Copy number variation in CEP57L1 predisposes to congenital absence of bilateral ACL and PCL ligaments

Human Genomics, Nov 2015

Background Absence of the anterior (ACL) or posterior cruciate ligament (PCL) are rare congenital malformations that result in knee joint instability, with a prevalence of 1.7 per 100,000 live births and can be associated with other lower-limb abnormalities such as ACL agnesia and absence of the menisci of the knee. While a few cases of absence of ACL/PCL are reported in the literature, a number of large familial case series of related conditions such as ACL agnesia suggest a potential underlying monogenic etiology. We performed whole exome sequencing of a family with two individuals affected by ACL/PCL. Results We identified copy number variation (CNV) deletion impacting the exon sequences of CEP57L1, present in the affected mother and her affected daughter based on the exome sequencing data. The deletion was validated using quantitative PCR (qPCR), and the gene was confirmed to be expressed in ACL ligament tissue. Interestingly, we detected reduced expression of CEP57L1 in Epstein–Barr virus (EBV) cells from the two patients in comparison with healthy controls. Evaluation of 3D protein structure showed that the helix-binding sites of the protein remain intact with the deletion, but other functional binding sites related to microtubule attachment are missing. The specificity of the CNV deletion was confirmed by showing that it was absent in ~700 exome sequencing samples as well as in the database of genomic variations (DGV), a database containing large numbers of annotated CNVs from previous scientific reports. Conclusions We identified a novel CNV deletion that was inherited through an autosomal dominant transmission from an affected mother to her affected daughter, both of whom suffered from the absence of the anterior and posterior cruciate ligaments of the knees.

A PDF file should load here. If you do not see its contents the file may be temporarily unavailable at the journal website or you do not have a PDF plug-in installed and enabled in your browser.

Alternatively, you can download the file locally and open with any standalone PDF reader:

http://www.humgenomics.com/content/pdf/s40246-015-0053-z.pdf

Copy number variation in CEP57L1 predisposes to congenital absence of bilateral ACL and PCL ligaments

Liu et al. Human Genomics Copy number variation in CEP57L1 predisposes to congenital absence of bilateral ACL and PCL ligaments Yichuan Liu 0 3 Yun Li 0 3 Michael E. March 0 3 Kenny Nguyen 0 3 Kexiang Xu 0 3 Fengxiang Wang 0 3 Yiran Guo 0 3 Brendan Keating 0 3 Joseph Glessner 0 3 Jiankang Li 2 Theodore J. Ganley 1 Jianguo Zhang 2 Matthew A. Deardorff 4 Xun Xu 2 Hakon Hakonarson 0 3 0 Center for Applied Genomics, The Children's Hospital of Philadelphia , 1014H, 3615 Civic Center Blvd, Abramson Building, Philadelphia, PA 19104 , USA 1 Center for Sports Medicine and Performance, The Children's Hospital of Philadelphia , Philadelphia, PA , USA 2 Beijing Genomics Institute , Shenzhen , China 3 Center for Applied Genomics, The Children's Hospital of Philadelphia , 1014H, 3615 Civic Center Blvd, Abramson Building, Philadelphia, PA 19104 , USA 4 Individualized Medical Genetics Center, The Children's Hospital of Philadelphia , Philadelphia, PA , USA Background: Absence of the anterior (ACL) or posterior cruciate ligament (PCL) are rare congenital malformations that result in knee joint instability, with a prevalence of 1.7 per 100,000 live births and can be associated with other lower-limb abnormalities such as ACL agnesia and absence of the menisci of the knee. While a few cases of absence of ACL/PCL are reported in the literature, a number of large familial case series of related conditions such as ACL agnesia suggest a potential underlying monogenic etiology. We performed whole exome sequencing of a family with two individuals affected by ACL/PCL. Results: We identified copy number variation (CNV) deletion impacting the exon sequences of CEP57L1, present in the affected mother and her affected daughter based on the exome sequencing data. The deletion was validated using quantitative PCR (qPCR), and the gene was confirmed to be expressed in ACL ligament tissue. Interestingly, we detected reduced expression of CEP57L1 in Epstein-Barr virus (EBV) cells from the two patients in comparison with healthy controls. Evaluation of 3D protein structure showed that the helix-binding sites of the protein remain intact with the deletion, but other functional binding sites related to microtubule attachment are missing. The specificity of the CNV deletion was confirmed by showing that it was absent in ~700 exome sequencing samples as well as in the database of genomic variations (DGV), a database containing large numbers of annotated CNVs from previous scientific reports. Conclusions: We identified a novel CNV deletion that was inherited through an autosomal dominant transmission from an affected mother to her affected daughter, both of whom suffered from the absence of the anterior and posterior cruciate ligaments of the knees. Copy number variation; Rare disease; Whole exome sequencing - Introduction Congenital absence of the anterior (ACL)/posterior cruciate ligaments (PCL) is an extremely unusual condition with a prevalence of 1.7 per 100,000 live births and was first reported in 1956 in a radiographic study of the knee [1–3]. The symptom of this disease usually associated with serious malformation or dislocation of the knees. ACL is the most common disorder, and it can be associated with hypoplasia or total PCL. There is little knowledge of the genetics information related to this disease, but a previous study in a large number of families suggested autosomal dominant inheritance of ACL [4]. In this study, we uncovered two individuals (mother and her daughter) in a large cohort of subjects with rare diseases, and we confirmed the underlying sequence copy number variations (CNVs) that predisposes to this disease. © 2016 Liu et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Methods Data selections Among 662 individuals from 212 families with Mendelian disease phenotypes, there was one family with two affected patients, including a mother (ID#4779933454) and her 13-year-old daughter (ID#1993197298), suffering from an absence of bilateral ACL and PCL ligaments. Their history was notable for joint instability and difficulty with ambulation. Absence of ACL and PCL was confirmed on MRI and by arthroscopy. The proband (daughter) has an unaffected younger sister and unaffected father, for both of whom DNA was not obtainable. However, the pattern of inheritance suggests it is autosomal dominant [4]; no other extended family members have a history of joint or lower-limb disorders. Exome captur (...truncated)


This is a preview of a remote PDF: http://www.humgenomics.com/content/pdf/s40246-015-0053-z.pdf

Yichuan Liu, Yun Li, Michael March, Nguyen Kenny, Kexiang Xu, Fengxiang Wang, Yiran Guo, Brendan Keating, Joseph Glessner, Jiankang Li, Theodore Ganley, Jianguo Zhang, Matthew Deardorff, Xun Xu, Hakon Hakonarson. Copy number variation in CEP57L1 predisposes to congenital absence of bilateral ACL and PCL ligaments, Human Genomics, 2015, pp. 31, 9, DOI: 10.1186/s40246-015-0053-z