Characterization of greater middle eastern genetic variation for enhanced disease gene discovery

The Greater Middle East (GME) has been a central hub of human migration and population admixture. The tradition of consanguinity, variably practiced in the Persian Gulf region, North Africa, and Central Asia1-3, has resulted in an elevated burden of recessive disease4. Here we generated a whole-exome GME variome from 1,111 unrelated subjects. We detected substantial diversity and admixture in continental and subregional populations, corresponding to several ancient founder populations with little evidence of bottlenecks. Measured consanguinity rates were an order of magnitude above those in other sampled populations, and the GME population exhibited an increased burden of runs of homozygosity (ROHs) but showed no evidence for reduced burden of deleterious variation due to classically theorized ‘genetic purging’. Applying this database to unsolved recessive conditions in the GME population reduced the number of potential disease-causing variants by four- to sevenfold. These results show variegated genetic architecture in GME populations and support future human genetic discoveries in Mendelian and population genetics

Fertility outcome in male and female patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Objective: To investigate fertility in a sample of Tunisian patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. Design: Tunisian bicentric prospective study. Setting: Endocrinology department, Hedi Chaker Hospital, Sfax, Tunisia and Department of Endocrinology and Internal Medicine, Tahar Sfar Hospital, Mahdia, Tunisia. Materials and methods: Twenty-six patients (11 M; 15 F), aged 16.5–48 years, were enrolled. Clinical, biological, hormonal and ultrasound examinations were performed to assess fertility. Results: Eighteen had the classical form and eight the non classic. One patient had palpable testicular nodule. Inhibin B level was decreased in four male patients. Semen analysis showed abnormalities in four of 10 patients. Testicular adrenal rest tumors (TARTs) were detected in 6/11 patients. Menstrual disorders and hirsutism were noted in four and nine female patients, respectively. Six patients showed polycystic ovary syndrome. Anti-Mullerian hormone level was reduced in four female patients. Among four female patients who wished to get pregnant, two of them achieved one successful pregnancy, miscarriage occurred in one patient and the remaining patient was sterile. Fertility issues in our patients appeared to be related to poor hormonal control and a result of noncompliance with medication schedules. Conclusion: Fertility in male and female patients with CAH is reduced. Early and adequate glucocorticoid therapy along with good compliance, careful monitoring of androgen levels and continuous psychological management could contribute to improved fertility rates in this population, even among those with the severe variant

Report of the Tunisian Registry of Primary Immunodeficiencies: 25-Years of Experience (1988-2012)

International audiencePrimary immunodeficiencies (PIDs) are a large group of diseases characterized by susceptibility to not only recurrent infections but also autoimmune diseases and malignancies. The aim of this study was to describe and analyze the distribution, clinical features and eventual outcome of PID among Tunisian patients. We reviewed the record of 710 patients diagnosed with Primary Immunodeficiency Diseases (PIDs) from the registry of the Tunisian Referral Centre for PIDs over a 25-year period. The male-to-female ratio was 1.4. The median age at the onset of symptoms was 6 months and at the time of diagnosis 2 years. The estimated prevalence was 4.3 per 100,000 populations. The consanguinity rate was found in 58.2 % of families. According to the International Union of Immunological Societies classification, spectrums of PIDs were as follows: combined T-cell and B-cell immunodeficiency disorders account for the most common category (28.6 %), followed by congenital defects of phagocyte (25.4 %), other well-defined immunodeficiency syndromes (22.7 %), predominant antibody deficiency diseases (17.7 %), diseases of immune dysregulation (4.8 %), defect of innate immunity (0.4 %) and complement deficiencies (0.4 %). Recurrent infections, particularly lower airway infections (62.3 %), presented the most common manifestation of PID patients. The overall mortality rate was 34.5 %, mainly observed with combined immunodeficiencies. The distribution of PIDs was different from that reported in Western countries, with a particularly high proportion of Combined Immunodeficiencies and phagocyte defects in number and/or function. More is needed to improve PID diagnosis and treatment in our country