8b6c8fbd-8ba8-45db-99e2-b061781e7e90 - samples
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ABSTRACT:
PROVIDER: EGAD00001009761 | EGA |
REPOSITORIES: EGA
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Project description:Disorders of isolated mineralocorticoid deficiency causing potentially life-threatening salt-wasting crisis early in life have been associated with gene variants of aldosterone biosynthesis or resistance, but in some patients no such variants are found. WNT/β-catenin signaling is crucial for differentiation and maintenance of the aldosterone producing adrenal zona glomerulosa (zG). We describe a highly consanguineous family with multiple perinatal deaths or infants presenting at birth with failure to thrive, severe salt-wasting crises associated with isolated hypoaldosteronism, nail anomalies, short stature, and deafness. Whole exome sequencing revealed a homozygous splice variant in the R-SPONDIN receptor LGR4 gene (c.618-1G>C) regulating WNT signaling. The resulting transcripts affected protein function and stability, and resulted in loss of Wnt/β-catenin signaling in vitro. The impact of LGR4 inactivation was analyzed by adrenal cortex specific ablation of Lgr4, using Lgr4Flox/Flox mated with Sf1:Cre mice. Inactivation of Lgr4 within the adrenal cortex in the mouse model caused decreased WNT signaling, aberrant zonation with deficient zG and reduced aldosterone production. Thus, human LGR4 mutations establish a direct link between LGR4 inactivation and decreased canonical WNT signaling with abnormal zG differentiation and endocrine function. Therefore, variants in WNT signaling and its regulators should systematically be considered in familial hyperreninemic hypoaldosteronism.
| EGAS00001006808 | EGA
Project description:A consanguineous family segregating anhidrosis (recessive, familial) Shared homozygous regions were identified by comparing SNP genotyping results from four affected family members
2014-09-05 | GSE61122 | GEO
Project description:A consanguineous family segregating anhidrosis (recessive, familial) Shared homozygous regions were identified by comparing SNP genotyping results from four affected family members Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from peripheral blood samples.
2014-09-05 | E-GEOD-61122 | biostudies-arrayexpress
Project description:We investigated the cause of gastrointestinal neoplasia in a man who developed adenocarcinoma of the ampulla of Vater at the age of 34, followed almost three decades later by adenomatous polyps and invasive adenocarcinomas of both the colon and stomach. Premature chromatid separation, mosaic variegated aneuploidy (MVA), combined with structural chromosome abnormalities were detected in his cells. We identified a homozygous intronic mutation, c.2386-11A>G in BUB1B which creates a de novo splice site that is favored over the authentic site. This study expands the phenotype of BUB1B mutations and MVA to include common adult-onset cancers and provides evidence for the interdependency of APC and BUBR1 proteins in humans. 2 biological replicates of 7 samples (lymphoblastoid cell line (LCL) of the affected proband, fibroblasts of the affected proband, LCLs from 2 relatives of the proband, LCLs from 2 unaffected controls, fibroblasts from 1 control) were processed at the same time.
2010-06-16 | E-GEOD-22206 | biostudies-arrayexpress
Project description:Purpose: Comorbid familial non-obstructive azoospermia (NOA) and congenital cataract (CC) has not been reported previously, and no single human gene has been associated with both diseases in humans. Our purpose is to uncover novel human mutations and genes causing familial NOA and CC. Methods: We performed whole-exome sequencing for two brothers with both NOA and CC from a consanguineous family.The proband was also carried out SNP array analysis. Mutation screening of TDRD7 was performed in another similar consanguineous family and 176 patients with azoospermia or CC alone and 520 healthy controls. Histological analysis was performed for the biopsied testicle sample in one patient, and knockout mice were constructed to verify the phenotype of the mutation in TDRD7. Results: Two novel loss-of-function mutations (c.324_325insA (T110Nfs*30) and (c.688-689insA (p.Y230X), respectively) of TDRD7 were found in the affected patients from the two unrelated consanguineous families. Histological analysis demonstrated a lack of mature sperm in the male patient’s seminiferous tubules. The mutations were not detected in patients with CC or NOA alone. Mice with Tdrd7 gene disrupted at a similar position precisely replicated the human syndrome. Conclusions: We identified TDRD7 causing CC as a new pathogenic gene for male azoospermia in human, with an autosomal recessive mode of inheritance.
2017-06-15 | GSE100019 | GEO
Project description:We identified a novel homozygous 15q13.3 microdeletion in a young boy with a complex neurodevelopmental disorder characterized by severe cerebral visual impairment with additional signs of congenital stationary night blindness (CSNB), congenital hypotonia with areflexia, profound intellectual disability, and refractory epilepsy. The mechanisms by which the genes in the deleted region exert their effect are unclear. In this paper we probed the role of downstream effects of the deletions as a contributing mechanism to the molecular basis of the observed phenotype. We analyzed gene expression of lymphoblastoid cells derived from peripheral blood of the proband and his relatives to ascertain the relative effects of the homozygous and heterozygous deletions. The proband with 15q13.3 homozygous deletion and his parents with 15q13.3 heterozygous deletions described in our previous report 15 were evaluated using Affymetrix aCGH-244K arrays (build hg18). The aCGH data were validated by qPCR using primers specific to CHRNA7 as previously described. 15 The extended family and comparison subjects were also screened using the CHRNA7 primers. Immortalized lymphoblastoid lines were created from the proband, his mother, father, a paternal half sister, a paternal half brother, a paternal grandmother and two paternal great uncles. Three lymphoblastoid lines from age- and sex- matched normally developing comparison subjects with normal chromosomes were obtained from the Coriell cell repository [(AG14724 (8 yo), AG14948 (10 yo), AG14980 (9 yo)] were used for gene expression comparison with the proband. The samples from the father, mother and paternal grandmother with heterozygous 15q13.3 deletions were compared to samples from lymphoblastoid cells from adult male and female subjects respectively (normal copy number for 15q13.3 determined by qPCR).
2013-02-17 | E-GEOD-43583 | biostudies-arrayexpress
Project description:Autism spectrum disorder (ASD) affects these core domains: ritualistic-repetitive behaviors, impaired social interaction, and deficits in non-verbal communication/language development. Although ASD is heritable, its extreme heterogeneity defies genetic analyses. A number of ASD susceptibility genes have been identified. The Lebanese population is ideal for uncovering recessive genes because of a high rate of shared ancestry, consanguineous marriages, and high number of offspring per family. We recruited 36 ASD families (ASD: 37, unaffected parents: 36, unaffected siblings: 33). Cytogenetics 2.7M Microarrays/CytoScan⢠HD arrays allowed mapping of homozygous regions of the genome.
2017-07-24 | E-MTAB-4963 | biostudies-arrayexpress
Project description:homozygosity mapping in a family with ovarian failure Two affected and four unafected siblings from consanguineous family were studied to identify shared regions of homozygosity in affected females with gonadal dysgenesis
2014-10-16 | E-GEOD-62347 | biostudies-arrayexpress
Project description:The association of congenital deafness and early-onset cataracts inherited as a recessive trait is a rare combination described in only a few syndromes with very few genes identified to date. Whole-genome sequencing was performed on 3 patients from independent sibships from a large consanguineous family presenting with severe deafness and early-onset cataracts as part of a variable neurological, sensorial and cutaneous syndrome. Medical assessments and imaging were used to define the phenotype. Genome sequencing was performed to unravel the altered genotype by subsequent bioinformatics analysis based on a specific physiopathological filtering approach. We identified a unique homozygous variant in intron 10 of the PSMC3 gene, encoding the 26S proteasome ATPase ring subunit 5 (Rpt5), with a predicted local splice effect as a new donor site (c.1127+337A>G, p.Ser376Argfs15*) confirmed by RT-PCR. Strikingly, fibroblasts derived from patients carrying the deep intronic homozygous PSMC3 pathogenic variant exhibited strong signs of perturbed protein homeostasis, as evidenced by increased accumulation of intracellular ubiquitin-modified proteins. Most interestingly and in contrast to control cells, patient fibroblasts failed to increase their amount of proteasomes following proteasome inhibition using the TCF11/Nrf1 pathway, indicating that these cells were unable to adapt to proteotoxic stress. By way of 2 different zebrafish assays we further show that loss of function of PSMC3 leads to inner ear development anomalies as well as cataracts alike the patient phenotype. We propose that the PSMC3 proteasome subunit dysfunction leads to a novel human syndrome that includes early onset cataracts and deafness and suggest that Rpt5 plays a major role in inner ear and lens development.
2020-04-28 | PXD015836 | Pride
Project description:Rare, biallelic loss-of-function mutations in DOCK8 result in a combined immune deficiency characterized by severe and recurrent cutaneous infections, eczema, allergies, and susceptibility to malignancy, as well as impaired humoral and cellular immunity and hyper-IgE. The advent of next-generation sequencing technologies has enabled the rapid molecular diagnosis of rare monogenic diseases, including inborn errors of immunity. These advances have resulted in the implementation of gene-guided treatments, such as hematopoietic stem cell transplant for DOCK8 deficiency. However, putative disease- causing variants revealed by next-generation sequencing need rigorous validation to demonstrate pathogenicity. Here, we report the eventual diagnosis of DOCK8 deficiency in a consanguineous family due to a novel homozygous intronic deletion variant that caused aberrant exon splicing and subsequent loss of expression of DOCK8 protein. Remarkably, the causative variant was not initially detected by clinical whole-genome sequencing but was subsequently identified and validated by combining advanced genomic analysis, RNA-seq, and flow cytometry. This case highlights the need to adopt multipronged confirmatory approaches to definitively solve complex genetic cases that result from variants outside protein-coding exons and conventional splice sites.
2023-05-19 | GSE185943 | GEO