61Male infertility affects ~7% of men in Western societies, but its causes remain poorly 62 understood. The most clinically severe form of male infertility is non-obstructive azoospermia 63 (NOA), which is, in part, caused by an arrest at meiosis, but so far only few genes have been 64 reported to cause germ cell arrest in males. To address this gap, whole exome sequencing 65 was performed in 60 German men with complete meiotic arrest, and we identified in three 66 unrelated men the same homozygous frameshift variant c.676dup (p.Trp226LeufsTer4) in 67 M1AP, encoding meiosis 1 arresting protein. Then, with collaborators from the International 68Male Infertility Genomics Consortium (IMIGC), we screened a Dutch cohort comprising 99 69 infertile men and detected the same homozygous variant c.676dup in a man with 70 hypospermatogenesis predominantly displaying meiotic arrest. We also identified two 71Portuguese men with NOA carrying likely biallelic loss-of-function (LoF) and missense 72 variants in M1AP among men screened by the Genetics of Male Infertility Initiative (GEMINI). 73Moreover, we discovered a homozygous missense variant p.(Pro389Leu) in M1AP in a 74 consanguineous Turkish family comprising five infertile men. M1AP is predominantly 75 expressed in human and mouse spermatogonia up to secondary spermatocytes and 76 previous studies have shown that knockout male mice are infertile due to meiotic arrest. 77Collectively, these findings demonstrate that both LoF and missense M1AP variants that 78 impair its protein cause autosomal-recessive meiotic arrest, non-obstructive azoospermia 79 and male infertility. In view of the evidence from several independent groups and 80 populations, M1AP should be included in the growing list of validated NOA genes. 81 82We originally selected 64 azoospermic but otherwise healthy male patients who attended the 132 Centre of Reproductive Medicine and Andrology (CeRA), University Hospital Münster 133 (N = 51) or the Clinic for Urology, Pediatric Urology and Andrology, Gießen (N = 13), for 134 couple infertility. This is a subset of all patients included in our large-scale Male Reproductive 135 Genomics (MERGE) study, which currently comprises >800 men including 514 with NOA 136 ( Figure S1). All of the 64 patients were diagnosed with complete bilateral germ cell arrest at 137 the spermatocyte stage after evaluating at least 100 seminiferous tubules in tissue sections 138 of both testes accompanied by a negative TESE outcome, i.e., no sperm could be recovered.

Definitions: Mutation detection rate refers to the detection of expected mutations according to pretest risk calculations; Mutation prevalence refers to the proportion of patients with a mutation of the whole cohort. AbstractTo date, a disease-causing mutation can be found in 15-30% of families with hereditary breast and ovarian cancer (HBOC) and it is believed that more than half of the cases still remain unsolved. Usually it is intended to perform genetic analyses in the family member with the most severe phenotype, which, however, may not always be possible. Moreover, no standard criteria have been established to define the person who is most suitable for genetic testing within a family: 'the best index case'.We therefore established clinical criteria to identify the best index case in HBOC and analyzed the impact on genetic testing. 130 patients who presented at our department from 2016 to 2018 were divided into two groups. In group A (N = 98) genetic analyses were performed in the best index case based on our criteria. In group B (N = 32) at least one other family member was considered a better index case. The detection rate of expected mutations was significantly higher for group A (64.3% vs. 32.0%, p = 0.034) while there was no significant difference of calculated mutation carrier risks between these groups. We conclude that the mutation detection rate in families with HBOC is notably higher after identifying the best index case for genetic testing according to the clinical selection criteria reported here.