Low autopsy acceptance after stillbirth in a disadvantaged French district: a mixed methods study

International audienceIn this study, we aimed to describe the autopsy acceptance rate and to understand the factors associated with declining an autopsy after stillbirth in a disadvantaged French district with a high migrant population. Between 1992 and 2015, the costs of autopsies for fetal and neonatal deaths in this district were completely covered by the local council (Conseil Général) and there was therefore no financial burden associated with an autopsy for families or for hospitals. We used a mixed-method approach using data from medical records and interviews with women experiencing a stillbirth collected as part of a population-based audit in the district in 2014

Pontocerebellar hypoplasia with rhombencephalosynapsis and microlissencephaly expands the spectrum of PCH type 1B

International audienc

Loss-of-function mutations in LGI4, a secreted ligand involved in schwann cell myelination, are responsible for arthrogryposis multiplex congenita

Arthrogryposis multiplex congenita (AMC) is a developmental condition characterized by multiple joint contractures resulting from reduced or absent fetal movements. Through genetic mapping of disease loci and whole-exome sequencing in four unrelated multiplex families presenting with severe AMC, we identified biallelic loss-of-function mutations in LGI4 (leucine-rich glioma-inactivated 4). LGI4 is a ligand secreted by Schwann cells that regulates peripheral nerve myelination via its cognate receptor ADAM22 expressed by neurons. Immunolabeling experiments and transmission electron microscopy of the sciatic nerve from one of the affected individuals revealed a lack of myelin. Functional tests using affected individual-derived iPSCs showed that these germline mutations caused aberrant splicing of the endogenous LGI4 transcript and in a cell-based assay impaired the secretion of truncated LGI4 protein. This is consistent with previous studies reporting arthrogryposis in Lgi4-deficient mice due to peripheral hypomyelination. This study adds to the recent reports implicating defective axoglial function as a key cause of AMC

The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and the wpk rat.

Meckel-Gruber syndrome is a severe autosomal, recessively inherited disorder characterized by bilateral renal cystic dysplasia, developmental defects of the central nervous system ( most commonly occipital encephalocele), hepatic ductal dysplasia and cysts and polydactyly(1-3). MKS is genetically heterogeneous, with three loci mapped: MKS1, 17q21-24 (ref. 4); MKS2, 11q13 ( ref. 5) and MKS3 ( ref. 6). We have refined MKS3 mapping to a 12.67-Mb interval (8q21.13-q22.1) that is syntenic to the Wpk locus in rat, which is a model with polycystic kidney disease, agenesis of the corpus callosum and hydrocephalus(7,8). Positional cloning of the Wpk gene suggested a MKS3 candidate gene, TMEM67, for which we identified pathogenic mutations for five MKS3-linked consanguineous families. MKS3 is a previously uncharacterized, evolutionarily conserved gene that is expressed at moderate levels in fetal brain, liver and kidney but has widespread, low levels of expression. It encodes a 995 - amino acid seven-transmembrane receptor protein of unknown function that we have called meckelin

Phenotypic spectrum and genomics of undiagnosed arthrogryposis multiplex congenita

Arthrogryposis multiplex congenita (AMC) is characterised by congenital joint contractures in two or more body areas. AMC exhibits wide phenotypic and genetic heterogeneity. Our goals were to improve the genetic diagnosis rates of AMC, to evaluate the added value of whole exome sequencing (WES) compared with targeted exome sequencing (TES) and to identify new genes in 315 unrelated undiagnosed AMC families