A homozygous FANCM frameshift pathogenic variant causes male infertility

Hui Fang,Hanwei Jiang,Hong Yin ,Manan Khan,Jun Huang,Suixing Fan,Yang Li,Xiaohua Jiang,Sajjad Hussain,Qiaomei Hao,Asim Ali,Xuefeng Xie,Hui Ma,Teka Khan,Mahmoud Huleihel,Ihtisham Bukhari,Furhan Iqbal,Jabeen Nazish,Liangwen Zhong,Huan Zhang,Jianing Gao,Muhammad Zubair,Tej K Pandita,Qinghua Shi,Beibei Zhang,Long Jiang,Jiahao Sha,Tao Li,Yuanwei Zhang

doi:10.1038/s41436-018-0015-7

Abstract

PurposeFanconi anemia (FA) genes play important roles in spermatogenesis. In mice, disruption of Fancm impairs male fertility and testicular integrity, but whether FANCM pathogenic variants (PV) similarly affect fertility in men is unknown. Here we characterize a Pakistani family having three infertile brothers, two manifesting oligoasthenospermia and one exhibiting azoospermia, born to first-cousin parents. A homozygous PV in FANCM (c.1946_1958del, p.P648Lfs*16) was found cosegregating with male infertility. Our objective is to validate that FANCM p.P648Lfs*16 is the PV causing infertility in this family. MethodsExome and Sanger sequencing were used for PV screening. DNA interstrand crosslink (ICL) sensitivity was assessed in lymphocytes from patients. A mouse model carrying a PV nearly equivalent to that in the patients (FancmΔC/ΔC) was generated, followed by functional analysis in spermatogenesis. ResultsThe loss-of-function FANCM PV increased ICL sensitivity in lymphocytes of patients and FancmΔC/ΔC spermatogonia. Adult FancmΔC/ΔC mice showed spermatogenic failure, with germ cell loss in 50.2% of testicular tubules and round-spermatid maturation arrest in 43.5% of tubules. In addition, neither bone marrow failure nor cancer/tumor was detected in all the patients or adult FancmΔC/ΔC mice. ConclusionThese findings revealed male infertility to be a novel phenotype of human patients with a biallelic FANCM PV.

Highlights

Male infertility affects approximately 7% of all men[1] and presents commonly with spermatogenic failure
These findings revealed male infertility to be a novel phenotype of human patients with a biallelic FANCM pathogenic variants (PV)
Clinical phenotypes We investigated the genetic cause of male infertility in a Pakistani family with three infertile brothers, who were born to a first-cousin marriage (Fig. 1a)

Summary

Introduction

Male infertility affects approximately 7% of all men[1] and presents commonly with spermatogenic failure. Fanconi anemia (FA) is a genetic disease with highly variable clinical manifestations, typically described as bone marrow failure, congenital defects, cancer predisposition, and cellular hypersensitivity to DNA interstrand crosslink (ICL)-inducing agents, such as mitomycin C (MMC) (In the OMIM database, the ID for Fanconi Anemia is #227650, and currently 21 genes are related to this disease, which are FANCA, B, C, D1, D2, E, F, G, I, J, L, M, N, O, P, Q, R, S, T, U, V, W (MIM *607139, *300515, *613899, *600185, *613984, *613976, *613897, *602956, *611360, *605882, *608111, *610355, *602774, *133520, *179617, *113705, *610538, *600375, *604094 and *614151, respectively).[5] Reduced fertility can be commonly found in FA patients with fertility being impaired in about half of female patients and almost all male patients.[6] To date, biallelic or X-linked recessive PV in any one of the FA genes (FANCA, B, C, D1, D2, E, F, G, I, J, L, M, N, O, P, Q, R, S, T, U, V, W) 7–10

Objectives

Methods

Results

Conclusion