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IntroductionArthrogryposis multiplex congenita (AMC) refers to a clinical presentation of congenital contractures involving two or more body areas. More than 400 distinct conditions may lead to AMC, making the aetiological diagnosis challenging. The objective of this work was to set up evidence-based recommendations for the diagnosis of AMC by taking advantage of both data from our nation-wide cohort of children with AMC and from the literature.Material and methodsWe conducted a retrospective single-centre observational study. Patients had been evaluated at least once at a paediatric age in the AMC clinic of Grenoble University Hospital between 2007 and 2019. After gathering data about their diagnostic procedure, a literature review was performed for each paraclinical investigation to discuss their relevance.ResultsOne hundred and twenty-five patients were included, 43% had Amyoplasia, 27% had distal arthrogryposis and 30% had other forms. A definitive aetiological diagnosis was available for 66% of cases. We recommend a two-time diagnostic process: first, non-invasive investigations that aim at classifying patients into one of the three groups, and second, selected investigations targeting a subset of patients.ConclusionThe aetiological management for patients with AMC remains arduous. This process will be facilitated by the increasing use of next-generation sequencing combined with detailed phenotyping. Invasive investigations should be avoided because of their limited yield.

The spliceosome, a ribonucleoprotein complex that includes proteins and small nuclear RNAs (snRNAs), catalyzes RNA splicing through intron excision and exon ligation to produce mature messenger RNAs, which, in turn serve as templates for protein translation. We identified four point mutations in the U4atac snRNA component of the minor spliceosome in patients with brain and bone malformations and unexplained postnatal death [microcephalic osteodysplastic primordial dwarfism type 1 (MOPD 1) or Taybi-Linder syndrome (TALS); Mendelian Inheritance in Man ID no. 210710]. Expression of a subgroup of genes, possibly linked to the disease phenotype, and minor intron splicing were affected in cell lines derived from TALS patients. Our findings demonstrate a crucial role of the minor spliceosome component U4atac snRNA in early human development and postnatal survival.

This article is the third in our series dedicated to the analysis of cardiac myoarchitecture as a nematic chiral liquid crystal (NCLC). Previously, we introduced the concept of topological defects (disclinations) and focused on their visual identification inside the compact myocardium. Herein, we investigate these using a mathematical and automated algorithm for the reproducible identification of a larger panel of topological defects throughout the myocardium of 13 perinatal and 11 early infant hearts. This algorithm identified an average of 29 ± 11 topological defects per slice with a 2D topological charge of m = +1/2 and an average of 27 ± 10 topological defects per slice with a 2D topological charge of m = −1/2. The excess of defects per slice with a 2D topological charge of m = +1/2 was statistically significant (p < 0.001). There was no significant difference in the distribution of defects with a 2D topological charge of m = +1/2 and m = −1/2 between perinatal and early infant hearts. These defects were mostly arranged in pairs, as expected in nematics, and located inside the trabecular myocardium. When isolated, defects with a 2D topological charge of m = +1/2 were located near the luminal extremity of the trabeculae and those with a 2D topological charge of m = −1/2 were located at the anterior and posterior part of the interventricular septum. These findings constitute an advance in the characterization of the deep cardiac myoarchitecture for application in developmental and pathological studies.

BackgroundCongenital anomalies of the kidney and urinary tract (CAKUT) represent a significant healthcare burden since it is the primary cause of chronic kidney in children. CNVs represent a recurrent molecular cause of CAKUT but the culprit gene remains often elusive. Our study aimed to define the gene responsible for CAKUT in patients with an 1q23.3q24.1 microdeletion.MethodsWe describe eight patients presenting with CAKUT carrying an 1q23.3q24.1 microdeletion as identified by chromosomal microarray analysis (CMA). Clinical features were collected, especially the renal and urinary tract phenotype, and extrarenal features. We characterised PBX1 expression and localisation in fetal and adult kidneys using quantitative RT-PCR and immunohistochemistry.ResultsWe defined a 276-kb minimal common region (MCR) that only overlaps with the PBX1 gene. All eight patients presented with syndromic CAKUT. CAKUT were mostly bilateral renal hypoplasia (75%). The most frequent extrarenal symptoms were developmental delay and ear malformations. We demonstrate that PBX1 is strongly expressed in fetal kidneys and brain and expression levels decreased in adult samples. In control fetal kidneys, PBX1 was localised in nuclei of medullary, interstitial and mesenchymal cells, whereas it was present in endothelial cells in adult kidneys.ConclusionsOur results indicate that PBX1 haploinsufficiency leads to syndromic CAKUT as supported by the Pbx1-null mice model. Correct PBX1 dosage appears to be critical for normal nephrogenesis and seems important for brain development in humans. CMA should be recommended in cases of fetal renal anomalies to improve genetic counselling and pregnancy management.

This is our second article devoted to the cardiac myoarchitecture considered as a nematic chiral liquid crystal (NCLC). While the first article focused on the myoarchitecture of the left ventricle (LV), this new article extends to the whole ventricular mass and introduces the concept of disclinations and topological singularities, which characterize the differences and relationships between the left and right ventricles (RV). At the level of the ventricular apices, we constantly observed a vortex shape at the LV apex, corresponding, in the terminology of liquid crystals, to a “+1 disclination”; we never observed this at the RV apex. At the level of the interventricular septum (IVS), we identified “−1/2 disclinations” at the anterior and posterior parts. During the perinatal period, there was a significant difference in their distribution, with more “−1/2 disclinations” in the posterior part of the IVS. After birth, concomitant to major physiological changes, the number of “−1/2 disclinations” significantly decreased, both in the anterior and posterior parts of the IVS. Finally, the description of the disclinations must be considered in any attempt to segment the whole ventricular mass, in biomechanical studies, and, more generally, for the characterization of myocardial remodeling.

There are still grey areas in the understanding of the myoarchitecture of the ventricular mass. This is despite the progress of investigation methods since the beginning of the 21st century (diffusion tensor magnetic resonance imaging, microcomputed tomography, and polarised light imaging). The objective of this article is to highlight the specificities and the limitations of polarised light imaging (PLI) of the unstained myocardium embedded in methyl methacrylate (MMA). Thus, to better differentiate our method from other PLI modes, we will refer to it by the acronym PLI-MMA. PLI-MMA shows that the myosin mesh of the compact left ventricular wall behaves like a biological analogous of a nematic chiral liquid crystal. Results obtained by PLI-MMA are: the main direction of the myosin molecules contained in an imaged voxel, the crystal liquid director n, and a regional isotropy index RI that is an orientation tensor, the equivalent of the crystal liquid order parameter. The vector n is collinear with the first eigenvector of diffusion tensor imaging (DTI-MRI). The RI has not been confounded with the diffusion tensor of DTI that gives information about the three eigenvectors of the ellipsoid of diffusion. PLI-MMA gives no information about the collagen network. The physics of soft matter has allowed the revisiting of Streeter’s conjecture on the myoarchitecture of the compact left ventricular wall: “geodesics on a nested set of toroidal surfaces”. Once the torus topology is understood, this characterisation of the myoarchitecture is more accurate and parsimonious than former descriptions. Finally, this article aims to be an enthusiastic invitation to a transdisciplinary approach between physicists of liquid crystals, anatomists, and specialists of imaging.

The World Health Organization conservatively estimates that 80 million people suffer from infertility worldwide. Male factors are believed to be responsible for 20–50% of all infertility cases, but microdeletions of the Y chromosome are the only genetic defects altering human spermatogenesis that have been reported repeatedly 1 . We focused our work on infertile men with a normal somatic karyotype but typical spermatozoa mainly characterized by large heads, a variable number of tails and an increased chromosomal content (OMIM 243060) 2 , 3 , 4 . We performed a genome-wide microsatellite scan on ten infertile men presenting this characteristic phenotype. In all of these men, we identified a common region of homozygosity harboring the aurora kinase C gene ( AURKC ) with a single nucleotide deletion in the AURKC coding sequence. In addition, we show that this founder mutation results in premature termination of translation, yielding a truncated protein that lacks the kinase domain. We conclude that the absence of AURKC causes male infertility owing to the production of large-headed multiflagellar polyploid spermatozoa.

BackgroundThe 3D architecture of the ventricular mass is poorly known, although in vivo imaging techniques show the physiological inhomogeneity of ventricular walls mechanics. Polarized light imaging makes it possible to quantitatively analyse the myosin filament orientation.AimsIn this paper, we focus on the study the 3D architecture and regional isotropy of myocardial cells.MethodsTwenty normal human hearts, 10 from the perinatal period and 10 from the post-neonatal period were studied by polarized light microscopy. In each voxel of the ventricular mass (90 × 90 × 500 µm) the principal orientation segment was automatically and unambiguously extracted as well as a regional isotropy index (regional orientation tensor of the voxel neighbourhood).ResultsDuring the first months of postnatal age, the median regional isotropy values decreased in the ventricular mesh. This global decrease was not homogeneous across the ventricular walls. From the perinatal to the neonatal period, this decrease was more marked in the inner two-third of the lateral left ventricular wall and in the right part of the interventricular septum. There was a progressive post-neonatal appearance of a particularly inhomogeneous secondary arrangement of myocardial cells with alternation of thick low-RI and thin high-RI areas.ConclusionsThis study has shown a postnatal change in ventricular myocardial architecture, which became more inhomogeneous. The cell rearrangements responsible for the inhomogeneity in ventricular myocardial architecture are revealed by a variation of the regional isotropy index. These major changes are probably an adaptive consequence of the major haemodynamic changes occurring after birth during the neonatal period that generates major parietal stress variations and parietal remodelling.

Cerebral palsy seems to be more common in term babies whose birthweight is low for their gestational age at delivery, but past analyses have been hampered by small datasets and Z-score calculation methods. We compared data from ten European registers for 4503 singleton children with cerebral palsy born between 1976 and 1990 with the number of births in each study population. Weight and gestation of these children were compared with reference standards for the normal spread of gestation and weight-for-gestational age at birth. Babies of 32–42 weeks' gestation with a birthweight for gestational age below the 10th percentile (using fetal growth standards) were 4–6 times more likely to have cerebral palsy than were children in a reference band between the 25th and 75th percentiles. In children with a weight above the 97th percentile, the increased risk was smaller (from 1·6 to 3·1), but still significant. Those with a birthweight about 1 SD above average always had the lowest risk of cerebral palsy. A similar pattern was seen in those with unilateral or bilateral spasticity, as in those with a dyskinetic or ataxic disability. In babies of less than 32 weeks' gestation, the relation between weight and risk was less clear. The risk of cerebral palsy, like the risk of perinatal death, is lowest in babies who are of above average weight-for-gestation at birth, but risk rises when weight is well above normal as well as when it is well below normal. Whether deviant growth is the cause or a consequence of the disability remains to be determined.

We demonstrated previously that 75% of infertile men with round, acrosomeless spermatozoa (globozoospermia) had a homozygous 200-Kb deletion removing the totality of DPY19L2. We showed that this deletion occurred by Non-Allelic Homologous Recombination (NAHR) between two homologous 28-Kb Low Copy Repeats (LCRs) located on each side of the gene. The accepted NAHR model predicts that inter-chromatid and inter-chromosome NAHR create a deleted and a duplicated recombined allele, while intra-chromatid events only generate deletions. Therefore more deletions are expected to be produced de novo. Surprisingly, array CGH data show that, in the general population, DPY19L2 duplicated alleles are approximately three times as frequent as deleted alleles. In order to shed light on this paradox, we developed a sperm-based assay to measure the de novo rates of deletions and duplications at this locus. As predicted by the NAHR model, we identified an excess of de novo deletions over duplications. We calculated that the excess of de novo deletion was compensated by evolutionary loss, whereas duplications, not subjected to selection, increased gradually. Purifying selection against sterile, homozygous deleted men may be sufficient for this compensation, but heterozygously deleted men might also suffer a small fitness penalty. The recombined alleles were sequenced to pinpoint the localisation of the breakpoints. We analysed a total of 15 homozygous deleted patients and 17 heterozygous individuals carrying either a deletion (n = 4) or a duplication (n = 13). All but two alleles fell within a 1.2-Kb region central to the 28-Kb LCR, indicating that >90% of the NAHR took place in that region. We showed that a PRDM9 13-mer recognition sequence is located right in the centre of that region. Our results therefore strengthen the link between this consensus sequence and the occurrence of NAHR.