Novel Compound Heterozygous Variants in CCDC40 Associated with Primary Ciliary Dyskinesia and Multiple Morphological Abnormalities of the Sperm Flagella

Yingjie Xu; Binyi Yang; Cheng Lei; Danhui Yang; Shuizi Ding; Chenyang Lu; Lin Wang; Ting Guo; Rongchun Wang; Hong Luo

doi:10.2147/PGPM.S359821

Novel Compound Heterozygous Variants in CCDC40 Associated with Primary Ciliary Dyskinesia and Multiple Morphological Abnormalities of the Sperm Flagella

Pharmgenomics Pers Med. 2022 Apr 15:15:341-350. doi: 10.2147/PGPM.S359821. eCollection 2022.

Authors

Yingjie Xu^#^{1

2

3}, Binyi Yang^#^{1

2

3}, Cheng Lei^{1

2

3}, Danhui Yang^{1

2

3}, Shuizi Ding^{1

2

3}, Chenyang Lu^{1

2

3}, Lin Wang^{1

2

3}, Ting Guo^{1

2

3}, Rongchun Wang^{1

2

3}, Hong Luo^{1

2

3}

Affiliations

¹ Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, People's Republic of China.
² Research Unit of Respiratory Disease, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, People's Republic of China.
³ Hunan Diagnosis and Treatment Center of Respiratory Disease, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, People's Republic of China.

^# Contributed equally.

Abstract

Primary ciliary dyskinesia (PCD) is a rare genetic disease caused by mutations of genes coding motile-cilia-related proteins. CCDC40 variants can cause PCD via disrupting the assembling of inner dynein and dynein regulating complex in cilia and flagella, but none has been reported associated with multiple morphological abnormalities of the sperm flagella (MMAF). We identified and validated the disease-causing variants in our patient via whole-exome and Sanger sequencing. We used high-speed video microscopy analysis (HSVA) and immunofluorescence to analyze the functional and structural deficiency of respiratory cilia. Papanicolaou staining and scanning electron microscope was applied to analyze the morphological sperm defects resulted from the PCD associated variants. We identified novel compound variants (c.901C>T, p.(Arg301*); c.2065_2068dup, p.(Ala690Glyfs*67)) in CCDC40 in a male patient with male infertility. HSVA revealed the rigid and stiff ciliary beating pattern. Immunofluorescence indicated loss of inner dynein arm protein DNAH2 both in cilia and the sperms of the patient. Diagnosis of MMAF was confirmed through sperm Papanicolaou staining and scanning electron microscope. We first describe a patient with a combination of PCD and MMAF associated with novel compound heterozygous variants in CCDC40. Our results present initial evidence that CCDC40 associated with MMAF, which expands the genetic spectrum of PCD and MMAF and provides precise clinical genetic counseling to this family.

Keywords: CCDC40; MMAF; PCD; male infertility.

Publication types

Case Reports

Grants and funding

This study was supported by the National Natural Science Foundation of China (82070003 to H.L, 81900002 to T.G), Natural Science Foundation of Hunan Province, China (2020JJ5805 to T.G, 2021JJ30943 to H.L), the Science and Technology Program of Changsha, China (kq1901120 to H.L), Xiangya Clinical Big Data System Construction Project in Pulmonary Inflammatory Disease of Central South University, and the National Key Clinical Specialty Construction Projects of China.