Severe nondominant hereditary spherocytosis due to uniparental isodisomy at the SPTA1 locus.
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ABSTRACT:
SUBMITTER: Bogardus H
PROVIDER: S-EPMC4562552 | biostudies-literature | 2014 Sep
REPOSITORIES: biostudies-literature
Publications
Severe nondominant hereditary spherocytosis due to uniparental isodisomy at the SPTA1 locus.
Bogardus Hannah H Schulz Vincent P VP Maksimova Yelena Y Miller Barbara A BA Li Peining P Forget Bernard G BG Gallagher Patrick G PG
Haematologica 20140603 9
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Project description: Not available
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Project description:BackgroundCYP1B1 variants and deletions are the most common cause of primary congenital glaucoma (PCG).MethodsWe investigated an individual with PCG from the Australian and New Zealand Registry of Advanced Glaucoma. We performed sequencing of the CYP1B1 gene, followed by Multiplex Ligation-dependent Probe Amplification and SNP array.ResultsWe identified a homozygous deletion of the CYP1B1 gene by Multiplex Ligation-dependent Probe Amplification and confirmed that the father was heterozygous for a CYP1B1 deletion but the mother had normal gene copy number. SNP array identified paternal uniparental isodisomy of the entire chromosome 2.ConclusionsThis study is the first report of a homozygous CYP1B1 whole gene deletion due to paternal uniparental isodisomy of chromosome 2 as a cause of PCG. These results illustrate the importance of genetic testing in providing appropriate genetic counseling regarding the risks of recurrence.
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Project description:Mucopolysaccharidosis type I (MPS I) is a rare lysosomal storage disease caused by biallelic mutations in IDUA, the gene coding for the lysosomal enzyme alpha L-iduronidase. Clinically MPS I is a chronic progressive multisystem disease typically presenting with coarse facial features, skeletal deformities, joint contractures, and multi-organ involvement. Hurler syndrome (MPS IH) represents the severe end of the spectrum of mucopolysaccharidosis type I and is characterized by central nervous system involvement leading to childhood dementia. Here we report on a severe affected MPS IH patient who is homozygous for a splice site mutation (c.158 + 1G > A) in the IDUA gene. Further analyses revealed maternal uniparental disomy of chromosome 4 with partial isodisomy of the telomeric end of chromosome 4 (4.p16.3p15.2), representing an extraordinary mode of inheritance with a much lower re-occurrence risk for MPS I in the family.
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Project description:LRBA deficiency was first described in 2012 as an autosomal recessive disorder caused by biallelic mutations in the LRBA gene (OMIM #614700). It was initially characterized as producing early-onset hypogammaglobulinemia, autoimmune manifestations, susceptibility to inflammatory bowel disease, and recurrent infection. However, further reports expanded this phenotype (including patients without hypogammaglobulinemia) and described LRBA deficiency as a clinically variable syndrome with a wide spectrum of clinical manifestations. We present the case of a female patient who presented with type 1 diabetes, psoriasis, oral thrush, and enlarged liver and spleen at the age of 8 months. She later experienced recurrent bacterial and viral infections, including pneumococcal meningitis and Epstein Barr viremia. She underwent two consecutive stem cell transplants at the age of 8 and 9 years, and ultimately died. Samples from the patient and her parents were subjected to whole exome sequencing, which revealed a homozygous 1-bp insertion in exon 23 of the patient's LRBA gene, resulting in frameshift and premature stop codon. The patient's healthy mother was heterozygous for the mutation and her father tested wild-type. This finding suggested that either one copy of the paternal chromosome 4 bore a deletion including the LRBA locus, or the patient inherited two copies of the mutant maternal LRBA allele. The patient's sequencing data showed a 1-Mb loss of heterozygosity region in chromosome 4, including the LRBA gene. Comparative genomic hybridization array of the patient's and father's genomic DNA yielded normal findings, ruling out genomic copy number abnormalities. Here, we present the first case of LRBA deficiency due to a uniparental disomy (UPD). In contrast to classical Mendelian inheritance, UPD involves inheritance of 2 copies of a chromosomal region from only 1 parent. Specifically, our patient carried a small segmental isodisomy of maternal origin affecting 1 Mb of chromosome 4.
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Project description:We described a clinical, laboratory, and genetic presentation of a pathogenic variant of the CYP1B1 gene through a report of a case of primary congenital glaucoma and a trio analysis of this candidate variant in the family with the sanger sequencing method and eventually completed our study with the secondary/incidental findings. This study reports a rare case of primary congenital glaucoma, an 8-year-old female child with a negative family history of glaucoma and uncontrolled intraocular pressure. This case's whole-exome sequencing data analysis presents a homozygous pathogenic single nucleotide variant in the CYP1B1 gene (NM 000104:exon3:c.G1103A:p.R368H). At the same time, this pathogenic variant was obtained as a heterozygous state in her unaffected father but not her mother. The diagnosis was made based on molecular findings of whole-exome sequencing data analysis. Therefore, the clinical reports and bioinformatics findings supported the relation between the candidate pathogenic variant and the disease. However, it should not be forgotten that primary congenital glaucoma is not peculiar to the CYP1B1 gene. Since the chance of developing autosomal recessive disorders with low allele frequency and unrelated parents is extraordinary in offspring. However, further data analysis of whole-exome sequencing and sanger sequencing method were applied to obtain the type of mutation and how it was carried to the offspring.
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Project description:Inherited vascular malformations are commonly autosomal dominantly inherited with high, but incomplete, penetrance; they often present as multiple lesions. We hypothesized that Knudson's two-hit model could explain this multifocality and partial penetrance. We performed a systematic analysis of inherited glomuvenous malformations (GVMs) by using multiple approaches, including a sensitive allele-specific pairwise SNP-chip method. Overall, we identified 16 somatic mutations, most of which were not intragenic but were cases of acquired uniparental isodisomy (aUPID) involving chromosome 1p. The breakpoint of each aUPID is located in an A- and T-rich, high-DNA-flexibility region (1p13.1-1p12). This region corresponds to a possible new fragile site. Occurrences of these mutations render the inherited glomulin variant in 1p22.1 homozygous in the affected tissues without loss of genetic material. This finding demonstrates that a double hit is needed to trigger formation of a GVM. It also suggests that somatic UPID, only detectable by sensitive pairwise analysis in heterogeneous tissues, might be a common phenomenon in human cells. Thus, aUPID might play a role in the pathogenesis of various nonmalignant disorders and might explain local impaired function and/or clinical variability. Furthermore, these data suggest that pairwise analysis of blood and tissue, even on heterogeneous tissue, can be used for localizing double-hit mutations in disease-causing genes.
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Project description:Dihydropyrimidine dehydrogenase (DPD) deficiency is a rare autosomal recessive disorder of the pyrimidine degradation pathway and can lead to intellectual disability, motor retardation, and seizures. Genetic variations in DPYD have also emerged as predictive risk factors for severe toxicity in cancer patients treated with fluoropyrimidines. We recently observed a child born to non-consanguineous parents, who demonstrated seizures, cognitive impairment, language delay, and MRI abnormalities and was found to have marked thymine-uraciluria. No residual DPD activity could be detected in peripheral blood mononuclear cells. Molecular analysis showed that the child was homozygous for the very rare c.257C > T (p.Pro86Leu) variant in DPYD. Functional analysis of the recombinantly expressed DPD mutant showed that the DPD mutant carrying the p.Pro86Leu did not possess any residual DPD activity. Carrier testing in parents revealed that the father was heterozygous for the variant but unexpectedly the mother did not carry the variant. Microsatellite repeat testing with markers covering chromosome 1 showed that the DPD deficiency in the child is due to paternal uniparental isodisomy. Our report thus extends the genetic spectrum underlying DPYD deficiency.
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Project description:Hereditary spherocytosis (HS) is a phenotypically and genetically heterogeneous disease. With the increased use of Next Generation Sequencing (NGS) techniques in the diagnosis of red blood cell disorders, the list of unique pathogenic mutations underlying HS is growing rapidly. In this study, we aimed to explore genotype-phenotype correlation in 95 HS patients genotyped by targeted NGS as part of routine diagnostics (UMC Utrecht, Utrecht, The Netherlands). In 85/95 (89%) of patients a pathogenic mutation was identified, including 56 novel mutations. SPTA1 mutations were most frequently encountered (36%, 31/85 patients), primarily in patients with autosomal recessive forms of HS. Three SPTA1 (α-spectrin) mutations showed autosomal dominant inheritance. ANK1 (ankyrin1) mutations accounted for 27% (23/85 patients) and SPTB (β-spectrin) mutations for 20% (17/85 patients). Moderate or severe HS was more frequent in patients with SPTB or ANK1 mutations, reflected by lower hemoglobin concentrations and higher reticulocyte counts. Interestingly, mutations affecting spectrin association domains of ANK1, SPTA1 and SPTB resulted in more severe phenotypes. Additionally, we observed a clear association between phenotype and aspects of red cell deformability as determined by the Laser assisted Optical Rotational Cell Analyzer (LoRRca MaxSis). Both maximal deformability and area under the curve were negatively associated with disease severity (respectively r = -0.46, p < 0.01, and r = -0.39, p = 0.01). Genotype-phenotype prediction in HS facilitates insight in consequences of pathogenic mutations for the assembly and dynamic interactions of the red cell cytoskeleton. In addition, we show that measurements of red blood cell deformability are clearly correlated with HS severity.
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