The prevalence of diseases caused by lysosome-related genes in a cohort of undiagnosed patients

Lysosomal diseases (LD) comprise a group of approximately 60 hereditary conditions caused by progressive accumulation of metabolites due to defects in lysosomal enzymes and degradation pathways, which lead to a wide range of clinical manifestations. The estimated combined incidence of LD is between 1 in 4000 to 1 in 13,000 live births, with recent data from pilot newborn screening studies showing even higher incidence. We aimed to determine the prevalence of the classical LD and other diseases caused by lysosome-related genes in our cohort of diagnostic odyssey patients. The Individualized Medicine Clinic at Mayo Clinic is increasingly utilizing whole exome sequencing (WES) to determine the genetic etiology of undiagnosed Mendelian disease. From September 2012 to April 2017, WES results from 350 patients with unexplained symptoms were reviewed. Disease-causing variants were identified in MYO6, CLN6, LRBA, KCTD7, and ARSB revealing a genetic diagnosis of a LD in 8 individuals from 5 families. Based on our findings, lysosome-related disorders may be collectively common, reaching up to 1.5% prevalence in a cohort of patients with undiagnosed diseases presenting to a genetics clinic

Haploinsufficiency as a disease mechanism in GNB1‐associated neurodevelopmental disorder

Abstract Background GNB1 encodes a subunit of a heterotrimeric G‐protein complex that transduces intracellular signaling cascades. Disruptions to the gene have previously been shown to be embryonic lethal in knockout mice and to cause complex neurodevelopmental disorders in humans. To date, the majority of variants associated with disease in humans have been missense variants in exons 5‐7. Methods Genetic sequencing was performed on two patients presenting with complex neurological phenotypes including intellectual disability, hypotonia, and in one patient seizures. Reported variants were assessed using RNA sequencing and functional BRET/BiFC assays. Results A splice variant reported in patient 1 was confirmed to cause usage of a cryptic splice site leading to a truncated protein product. Patient 2 was reported to have a truncating variant. BRET and BiFC assays of both patient variants confirmed both were deficient in inducing GPCR‐induced G protein activation due to lack of dimer formation with the Gγ subunit. Conclusion Here, we report two patients with functionally confirmed loss of function variants in GNB1 and neurodevelopmental phenotypes including intellectual disability, hypotonia, and seizures in one patient. These results suggest haploinsufficiency of GNB1 is a mechanism for neurodevelopmental disorders in humans

Shared and Unique Susceptibility Genes in a Mouse Model of Graves’ Disease Determined in BXH and CXB Recombinant Inbred Mice

Susceptibility genes for TSH receptor (TSHR) antibodies and hyperthyroidism can be probed in recombinant inbred (RI) mice immunized with adenovirus expressing the TSHR A-subunit. The RI set of CXB strains, derived from susceptible BALB/c and resistant C57BL/6 (B6) mice, were studied previously. High-resolution genetic maps are also available for RI BXH strains, derived from B6 and C3H/He parents. We found that C3H/He mice develop TSHR antibodies, and some animals become hyperthyroid after A-subunit immunization. In contrast, the responses of the F1 progeny of C3H/He × B6 mice, as well as most BXH RI strains, are dominated by the B6 resistance to hyperthyroidism. As in the CXB set, linkage analysis of BXH strains implicates different chromosomes (Chr) or loci in the susceptibility to induced TSHR antibodies vs. hyperthyroidism. Importantly, BXH and CXB mice share genetic loci controlling the generation of TSHR antibodies (Chr 17, major histocompatibility complex region, and Chr X) and development of hyperthyroidism (Chr 1 and 3). Moreover, some chromosomal linkages are unique to either BXH or CXB strains. An interesting candidate gene linked to thyroid-stimulating antibody generation in BXH mice is the Ig heavy chain locus, suggesting a role for particular germline region genes as precursors for these antibodies. In conclusion, our findings reinforce the importance of major histocompatibility complex region genes in controlling the generation of TSHR antibodies measured by TSH binding inhibition. Moreover, these data emphasize the value of RI strains to dissect the genetic basis for induced TSHR antibodies vs. their effects on thyroid function in Graves’ disease

Plato argénteo nº 38.215 . Cabeza antropomorfa diademada - ABE0162_AR

Proyectos del Plan Nacional I+D+I con referencias PB94-0129, PB97-1132, BHA 2002-00138, HUM 2006-06250/HISTProyectos de la CAM con referencias 06/0020/1997, 06/0094/1998, 06/0090/2000, 06/0043/2001Programa Consolider-Ingenio 2010 con sigla CSD2007-00058NoMuseo Arqueológico Nacional (Madrid)AbengibrePlato argénteo nº 38.215 . Cabeza antropomorfa diademad

Loss-of-function variants in CUL3 cause a syndromic neurodevelopmental disorder

variants in (Cullin-3 ubiquitin ligase) have been strongly associated with neurodevelopmental disorders (NDDs), but no large case series have been reported so far. Here we aimed to collect sporadic cases carrying rare variants in describe the genotype-phenotype correlation, and investigate the underlying pathogenic mechanism. Genetic data and detailed clinical records were collected via multi-center collaboration. Dysmorphic facial features were analyzed using GestaltMatcher. Variant effects on CUL3 protein stability were assessed using patient-derived T-cells. We assembled a cohort of 35 individuals with heterozygous variants presenting a syndromic NDD characterized by intellectual disability with or without autistic features. Of these, 33 have loss-of-function (LoF) and two have missense variants. LoF variants in patients may affect protein stability leading to perturbations in protein homeostasis, as evidenced by decreased ubiquitin-protein conjugates . Specifically, we show that cyclin E1 (CCNE1) and 4E-BP1 (EIF4EBP1), two prominent substrates of CUL3, fail to be targeted for proteasomal degradation in patient-derived cells. Our study further refines the clinical and mutational spectrum of -associated NDDs, expands the spectrum of cullin RING E3 ligase-associated neuropsychiatric disorders, and suggests haploinsufficiency via LoF variants is the predominant pathogenic mechanism

Point Mutations in Exon 1B of APC Reveal Gastric Adenocarcinoma and Proximal Polyposis of the Stomach as a Familial Adenomatous Polyposis Variant

International audienceGastric 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