 in inherited risk

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Julie E. Feusier , Michael J. Madsen , Brian J. Avery , Justin A. Williams , Deborah M. Stephens , Boyu
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Hu , Afaf E. G. Osman , Martha J. Glenn , Nicola J. Camp 1,2
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Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
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Division of Hematology and Hematological Malignancies, Department of Internal Medicine, University of Utah, Salt Lake City,
UT 84112, USA.
Correspondence to: Nicola J. Camp, PhD, Huntsman Cancer Institute, University of Utah, 2000 Cir of Hope Dr #1950, Salt Lake
City, UT 84112, USA. E-mail: Nicki.Camp@hci.utah.edu
How to cite this article: Feusier JE, Madsen MJ, Avery BJ, Williams JA, Stephens DM, Hu B, Osman AEG, Glenn MJ, Camp NJ.
Shared genomic segment analysis in a large high-risk chronic lymphocytic leukemia pedigree implicates CXCR4 in inherited risk. J
Transl Genet Genom 2021;5:189-99. https://dx.doi.org/10.20517/jtgg.2021.05
Received: 27 Feb 2021 First Decision: 28 Apr 2021 Revised: 1 May 2021 Accepted: 13 May 2021 First online: 15 Jun 2021
Academic Editor: Susan L. Slager Copy Editor: Xi-Jun Chen Production Editor: Xi-Jun Chen

Abstract
Aim: Chronic lymphocytic leukemia (CLL) has been shown to cluster in families. First-degree relatives of
individuals with CLL have an ~8 fold increased risk of developing the malignancy. Strong heritability suggests
pedigree studies will have good power to localize pathogenic genes. However, CLL is relatively rare and
heterogeneous, complicating ascertainment and analyses. Our goal was to identify CLL risk loci using unique
resources available in Utah and methods to address intra-familial heterogeneity.

Methods: We identified a six-generation high-risk CLL pedigree using the Utah Population Database. This pedigree
contains 24 CLL cases connected by a common ancestor. We ascertained and genotyped eight CLL cases using a
high-density SNP array, and then performed shared genomic segment (SGS) analysis - a method designed for
extended high-risk pedigrees that accounts for heterogeneity.
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Results: We identified a genome-wide significant region (P = 1.9 × 10 , LOD-equivalent 5.6) at 2q22.1. The 0.9 Mb
region was inherited through 26 meioses and shared by seven of the eight genotyped cases. It sits within a ~6.25
Mb locus identified in a previous linkage study of 206 small CLL families. Our narrow region intersects two genes,
including CXCR4 which is highly expressed in CLL cells and implicated in maintenance and progression.

© The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0
International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing,
adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as
long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and
indicate if changes were made.

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