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

Human Genomics

Hakon Hakonarson²  Xun Xu¹  Matthew A. Deardorff⁴  Jianguo Zhang¹  Theodore J. Ganley³  Jiankang Li¹  Joseph Glessner²  Brendan Keating²  Yiran Guo²  Fengxiang Wang²  Kexiang Xu²  Nguyen Kenny²  Michael E. March²  Yun Li²  Yichuan Liu² 

[1] Beijing Genomics Institute, Shenzhen, China;Center for Applied Genomics, The Children’s Hospital of Philadelphia, 1014H, 3615 Civic Center Blvd, Abramson Building, Philadelphia 19104, PA, USA;Center for Sports Medicine and Performance, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA;Individualized Medical Genetics Center, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

关键词: Whole exome sequencing;    Rare disease;    Copy number variation;   

Others  :  1232633
DOI  :  10.1186/s40246-015-0053-z

 received in 2015-07-23, accepted in 2015-10-31,  发布年份 2015

【 摘 要 】

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.

【 授权许可】

   
2015 Liu et al.

【 图 表 】

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