RT Journal Article SR Electronic T1 Novel homozygous CFAP69 mutations in humans and mice cause severe asthenoteratospermia with multiple morphological abnormalities of the sperm flagella JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 96 OP 103 DO 10.1136/jmedgenet-2018-105486 VO 56 IS 2 A1 Xiaojin He A1 Weiyu Li A1 Huan Wu A1 Mingrong Lv A1 Wangjie Liu A1 Chunyu Liu A1 Fuxi Zhu A1 Caihua Li A1 Youyan Fang A1 Chenyu Yang A1 Huiru Cheng A1 Junqiang Zhang A1 Jing Tan A1 Tingting Chen A1 Dongdong Tang A1 Bing Song A1 Xue Wang A1 Xiaomin Zha A1 Hongyan Wang A1 Zhaolian Wei A1 Shenmin Yang A1 Hexige Saiyin A1 Ping Zhou A1 Li Jin A1 Jian Wang A1 Zhiguo Zhang A1 Feng Zhang A1 Yunxia Cao YR 2019 UL http://jmg.bmj.com/content/56/2/96.abstract AB Background Male infertility is a major issue of human reproduction health. Asthenoteratospermia can impair sperm motility and cause male infertility. Asthenoteratospermia with multiple morphological abnormalities of the flagella (MMAF) presents abnormal spermatozoa with absent, bent, coiled, short and/or irregular-calibre flagella. Previous studies on MMAF reported that genetic defects in cilia-related genes (eg, AKAP4, DNAH1, CFAP43, CFAP44 and CFAP69) are the major cause of MMAF. However, the known MMAF-associated genes are only responsible for approximately 30% to 50% of human cases. We further investigated the cases with MMAF in search of additional genes mutated in this condition.Methods and results We conducted whole exome sequencing in a male individual with MMAF from a consanguineous Han Chinese family. Sanger sequencing was also conducted in additional individuals with MMAF. Intriguingly, a homozygous frameshift mutation (p.Leu357Hisfs*11) was identified in the gene encoding CFAP69 (cilia and flagella-associated protein 69), which is highly expressed in testis. The subsequent Sanger sequencing of the CFAP69 coding regions among 34 additional individuals with MMAF revealed a case with homozygous nonsense mutation (p.Trp216*) of CFAP69. Both of these CFAP69 loss-of-function mutations were not present in the human population genome data archived in the 1000 Genomes Project and ExAC databases, nor in 875 individuals of two Han Chinese control populations. Furthermore, we generated the knockout model in mouse orthologue Cfap69 using the CRISPR-Cas9 technology. Remarkably, male Cfap69-knockout mice manifested with MMAF phenotypes.Conclusion Our experimental findings elucidate that homozygous loss-of-function mutations in CFAP69 can lead to asthenoteratospermia with MMAF in humans and mice.