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International audience; Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) is an autosomal-dominant cancer-predisposition syndrome with a significant risk of gastric, but not colorectal, adenocarcinoma. We mapped the gene to 5q22 and found loss of the wild-type allele on 5q in fundic gland polyps from affected individuals. Whole-exome and -genome sequencing failed to find causal mutations but, through Sanger sequencing, we identified point mutations in APC promoter 1B that co-segregated with disease in all six families. The mutations reduced binding of the YY1 transcription factor and impaired activity of the APC promoter 1B in luciferase assays. Analysis of blood and saliva from carriers showed allelic imbalance of APC, suggesting that these mutations lead to decreased allele-specific expression in vivo. Similar mutations in APC promoter 1B occur in rare families with familial adenomatous polyposis (FAP). Promoter 1A is methylated in GAPPS and sporadic FGPs and in normal stomach, which suggests that 1B transcripts are more important than 1A in gastric mucosa. This might explain why all known GAPPS-affected families carry promoter 1B point mutations but only rare FAP-affected families carry similar mutations, the colonic cells usually being protected by the expression of the 1A isoform. Gastric polyposis and cancer have been previously described in some FAP-affected individuals with large deletions around promoter 1B. Our finding that GAPPS is caused by point mutations in the same promoter suggests that families with mutations affecting the promoter 1B are at risk of gastric adenocarcinoma, regardless of whether or not colorectal polyps are present.

Foetal akinesia/hypokinesia is an absence or decrease of movement in utero resulting in a spectrum of anomalies characterised by intrauterine growth retardation, contractures, craniofacial anomalies, limb anomalies, pulmonary hypoplasia and polyhydramnios. Despite a large number of disease genes (>30) being associated with this heterogenous group of disorders, the majority of cases are without a genetic diagnosis. The aim of this study was to investigate the use of whole exome sequencing (WES) to identify the causative gene/s in a preliminary set of four families with foetal akinesia. In three families presenting with foetal akinesia and nemaline bodies, all the known nemaline myopathy genes were excluded by WES. The fourth family presented with lethal multiple pterygium syndrome. WES of DNA from two affected sibs revealed compound heterozygous mutations in the glycogen branching enzyme-1 gene ( GBE1 ): a known splice site mutation (c.691+2T>C) and a novel missense mutation (c.956A>G; p.His319Arg) at a highly conserved residue. Each parent carried one of the mutations. GBE1 mutations are known to cause glycogen storage disease IV (GSD IV), a subset of which present with a severe neuromuscular foetal akinesia phenotype. In light of the genetic findings, the muscle pathology was reviewed and PAS positive, diastase resistant faintly refractile material was observed, consistent with GSD IV. Our data highlight that novel nemaline myopathy gene/s remain to be identified and that WES can be used successfully for the diagnosis of foetal akinesias. This study expands the genotype–phenotype correlation of GBE1 mutations: (1) since GSD IV should now be considered in cases presenting as lethal multiple pterygium syndrome and (2) since the vast majority of known foetal akinesia GSD IV cases are due to large indels or frameshift mutations and it is generally considered that the type of the mutations corresponds with clinical severity.