GREB1L variants in familial and sporadic hereditary urogenital adysplasia and Mayer-Rokitansky-Kuster-Hauser syndrome

International audienceCongenital uterine anomalies (CUA) may have major impacts on the health and social well-being of affected individuals. Their expressivity is variable, with the most severe end of the spectrum being the absence of any fully or unilaterally developed uterus (aplastic uterus), which is a major feature in Mayer-Rokitansky-Kuster-Hauser syndrome (MRKH). So far, etiologies of CUA remain largely unknown. As reports of familial occurrences argue for strong genetic contributors in some cases, we performed whole exome sequencing in nine multiplex families with recurrence of uterine and kidney malformations, a condition called hereditary urogenital adysplasia. Heterozygous likely causative variants in the gene GREB1L were identified in four of these families, confirming GREB1L as an important gene for proper uterine and kidney development. The apparent mode of inheritance was autosomal dominant with incomplete penetrance. The four families included fetuses with uterovaginal aplasia and bilateral renal agenesis, highlighting the importance to investigate GREB1L in such phenotypes. Subsequent sequencing of the gene in a cohort of 68 individuals with MRKH syndrome or uterine malformation (mostly sporadic cases) identified six additional variants of unknown significance. We therefore conclude that heterozygous GREB1L variants contribute to MRKH syndrome and this probably requires additional genetic or environmental factors for full penetrance

Rapid Whole Genome Sequencing Diagnoses and Guides Treatment in Critically Ill Children in Belgium in Less than 40 Hours

Rapid Whole Genome Sequencing (rWGS) represents a valuable exploration in critically ill pediatric patients. Early diagnosis allows care to be adjusted. We evaluated the feasibility, turnaround time (TAT), yield, and utility of rWGS in Belgium. Twenty-one unrelated critically ill patients were recruited from the neonatal intensive care units, the pediatric intensive care unit, and the neuropediatric unit, and offered rWGS as a first tier test. Libraries were prepared in the laboratory of human genetics of the University of Liège using Illumina DNA PCR-free protocol. Sequencing was performed on a NovaSeq 6000 in trio for 19 and in duo for two probands. The TAT was calculated from the sample reception to the validation of results. Clinical utility data were provided by treating physicians. A definite diagnosis was reached in twelve (57.5%) patients in 39.80 h on average (range: 37.05–43.7). An unsuspected diagnosis was identified in seven patients. rWGS guided care adjustments in diagnosed patients, including a gene therapy, an off-label drug trial and two condition-specific treatments. We successfully implemented the fastest rWGS platform in Europe and obtained one of the highest rWGS yields. This study establishes the path for a nationwide semi-centered rWGS network in Belgium

Territoires sorciers

Depuis une quinzaine d’années, les études sur la « sorcellerie » ont mis en place un nouveau paradigme liant modernité et sorcellerie. La majorité des travaux, anglophones pour la plupart, substantialisent le phénomène de sorcellerie comme étant la preuve et l’épreuve de la modernité. Ils s’appuient sur des terrains et des expériences touchant l’Afrique centrale et l’Afrique du Sud et, lorsqu’il s’agit de l’Afrique de l’Ouest ou de l’Est, des pays dont le dénominateur commun est d’être des régions fortement marquées par le christianisme. Dans ce numéro, nous avons tenté de redresser l’équilibre en présentant des textes évoquant d’autres régions et la présence de l’islam, singulièrement absent dans la littérature actuelle

Devastating Decline of Forest Elephants in Central Africa.

African forest elephants– taxonomically and functionally unique–are being poached at accelerating rates, but we lack range-wide information on the repercussions. Analysis of the largest survey dataset ever assembled for forest elephants (80 foot-surveys; covering 13,000 km; 91,600 person-days of fieldwork) revealed that population size declined by ca. 62% between 2002–2011, and the taxon lost 30% of its geographical range. The population is now less than 10% of its potential size, occupying less than 25% of its potential range. High human population density, hunting intensity, absence of law enforcement, poor governance, and proximity to expanding infrastructure are the strongest predictors of decline. To save the remaining African forest elephants, illegal poaching for ivory and encroachment into core elephant habitat must be stopped. In addition, the international demand for ivory, which fuels illegal trade, must be dramatically reduced

Par la fenestre

Les auteurs de ces contributions aux Actes du colloque du CUER MA (2002) explorent des domaines variés de la civilisation médiévale : histoire, droit, médecine, théologie, littérature, peinture. Par les textes juridiques et des documents d'archives divers, il apparaît que la fenêtre est une frontière par laquelle tente de se définir le territoire de chacun. Les traités médicaux sur la peste montrent à quel point la fenêtre est perçue comme un lieu ambigu par où peut entrer un air vicié ou sain. L'imagination et la réflexion font de cette béance dans le mur l'espace de la marginalité, mais aussi du passage possible vers un autre monde, que ce soit par les moyens de l'écriture, de la peinture ou de l'art du vitrail. Les études littéraires sur l'emploi de ce motif de « la vue par la fenêtre » portent sur l'épopée, le roman, la lyrique, l'hagiographie, le théâtre. Les variations textuelles que suscite ce motif témoignent d'une littérature qui réfléchit sur ses moyens et offre des points de vue sur le texte en train de se construire

Range-wide indicators of African great ape density distribution

Species distributions are influenced by processes occurring at multiple spatial scales. It is therefore insufficient to model species distribution at a single geographic scale, as this does not provide the necessary understanding of determining factors. Instead, multiple approaches are needed, each differing in spatial extent, grain, and research objective. Here, we present the first attempt to model continent-wide great ape density distribution. We used site-level estimates of African great ape abundance to (1) identify socioeconomic and environmental factors that drive densities at the continental scale, and (2) predict range-wide great ape density. We collated great ape abundance estimates from 156 sites and defined 134 pseudo-absence sites to represent additional absence locations. The latter were based on locations of unsuitable environmental conditions for great apes, and on existing literature. We compiled seven socioeconomic and environmental covariate layers and fitted a generalized linear model to investigate their influence on great ape abundance. We used an Akaike-weighted average of full and subset models to predict the range-wide density distribution of African great apes for the year 2015. Great ape densities were lowest where there were high Human Footprint and Gross Domestic Product values; the highest predicted densities were in Central Africa, and the lowest in West Africa. Only 10.7% of the total predicted population was found in the International Union for Conservation of Nature Category I and II protected areas. For 16 out of 20 countries, our estimated abundances were largely in line with those from previous studies. For four countries, Central African Republic, Democratic Republic of the Congo, Liberia, and South Sudan, the estimated populations were excessively high. We propose further improvements to the model to overcome survey and predictor data limitations, which would enable a temporally dynamic approach for monitoring great apes across their range based on key indicators

The impact of clinical genome sequencing in a global population with suspected rare genetic disease

There is mounting evidence of the value of clinical genome sequencing (cGS) in individuals with suspected rare genetic disease (RGD), but cGS performance and impact on clinical care in a diverse population drawn from both high-income countries (HICs) and low- and middle-income countries (LMICs) has not been investigated. The iHope program, a philanthropic cGS initiative, established a network of 24 clinical sites in eight countries through which it provided cGS to individuals with signs or symptoms of an RGD and constrained access to molecular testing. A total of 1,004 individuals (median age, 6.5 years; 53.5% male) with diverse ancestral backgrounds (51.8% non-majority European) were assessed from June 2016 to September 2021. The diagnostic yield of cGS was 41.4% (416/1,004), with individuals from LMIC sites 1.7 times more likely to receive a positive test result compared to HIC sites (LMIC 56.5% [195/345] vs. HIC 33.5% [221/659], OR 2.6, 95% CI 1.9-3.4, p < 0.0001). A change in diagnostic evaluation occurred in 76.9% (514/668) of individuals. Change of management, inclusive of specialty referrals, imaging and testing, therapeutic interventions, and palliative care, was reported in 41.4% (285/694) of individuals, which increased to 69.2% (480/694) when genetic counseling and avoidance of additional testing were also included. Individuals from LMIC sites were as likely as their HIC counterparts to experience a change in diagnostic evaluation (OR 6.1, 95% CI 1.1-∞, p = 0.05) and change of management (OR 0.9, 95% CI 0.5-1.3, p = 0.49). Increased access to genomic testing may support diagnostic equity and the reduction of global health care disparities

Estimated change in elephant dung density (/km²) distribution during 2002–2011 across the Central African forests.

<p>Results are shown as a percentage of the total area of potential elephant habitat overall (A & B) and by country (C & D) for the predictive model with variables: (A & C) survey year, Human Influence Index, corruption and the presence/absence of guards, and (B & D) survey year, proximity to road, human population density, corruption and the presence/absence of guards. The dung density (per km²) intervals are unequal and correspond to the following elephant population categories: extremely low density (0–100), very low (100–250), low (250–500), medium (500–1,000), high (1,000–3,000) and very high (3,000–7,500). With the loss of very high elephant populations in 2011, there is a significant shift into the lower density intervals over the nine years.</p

Elephant dung density and range reduction across the Central African forests.

<p>Predictions are shown for (A) 2002 and (B) 2011 for the model with variables: survey year∧, Human Influence Index***, corruption*** and the presence/absence of guards***, and (C) 2002 and (D) 2011 for the model with variables: survey year∧, proximity to road∧, human population density***, corruption*** and the presence/absence of guards*** (P-values are: ‘***’ <0.001 and ‘∧’ <0.1). Increasingly darker shades of green correspond to higher densities, grey represents extremely low elephant density range (the first interval: 0–100 elephant dung piles/km²) and white is non-habitat (80 survey sites outlined in red). Cutpoints are: 0; 100; 250; 500; 1,000; 1,500; 3,000; 5,000; and 7,500 dung piles/km². Countries 1–5 are: Cameroon; Central African Republic; Republic of Congo; DRC; Gabon.</p

Encounter rate of elephant dung per kilometre.

<p>Results are shown for the 80 survey sites in Central Africa included in this study. Grey shading represents forest cover.</p