Exome Sequencing to Identify Novel Variants Associated with Secondary Amenorrhea and Premature Ovarian Insufficiency (POI) in Saudi Women.

BACKGROUND AND OBJECTIVES: Post-pubertal disappearance of menstrual cycles (secondary amenorrhea) associated with premature follicular depletion is a heterogeneous condition. Patients with this disease have low levels of gonadal hormones and high levels of gonadotropins. It is one of the causes of female infertility and a strong genetic component is attributed as an underlying cause of this condition. Although variants in several genes have been associated with the condition, the cause of the disease remains undetermined in the vast majority of cases. Methodology and Materials: Ten Saudi married women experiencing secondary amenorrhea were referred to a center for genetics and inherited diseases for molecular investigation. A family-based study design was used. Intensive clinical examinations, including pelvic ultra-sonography (U/S) and biochemical evaluations, were carried out. Karyotypes were normal in all cases and polycystic ovarian syndrome (PCOS) was excluded by using Rotterdam consensus criteria. Patients' DNA samples were whole-exome sequenced (WES). Bidirectional Sanger sequencing was then utilized to validate the identified candidate variants. The pathogenicity of detected variants was predicted using several types of bioinformatics software. RESULTS: Most of the patients have a normal uterus with poor ovarian reserves. Exome sequence data analysis identified candidate variants in genes associated with POI in 60% of cases. Novel variants were identified in HS6ST1, MEIOB, GDF9, and BNC1 in POI-associated genes. Moreover, a homozygous variant was also identified in the MMRN1 gene. Interestingly, mutations in MMRN1 have never been associated with any human disease. The variants identified in this study were not present in 125 healthy Saudi individuals. CONCLUSIONS: WES is a powerful tool to identify the underlying variants in genetically heterogeneous diseases like secondary amenorrhea and POI. In this study, we identified six novel variants and expanded the genotype continuum of POI. Unravelling the genetic landscape of POI will help in genetic counselling, management, and early intervention.

Association of Homozygous PROP1 Mutation in a Saudi Family with Combined Pituitary Hormone Deficiency.

Background and Objectives: Combined pituitary hormone deficiency (CPHD) is a rare heterogeneous disease. It is characterized by the deficiency of growth hormone (GH) and shortage of at least one or more other hormones of the pituitary gland including thyroid-stimulating hormone (TSH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and prolactin. Rare pathogenic variants in nearly 30 genes have been identified as an underlying cause of CPHD pathogenicity. Among these genes, paired-like homeobox 1 (PROP1) has been reported to be the most common cause of CPHD. Materials and Methods: In the present study, we investigated a large family of Saudi origin with three adult sisters suffering from short stature in combination of secondary amenorrhea. Results: Whole-exome sequencing followed by Sanger sequencing shows a homozygous missense variant (NM_006261.5; c.211C > T; p.R71C) in the PROP1 gene segregating with the disease phenotype within the family. In silico analysis studies show that this variant is highly conserved among several orthologues and is predicted as likely pathogenic using various bioinformatics tools. Conclusions: Our finding presents the first Saudi familial case of autosomal recessive form of CPHD caused by the PROP1 variant.

Hepatitis B and C virus prevalence in couples attending an in vitro fertilization clinic in a tertiary care hospital in Saudi Arabia: comparison with ten years earlier.

BACKGROUND: Viral hepatitis B (HBV) and C (HCV) are a major public health problem in Saudi Arabia. Recent data has indicated a major reduction in viral hepatitis prevalence in Saudi population. However, there is limited data for infertile Saudi couples. OBJECTIVES: To determine the prevalence of HCV and HBV attending an in vitro fertilization (IVF) clinic in Saudi Arabia between 2012 and 2015 to compare with the prevalence 10 years earlier in the same center. DESIGN: Retrospective prevalence study. SETTING: Tertiary care center in Riyadh. PATIENTS AND METHODS: Data on the prevalence of HBV and HCV was collected on all couples seen at the IVF unit between 2002-2005 and 2012-2015. MAIN OUTCOME MEASURE(S): Prevalence of HBV and HCV. RESULTS: In 4442 patients during 2002-2005 and 5747 patients during 2012-2015, the prevalence of HBV was significantly less in 2012-2015 compared with 2002-2005 (1.67% [97 patients] vs 4.7% [210 patients], P < .0001), respectively, but HCV prevalence was similar for the two periods (0.7% for both periods) (P=.887). The hepatitis B seroprevalence rate was higher in males compared to females during 2002-2005 (6.3% vs 3.1%) (P < .0001) and 2012-2015 (2.4% vs 1.1% ) (P < .0001), respectively. CONCLUSION: The significant drop in HBV prevalence was most likely due to the introduction of the vaccination program in 1989, while reasons for HCV prevalence remaining unchanged are unclear. LIMITATION: No data on confounding factors that may have affected the prevalence.