Sequence analysis of 37 candidate genes for male infertility: challenges in variant assessment and validating genes.

BACKGROUND: The routine genetic analysis for diagnosing male infertility has not changed over the last twenty years, and currently available tests can only determine the etiology of 4% of unselected infertile patients. Thus, to create new diagnostic assays, we must better understand the molecular and genetic mechanisms of male infertility. Although next-generation sequencing allows for simultaneous analysis of hundreds of genes and the discovery of novel candidates related to male infertility, so far only a few gene candidates have enough sound evidence to support the gene-disease relationship. OBJECTIVE: Since complementary studies are required to validate genes, we aimed to analyze the presence of potentially pathogenic rare variants in a set of candidate genes related to azoospermia in a hitherto understudied South American population. SUBJECTS AND METHODS: We performed whole exome sequencing in a group of 16 patients with non-obstructive azoospermia from Ribeirão Preto, Brazil. Based on a recent systematic review of monogenic causes of male infertility, we selected a set of 37 genes related to azoospermia, Sertoli-Cell-Only histology, and spermatogenic arrest to analyze. The identified variants were confirmed by Sanger sequencing, and their functional consequence was predicted by in silico programs. RESULTS: We identified potential pathogenic variants in seven genes in six patients. Two variants, c.671A>G (p.(Asn224Ser)) in DMRT1 and c.91C>T (p.(Arg31Cys)) in REC8, have already been described in association with azoospermia. We also found new variants in genes that already have moderate evidence of being linked to spermatogenic failure (TEX15, KLHL10), in genes with limited evidence (DNMT3B, TEX14) and in one novel promising candidate gene that has no evidence so far (SYCE1L). DISCUSSION: Although this study included a small number of patients, the process of rationally selecting genes allowed us to detect rare potentially pathogenic variants, providing supporting evidence for validating candidate genes associated with azoospermia.

Assessment and treatment of abstinence in the infant of the drug-dependent mother.

To accomplish the assessment and treatment of abstinence in the infant of the drug dependent mother, a scoring system has been devised for use as a clinical and research tool. The score monitors the passively addicted infant in a more comprehensive and precise way than has previously been described, and permits us to be more objective in our clinical estimates of the abstinence syndrome. Further, this scoring system has been used by relating it to the dosage schedule of phenobarbital or paregoric as part of an ongoing research project designed to test the comparative usefulness of recommended treatments for neonates with abstinence symptoms. It has been found useful also in following the progression or diminution of symptomatology before, during and after drug therapy. Moreover, the scoring system provides a basis for developing uniform criteria for the assessment and treatment of the neonate of the addicted mother.

Neonatal abstinence syndrome: assessment and management.

A scoring system for the neonatal abstinence syndrome has been devised and implemented as both a clinical and investigative tool. The score monitors the passively addicted infant in a more comprehensive and objective fashion, and facilitates a more precise evaluation of the clinical status of the infant undergoing withdrawal. In addition, the scoring system has been applied in research designed to test the comparative usefulness of various pharmacologic agents currently recommended for the neonatal abstinence syndrome, and has been found useful in following the progression and diminution of withdrawal symptomatology before, during, and after therapy. Furthermore, the scoring system provides a basis ofr developing uniform criteria for the assessment and treatment of the neonate born to the addicted mother.

Management of sexually assaulted females.

PIP: The victim of sexual assault has 5 needs: 1) care of injuries, 2) prevention of venereal disease, 3) prevention/alleviation of psychologic damage, 4) medicolegal examination with documentation for law enforcement authorities, and 5) prevention of pregnancy. The staff of Philadelphia General Hospital, in a program designed to meet these needs, treated 480 (24.6 per 100,000 population) victims of sexual assault in 1968. 70% were ages 14-44, 24% below 14 years of age. In this program, serologic testing and cultures are followed by intramuscular injection of penicillin, 2,400,000 units. Both pediatric and adult victims are treated with reassurance, close follow-up and psychiatric referral as indicated. Detection of motile spermatozoa by examination of vaginal aspirate by a qualified experienced laboratory technician is of utmost importance. Postcoital contraceptive therapy revealed a high incidence of gastrointestinal side effects and 4 pregnancies were established in the treated cycle.^ieng