Novel Genomic Variants, Atypical Phenotypes and Evidence of a Digenic/Oligogenic Contribution to Disorders/Differences of Sex Development in a Large North African Cohort.

In a majority of individuals with disorders/differences of sex development (DSD) a genetic etiology is often elusive. However, new genes causing DSD are routinely reported and using the unbiased genomic approaches, such as whole exome sequencing (WES) should result in an increased diagnostic yield. Here, we performed WES on a large cohort of 125 individuals all of Algerian origin, who presented with a wide range of DSD phenotypes. The study excluded individuals with congenital adrenal hypoplasia (CAH) or chromosomal DSD. Parental consanguinity was reported in 36% of individuals. The genetic etiology was established in 49.6% (62/125) individuals of the total cohort, which includes 42.2% (35/83) of 46, XY non-syndromic DSD and 69.2% (27/39) of 46, XY syndromic DSD. No pathogenic variants were identified in the 46, XX DSD cases (0/3). Variants in the AR, HSD17B3, NR5A1 and SRD5A2 genes were the most common causes of DSD. Other variants were identified in genes associated with congenital hypogonadotropic hypogonadism (CHH), including the CHD7 and PROKR2. Previously unreported pathogenic/likely pathogenic variants (n = 30) involving 25 different genes were identified in 22.4% of the cohort. Remarkably 11.5% of the 46, XY DSD group carried variants classified as pathogenic/likely pathogenic variant in more than one gene known to cause DSD. The data indicates that variants in PLXNA3, a candidate CHH gene, is unlikely to be involved in CHH. The data also suggest that NR2F2 variants may cause 46, XY DSD.

Expanding DSD Phenotypes Associated with Variants in the DEAH-Box RNA Helicase DHX37.

Missense variants in the RNA-helicase DHX37 are associated with either 46,XY gonadal dysgenesis or 46,XY testicular regression syndrome (TRS). DHX37 is required for ribosome biogenesis, and this subgroup of XY DSD is a new human ribosomopathy. In a cohort of 140 individuals with 46,XY DSD, we identified 7 children with either 46,XY complete gonadal dysgenesis or 46,XY TRS carrying rare or novel DHX37 variants. A novel p.R390H variant within the RecA1 domain was identified in a girl with complete gonadal dysgenesis. A paternally inherited p.R487H variant, previously associated with a recessive congenital developmental syndrome, was carried by a boy with a syndromic form of 46,XY DSD. His phenotype may be explained in part by a novel homozygous loss-of-function variant in the NGLY1 gene, which causes a congenital disorder of deglycosylation. Remarkably, a homozygous p.T477H variant was identified in a boy with TRS. His fertile father had unilateral testicular regression with typical male genital development. This expands the DSD phenotypes associated with DHX37. Structural analysis of all variants predicted deleterious effects on helicase function. Similar to all other known ribosomopathies, the mechanism of pathogenesis is unknown.

Prédisposition génétique à la néphropathie diabétique: rôle du polymorphisme I/D du gène ACE / Genetic Predisposition to Diabetic Nephropathy: Role of I/D ACE Gene Polymorphism

Introduction - La néphropathie diabétique est la principale cause de la maladie rénale chronique et représente la complication la plus fréquente et la plus grave du diabète. Sa pathogénie exacte est complexe et noncomplètement élucidée. Plusieurs facteurs et mécanismes contribuent au développement et à l'issue de cette pathologie. Les objectifs de notre travail sont de déterminer la fréquence du polymorphisme Insertion(I)/Délétion (D) du gène ACE (angiotensin-converting enzyme) chez des patients diabétiques avec et sans néphropathie et d'établir la relation entre ce polymorphisme et la néphropathie diabétique dans une population de l'Est algérien. Matériel et Méthodes - Nous avons recruté à cet effet, vingt neuf sujets diabétiques avec néphropathie et trente témoins diabétiques sans néphropathie. L'extraction de l'ADN a été réalisée sur du sang frais par la méthode au NaCl et le polymorphisme I/D du gène ACE a été déterminé par PCR (polymérase Chaine Réaction). Un consentement éclairé a été obtenu de l'ensemble des participants. Résultats - La durée moyenne du diabète chez noscas est de 19,21 ± 9,31ans ; celle des témoins est de 10,67 ± 7,66 ans. Le diabète de type 1 est plus fréquent chez les néphropathes (72,41%), chez les témoins la fréquence du diabète de type 2 est plus importante (73.33%). Les complications macro-angiopathiques sont plus prévalentes chez les néphropathes. De plus l'association de deux ou plusieurs complications est fréquemment retrouvée. Les fréquences des allèles I et D sont respectivement 13,79 % et 86,21 % chez les sujets témoins alors que les fréquences alléliques chez les sujets avec néphropathie sont respectivement 19,64 % et 80,36 %. Conclusion - Aucune association significative entre ce polymorphisme et la néphropathie diabétique n'a été démontrée.

Angiotensin-converting enzyme insertion/deletion gene polymorphisms and the risk of glioma in an Algerian population.

INTRODUCTION: Just recently, it has been established that the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism is linked to the pathogenesis and to the evolution of human cancers. Therefore, the present study was concerned with the investigation of an eventual association between glioma and I/D polymorphism of the ACE gene. METHODS: The expression of ACE gene was detected by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) analysis in 36 Algerian patients with glioma and 195 healthy controls. RESULTS: In glioma cases, allelic frequencies and genotypes distribution of the ACE I/D polymorphism were different from controls cases. ACE DD genotype were highly presented in glioma cases (63.9%) than controls (33.8%) and conferred 3.64-fold risk for predisposition in glioma cases (vs ID genotype, p<0.001). Recessive model (ACE II + ID genotypes vs DD) was associated with a 72% reduced risk of glioma (OR = 0.28, 95% CI: 0.13-0.60, p <0.001). Per copy D allele frequency was found higher in glioma cases (79.2%) than in controls (63.3 %), OR = 2.20, 95% CI: 1.20 - 4.03, p = 0.009. CONCLUSION: The obtained data showed that the presence of the D allele might be a risk factor for the development of glioma. Further studies considering different ethnic groups with large samples are required to confirm this finding.

La fonction thyroïdienne au cours du premier trimestre de la grossesse / Thyroid function in the first trimester of pregnancy

Introduction : Les dysthyroïdies représentent les secondes pathologies les plus fré-quentes après le diabète chez la femme enceinte. La thyroïde subit de nombreux changements physiologiques pendant la grossesse et son activité fonctionnelle augmente de 50%. Les hormones thyroïdiennes jouent un rôle im-portant dans les premiers stades du développement du cerveau. Au cours du premier trimestre, le fœtus est dépendant de la production d'hormones thyroïdiennes mater-nelles. Il est donc important de détecter, typer et éventuellement traiter toute anomalie thyroïdienne au début de la grossesse; l'idéal étant bien évidemment une prise en charge de ces pathologies avant la conception.Patients et méthodes - Dans ce travail, nous avons étudié les variations des concen-trations plasmatiques des paramètres du bilan thyroïdien à savoir l'hormone thyréos-timulante (TSH), la thyroxine libre (fT4) et tri-iodothyronine libre (fT3) chez cinquante gestantes au 1ertrimestre de la grossesse.Résultats - Parmi les cinquante femmes enceintes au 1er trimestre concernées par notre étude, 11 étaient au 1er mois, 19 au 2ème et 20 au 3ème mois de grossesse. L'âge moyen de nos gestantes était de 30±6,76 ans avec des extrêmes allant de 17 à 45 ans. Le dosage de la TSH a révélé une valeur moyenne chez nos gestantes de 2,37± 4,01mUI/L avec des extrêmes allant de 0,031 à 26,37mUI/L. La prévalence de l'hypothyroïdie dans notre série était de 8 %. Les deux autres paramètres du bilan thyroïdien (fT3, fT4) ont présenté une élévation de leurs concentrations au premier mois puis une stabilisation au 2ème et 3ème mois de grossesse.Conclusion - Les dysthyroïdies sont fréquentes dans notre population d'étude, elles doivent être systématiquement recherchées chez toute femme enceinte et correcte-ment prises en charge afin de prévenir les complications à la fois maternelles et fœtales.

Introduction - Dysthyroidism represents the second most frequent pathologies after diabetes in pregnant women. The thyroid undergoes many physiological changes during pregnancy and its functional activity increases by 50%. Thyroid hormones play an important role in the early stages of brain development. During the first trimester, the fetus is dependent on the production of maternal thyroid hormones. It is therefore important to detect, type and possibly treat any thyroid abnormality at the start of pregnancy; ideally, of course, taking care of these pathologies before conception. Patients and methods - we studied the variations in the plasma concentrations of the parameters of the thyroid balance, namely the thyroid stimulating hormone (TSH), the free thyroxine (fT4) and the free tri-iodothyronine (fT3) in fifty pregnant women in the 1st trimester of pregnancy. Results - Among the fifty pregnant women in the 1st trimester concerned by our study, 11 were in the 1st month, 19 in the 2nd and 20 in the 3rd month of pregnancy. The average age of our pregnant women was 30 ± 6.76 years with extremes ranging from 17 to 45 years old. The TSH assay revealed an average value in our pregnant women of 2.37 ± 4.01 mUI/L with extremes ranging from 0.031 to 26.37 mUI/L. The prevalence of hypothyroidism in our series was 8%. The other two parameters of the thyroid balance (fT3, fT4) showed an increase in their concentrations in the first month and then stabilization in the 2nd and 3rd month of pregnancy. Conclusion - Dysthyroidism is frequent in our study population, it must be systematically sought in any pregnant woman and properly managed in order to prevent complications both maternal and fetal.

γ-sarcoglycan and dystrophin mutation spectrum in an Algerian cohort.

INTRODUCTION: We report the genetic analysis of a large series of 76 Algerian patients from 65 unrelated families who presented with early onset severe muscular dystrophy and a clinical phenotype resembling limb-girdle muscular dystrophy type 2C. METHODS: To define the genetic basis of the diseases in these families, we undertook a series of analyses of the γ-sarcoglycan (SGCG) and DMD genes. RESULTS: Fifteen families were shown to carry SGCG variants. Only 2 kinds of causative mutations were identified in the population, mostly in the homozygous state: the well-known c.525delT and the previously described c.87dupT. In the DMD gene, 12 distinctive patterns of deletion were identified, mostly affecting the dystrophin central region. CONCLUSIONS: Our data suggest that a simple molecular screen consisting of 2 allele-specific polymerase chain reactions (PCRs) and a set of 3 multiplex PCRs can diagnose half of the patients who present with progressive muscular dystrophy in the developing nation of Algeria. Muscle Nerve 56: 129-135, 2017.