Autor(es):
Lopes, Alexandra 
; Aston, Kenneth I. ; Thompson, Emma E ; Carvalho, Filipa ; Gonçalves, João ; Huang, N. ; Matthiesen, Rune ; Noordam, Michiel J. ; Quintela, Ines ; Ramu, Avinash ; Seabra, Catarina ; Wilfert, Amy B. ; Dai, Juncheng ; Downie, Jonathan ; Fernandes, Susana ; Guo, Xuejiang ; Shah, Jiahao ; Amorim, Antonio ; Barros, Alberto ; Carracedo, A. ; Hu, Z. ; Hurles, M.E. ; Moskovtsev, S. ; Ober, C. ; Paduch, D.A. ; Schiffman, J.D. ; Schlegel, P.N. ; Sousa, M. ; Carrell, D.T. ; Conrad, D.F.
Data: 2013
Identificador Persistente: http://hdl.handle.net/10400.18/2157
Origem: Repositório Científico do Instituto Nacional de Saúde
Assunto(s): Human Infertility; Human Spermatogenesis; Male Infertility; DMRT1; CNV; Azoospermia; Oligozoospermia; Array; Doenças Genéticas
Descrição
Gonadal failure, along with early pregnancy loss and perinatal death, may be an important filter that limits the propagation
of harmful mutations in the human population. We hypothesized that men with spermatogenic impairment, a disease with
unknown genetic architecture and a common cause of male infertility, are enriched for rare deleterious mutations
compared to men with normal spermatogenesis. After assaying genomewide SNPs and CNVs in 323 Caucasian men with
idiopathic spermatogenic impairment and more than 1,100 controls, we estimate that each rare autosomal deletion
detected in our study multiplicatively changes a man’s risk of disease by 10% (OR 1.10 [1.04–1.16], p,261023), rare X-linked
CNVs by 29%, (OR 1.29 [1.11–1.50], p,161023), and rare Y-linked duplications by 88% (OR 1.88 [1.13–3.13], p,0.03). By
contrasting the properties of our case-specific CNVs with those of CNV callsets from cases of autism, schizophrenia, bipolar
disorder, and intellectual disability, we propose that the CNV burden in spermatogenic impairment is distinct from the
burden of large, dominant mutations described for neurodevelopmental disorders. We identified two patients with
deletions of DMRT1, a gene on chromosome 9p24.3 orthologous to the putative sex determination locus of the avian ZW
chromosome system. In an independent sample of Han Chinese men, we identified 3 more DMRT1 deletions in 979 cases of
idiopathic azoospermia and none in 1,734 controls, and found none in an additional 4,519 controls from public databases.
The combined results indicate that DMRT1 loss-of-function mutations are a risk factor and potential genetic cause of human
spermatogenic failure (frequency of 0.38% in 1306 cases and 0% in 7,754 controls, p = 6.261025). Our study identifies other
recurrent CNVs as potential causes of idiopathic azoospermia and generates hypotheses for directing future studies on the
genetic basis of male infertility and IVF outcomes.
