De novo mutations are known to play a prominent role in sporadic disorders with reduced fitness. We hypothesize that de novo mutations play an important role in severe male infertility and explain a portion of the genetic causes of this understudied disorder. To test this hypothesis, we utilize trio-based exome sequencing in a cohort of 185 infertile males and their unaffected parents. Following a systematic analysis, 29 of 145 rare (MAF < 0.1%) protein-altering de novo mutations are classified as possibly causative of the male infertility phenotype. We observed a significant enrichment of loss-of-function de novo mutations in loss-of-function-intolerant genes (p-value = 1.00 × 10−5) in infertile men compared to controls. Additionally, we detected a significant increase in predicted pathogenic de novo missense mutations affecting missense-intolerant genes (p-value = 5.01 × 10−4) in contrast to predicted benign de novo mutations. One gene we identify, RBM5, is an essential regulator of male germ cell pre-mRNA splicing and has been previously implicated in male infertility in mice. In a follow-up study, 6 rare pathogenic missense mutations affecting this gene are observed in a cohort of 2,506 infertile patients, whilst we find no such mutations in a cohort of 5,784 fertile men (p-value = 0.03). Our results provide evidence for the role of de novo mutations in severe male infertility and point to new candidate genes affecting fertility.

Human papilloma virus (HPV) is now a well-known risk factor for head and neck cancer besides smoking and alcohol. Most studies mentioned that patients affected with high-risk HPV cancers have a better outcome, and many clinical trials are trying to prove that such group of patients can receive a different and less aggressive treatment than the HPV-negative group. Although such field has received great interest within different countries and continents, African and Egyptian populations are not yet well studied within the literature. Our aim was to detect the prevalence of HPV in oropharyngeal (OP), lip and tongue squamous cell carcinoma (SSC) and correlate the viral prevalence with different clinicopathologic parameters as well as patients’ outcome. HPV detection was done on 99 cases from the lip (29), tongue (38) and oropharynx (32) diagnosed at the Pathology Department of the National Cancer Institute, Cairo University. p16 immunohistochemistry was performed on all cases, followed by HPV DNA in situ hybridization (ISH) for p16-positive cases. The prevalence of HPV in OPSSC was 28% and in lip and tongue cancers lumped together was 37%. There was more than 90% concordance between p16 and HPV DNA ISH results. HPV positivity showed a statistically significant correlation with better disease-free survival (DFS), which was also maintained for OP cases. HPV is highly prevalent in OP and common oral cavity cancers in the Egyptian population. HPV positivity correlated significantly with better DFS, especially in OP cancers.

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The age-adjusted incidence of Hodgkin's lymphoma (HL) is markedly higher in Saudi Arabia than in the USA, and accounts for 10.5% of all neoplasias in children aged 15 years or older in Saudi Arabia. Epstein-Barr virus (EBV) infection has been suspected to cause high HL incidence in developing countries. To investigate the role of EBV for the high frequency of HL in Saudi Arabia, we analysed 169 HLs from Saudi Arabia and 30 HLs from Europe for EBV infection by in situ hybridization with fluorescence in-conjugated EBV on tissue microarray sections. All Saudi Arabian and European HLs were analysed in one experiment under identical conditions. Unexpectedly, our data show only minor, insignificant differences in EBV infection rates between Saudi Arabian (42 out of 147 informative cases 28.6%) and European HL (nine out of 30 informative cases; 30%; P = 0.8752). Within the Saudi Arabian population, EBV infection was most frequently seen in mixed cellularity HL (52.4%). This was significantly more frequent than in nodular sclerosing HL (26.1%; P = 0.0236). EBV positivity was unrelated to patient prognosis. In conclusion, our data strongly suggest that EBV is not the main cause for the high prevalence of HL in Saudi Arabia. This would be consistent with a major role of genetic susceptibility genes for HL in these populations. The Saudi Arabian population, with high consanguinity and large families, would prove ideal for identifying HL susceptibility genes.

De novo mutations (DNMs) are known to play a prominent role in sporadic disorders with reduced fitness. We hypothesize that DNMs play an important role in male infertility and explain a significant fraction of the genetic causes of this understudied disorder. To test this hypothesis, we performed trio-based exome-sequencing in a unique cohort of 185 infertile males and their unaffected parents. Following a systematic analysis, 29 of 145 rare protein altering DNMs were classified as possibly causative of the male infertility phenotype. We observed a significant enrichment of Loss-of-Function (LoF) DNMs in LoF-intolerant genes (p-value=1.00x10-5) as well as predicted pathogenic missense DNMs in missense-intolerant genes (p-value=5.01x10-4). One DNM gene identified, RBM5, is an essential regulator of male germ cell pre-mRNA splicing. In a follow-up study, 5 rare pathogenic missense mutations affecting this gene were observed in a cohort of 2,279 infertile patients, with no such mutations found in a cohort of 5,784 fertile men (p-value=0.009). Our results provide the first evidence for the role of DNMs in severe male infertility and point to many new candidate genes affecting fertility.