A novel TBX19 gene mutation in patients with isolated ACTH deficiency
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB59437 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR10850779.fastq.gz | Fastqsanger.gz | |||
| ERR10850779_1.fastq.gz | Fastqsanger.gz | |||
| ERR10850779_2.fastq.gz | Fastqsanger.gz | |||
| ERR10850780.fastq.gz | Fastqsanger.gz | |||
| ERR10850780_1.fastq.gz | Fastqsanger.gz |
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Project description:Isolated ACTH deficiency (IAD) is a life-threatening condition, particularly in the neonatal period, while a main consequence of undiagnosed isolated ACTH deficiency in survivors is cognitive impairment. TBX19 is involved in the differentiation and proliferation of corticotropic cells and TBX19 mutations are responsible for more than 60% of neonatal cases of IAD. We describe a new variant of the main TBX19 transcript (NM 005149.3, c.840del (p.(Glu280Asp fs*27)), classified as pathogenic, whose pathogenicity is assumed to be due to nonsense mediated decay leading to non-expression of T-box transcription factor TBX19. Moreover we summarize the TBX19 mutations published as individual cases since our last large cohort. Interestingly, this pathogenic variant was identified in four patients from three apparently unrelated families. Two of these families were consanguineous, and after investigations all of three were discovered to have roots in the same mountainous region of northern Morocco, suggesting a founder effect. Early diagnosis, timely treatment (hydrocortisone therapy) and preventive education allowed normal development, growth and quality of life in all patients.
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Project description:Disorders of sexual development (DSDs) are characterized by a heterogeneous group of congenital conditions associated with atypical development of the sex chromosomes, gonadal or anatomical sex. We report the case of a child with an isolated micropenis, a typical feature of the 46,XY DSD showing low basal testosterone levels and post-stimulation with the hCG test. Molecular analysis using a next-generation sequencing (NGS) panel of 50 genes involved in DSDs was performed, revealing a heterozygous mutation, c.1040G > ANM_000102.4, in the CYP17A1 gene. Sanger sequencing was used to confirm the gene variant detected by NGS; it was also performed to his parents, revealing the presence of the same mutation in the mother, who presented no features of the disease. Then, the serum steroid profile was determined by liquid chromatography coupled to tandem mass spectrometry analysis. Interestingly, this analysis highlighted low levels of testosterone, progesterone, and dehydroepiandrostenedione, as also confirmed by a stimulus test with ACTH. These results suggest that, in some cases, heterozygous mutations in recessive genes involved in adrenal steroidogenesis can also affect the patient’s phenotype.
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Project description:Isolated sulfite oxidase deficiency is a rare autosomal recessive inborn error of sulfur metabolism. Clinical features generally include devastating neurologic dysfunction, ectopia lentis, and increased urinary excretion of sulfite, thiosulfate, and S-sulfocysteine. Missed diagnosis is not unusual because of variability in the sensitivity of the urinary sulfite and thiosulfate screening test. We present clinical, biochemical, and molecular data on two unrelated patients with isolated sulfite oxidase deficiency. The two patients belong to an Indigenous genetic isolate in Manitoba, Canada. Both patients (one male and one female, both now deceased) developed neonatal seizures and demonstrated progressive neurodevelopmental delay. Based on increased urinary excretion of sulfite, thiosulfate, and S-sulfocysteine and normal serum uric acid levels, sulfite oxidase deficiency was suspected. Both patients have a homozygous 4-bp deletion, 1347-1350delTTGT in the sulfite oxidase gene (SUOX), predicting a premature termination of the sulfite oxidase protein leading to absence of the carboxy-terminal third portion of the protein. This domain contains most of the contact sites essential for enzyme dimerization. This deletion mutation resulted in sulfite oxidase deficiency with early-onset severe clinical phenotype.
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Project description:IntroductionCongenital isolated adrenocorticotropic hormone deficiency (CIAD) is a rare disease characterized by low adrenocorticotropic hormone (ACTH) and cortisol levels. To date, recurrent pulmonary infections in infancy have not been reported as an accompanying symptom of CIAD.Case presentationA 7-year-old boy was hospitalized nine times for recurrent lower respiratory tract infections. The results of all tests for the possible causes of wheezing were within the normal limits. His ACTH and cortisol levels were persistently low. All other pituitary hormone levels, and adrenal ultrasound and pituitary magnetic resonance imaging results, were normal. Molecular analyses confirmed the diagnosis of CIAD by identifying compound heterozygosity for two mutations in the TBX19 gene. The first was a novel frameshift c.665delG variant in exon 4 of the TBX19 gene, leading to premature termination that was predicted to result in a non-functional truncated protein. The second was a nonsense C-to-T transition in exon 6 of the TBX19 gene, resulting in an arg286-to-ter mutation (dbSNP: rs74315376). Both parents were heterozygous for one of the mutations.ConclusionHere, we presented a new mutation in the TBX19 gene in a patient with CIAD who presented with recurrent respiratory tract infections. This expands the mutation spectrum in this disorder. To conclude, adrenal insufficiency should be considered in patients with unexplained recurrent infections to prevent a delay in diagnosis.
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Project description:ObjectiveTo investigate the GCM2 gene in three siblings with congenital hypoparathyroidism and perform functional analysis.Materials and methodsWe sequenced the GCM2 gene by PCR and analyzed the functional consequence of the mutation by transient transfection studies. Haplotype analysis was performed.ResultsWe identified a nucleotide change, c.408C>A, in exon 3 that is predicted to truncate the Gcm2 protein (p.Tyr136Ter). All three affected siblings were homozygous and both parents were heterozygous for the mutation. Transfection studies revealed the mutant mRNA but not expression of the Gcm2 protein. Haplotype analysis revealed that the two mutant GCM2 alleles shared genotypes on chromosome 6p24.2.ConclusionsWe describe the first GCM2 mutation in exon 3 in patients with severe congenital hypoparathyroidism. Informative genetic markers could not exclude identity by descent for the mutant alleles. Gcm2 protein was not detected after transfection, suggesting that complete lack of Gcm2 action accounts for severe hypoparathyroidism.
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Project description:ObjectiveSince Wnt signaling plays an important role in both tooth agenesis and altered intestine homeostasis, the aim was to compare gastrointestinal symptoms in patients with isolated oligodontia caused by a Wnt pathway gene mutation and controls.MethodsA case-control study was designed to compare self-reported gastrointestinal symptoms among patients with isolated oligodontia, caused by a Wnt signaling gene mutation, and fully dentate controls. The Gastrointestinal Symptom Rating Scale (GSRS) was used to assess gastrointestinal symptoms. Prevalence and severity of gastrointestinal symptoms among patients and age- and gender-matched controls were evaluated.ResultsTwenty patients with isolated oligodontia and a pathogenic variant in the wnt pathway genes WNT10A, LRP6, or PAX9 participated. The prevalence of gastrointestinal symptoms was higher in the oligodontia patients compared to their controls (Χ2 (1) = 87.33, p = .008). Mean GSRS total scores (p = .011) and domain scores for "abdominal pain" (p = .022), "reflux" (p = .003) and constipation (p = .030) were higher for these oligodontia patients compared to their controls.ConclusionGastrointestinal symptoms are more prevalent and more severe in patients with isolated oligodontia and a deficiency in a Wnt pathway-related gene, when compared to controls without tooth agenesis.
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Project description:BackgroundDihidropyrimidinase (DHP) deficiency is an inherited inborn error of pyrimidine metabolism with a variable clinical presentation and even asymptomatic subjects. Dihydropyrimidinase is encoded by the DPYS gene, thus pathogenic mutations in this gene can cause DHP deficiency. To date, several variations in the DPYS gene have been reported but only 23 of them have been confirmed to be pathogenic. Therefore, the biochemical, clinical and genetic aspects of this disease are still unclear.Case presentationHere, we report a 22-year-old woman with DHP deficiency. To identify the genetic cause of DHP deficiency in this patient, Whole Exome Sequencing (WES) was performed, which revealed a novel homozygote stop gain mutation (NM_001385: Exon 9, c.1501 A > T, p.K501X) in the DPYS gene. Sanger sequencing was carried out on proband and other family members in order to confirm the identified mutation. According to the homozygote genotype of the patient and heterozygote genotype of her parents, the autosomal recessive pattern of inheritance was confirmed. In addition, bioinformatics analysis of the identified variant using Mutation Taster and T-Coffee Multiple Sequence Alignment showed the pathogenicity of mutation. Moreover, mRNA expression level of DPYS gene in the proband's liver biopsy showed about 6-fold reduction compared to control, which strongly suggested the pathogenicity of the identified mutation.ConclusionsThis study identified a novel pathogenic stop gain mutation in DPYS gene in a DHP deficient patient. Our findings can improve the knowledge about the genetic basis of the disease and also provide information for accurate genetic counseling for the families at risk of these types of disorders.
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2013-12-31 | E-GEOD-17161 | biostudies-arrayexpress