Case Report: Complete Maternal Uniparental Isodisomy of Chromosome 5 (iUPD(5)mat) With PCSK1 Nonsense Variant in an Infant With Recurrent Diarrhea.
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ABSTRACT:
SUBMITTER: Qian Y
PROVIDER: S-EPMC8134681 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Rod monochromacy (complete congenital achromatopsia) is inherited as an autosomal recessive trait of unknown genetic location. The disorder is characterized by total absence of color discrimination because retinal cone photoreceptors do not develop; systemic features do not occur. A 20-year-old white female with rod monochromacy presented with short stature (less than 5th percentile), mild developmental delay, premature puberty, small hands and feet (length less than 5th percentile), minimal dysmorphism, and a reproductive history of three consecutive first-trimester miscarriages. Cytogenetic analysis showed 45,XX,rob(14;14) in all 30 cells examined. Southern analysis of DNA from the patient and her phenotypically normal mother and two brothers (her father is deceased) ascertained the parental origin of the 14;14 Robertsonian translocation. Analysis of RFLPs associated with nine VNTR probes and two dinucleotide repeat polymorphisms from chromosome 14 demonstrated that the patient had inherited two copies of a single allele, each of which was maternally derived. A fully informative RFLP analysis of three probes from chromosome 14 enabled reconstruction of the paternal haplotype and showed the lack of any paternal contribution to the subject. These data are consistent with maternal isodisomy for all portions of chromosome 14 tested by these markers. This finding suggests that rod monochromacy maps to chromosome 14, and it emphasizes the importance of uniparental isodisomy to provide a putative chromosomal assignment of a gene for a rare autosomal recessive disorder.
| S-EPMC1682625 | biostudies-other
Project description:Background:Uniparental disomy (UPD) is a rare condition in which a child inherits both copies of a chromosome or chromosome segment from one parent. Medical consequences of UPD may include abnormal imprinting, unmasking of genetic disease, and somatic mosaicism; alternatively, the condition may be clinically silent. We present a case of maternal UPD for chromosome 6, a rare condition previously reported less than 20 times. In our patient with a normal phenotype, the condition was discovered through abnormal paternity testing results. Uniparental isodisomy is a rare cause of discordant parentage testing results, but it is an important phenomenon to recognize. Case presentation:We present a female born at 32?weeks gestational age with birth weight 10-25%ile when corrected for prematurity. Paternity testing was obtained for legal reasons, and initial results appeared to exclude the alleged father. However, the lab performed additional testing which indicated that the patient was homozygous for maternal alleles for all three tested loci located on chromosome 6. Based on these results, the patient was referred for a medical genetics evaluation for possible maternal uniparental disomy. She presented for her consultation at 10?months of age and appeared to be developing appropriately. Her age-adjusted weight, length, and head circumference were <3%ile, 10%ile, and 25%ile respectively. Chromosomal microarray testing confirmed maternal UPD6. The patient was seen again at 14?months of age, and her weight and length were 10-25%ile. She had not developed concerning symptoms or physical exam findings. Conclusions:The presence of UPD, especially in asymptomatic patients, has implications for paternity testing, as standard methods may miss cases of both isodisomy and heterodisomy. This rare inheritance pattern should be considered when discordant paternity results come under suspicion. It is unusual for a parentage testing lab to perform the amount of testing done for this case, but the initial inconsistencies necessitated further investigation. UPD6 has uncertain effects and variable phenotypes, so this patient's genetic abnormality likely would have gone undiscovered if not for the non-medical indication for the laboratory analysis. Her asymptomatic presentation raises the possibility that UPD may be more common than previously estimated.
| S-EPMC6302445 | biostudies-other
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.
| S-EPMC7582098 | biostudies-literature
Project description:BackgroundThe main symptoms of congenital chloride diarrhea (CCD) main symptoms are watery diarrhea, hypochloremia, and hypokalemic metabolic alkalosis. Silver-Russell syndrome (SRS) is a heterogeneous imprinting disorder characterized by severe intrauterine retardation, poor postnatal growth, and facial dysmorphism.MethodsParent-offspring trio whole-exome sequencing was used to identify the causal variants. Sequencing reads were mapped to the reference of human genome version hg19. Sanger sequencing was performed as a confirmatory experiment.ResultsThe proband was a patient with SRS caused by maternal uniparental disomy 7. The CCD of the proband was caused by homozygous variant c.1515-1 (IVS13) G>A; both mutated alleles were inherited from her mother.ConclusionWe report the first clinical case of CCD and SRS occurring together. Patients with milder phenotypes may be difficult to diagnose in early stage, but close monitoring of potential complications is important for identification.
| S-EPMC8274990 | biostudies-literature
Project description:BACKGROUND:Maternal uniparental disomy of chromosome 6 (upd(6)mat) is a rare finding and its clinical relevance is currently unclear. Based on clinical data from two new cases and patients from the literature, the pathogenetic significance of upd(6)mat is delineated. METHODS:Own cases were molecularly characterized for isodisomic uniparental regions on chromosome 6. For further cases with upd(6)mat, a literature search was conducted and genetic and clinical data were ascertained. RESULTS:Comparison of isodisomic regions between the new upd(6)mat cases and those from four reports did not reveal any common isodisomic region. Among the patients with available cytogenetic data, five had a normal karyotype in lymphocytes, whereas a trisomy 6 (mosaicism) was detected prenatally in four cases. A common clinical picture was not obvious in upd(6)mat, but intrauterine growth restriction (IUGR) and preterm delivery were frequent. CONCLUSION:A common upd(6)mat phenotype is not obvious, but placental dysfunction due to trisomy 6 mosaicism probably contributes to IUGR and preterm delivery. In fact, other clinical features observed in upd(6)mat patients might be caused by homozygosity of recessive mutations or by an undetected trisomy 6 cell line. Upd(6)mat itself is not associated with clinical features, and can rather be regarded as a biomarker. In case upd(6)mat is detected, the cause for the phenotype is identified indirectly, but the UPD is not the basic cause.
| S-EPMC5702562 | biostudies-literature
Project description:Purpose:Inherited retinal dystrophies are a clinically and genetically heterogeneous group of disorders. Molecular diagnosis has proven utility for affected individuals. In this study, we report an individual enrolled in the Australian Inherited Retinal Disease Registry and DNA Bank diagnosed with clinical features overlapping between Leber congenital amaurosis and retinitis pigmentosa. Methods:DNA from the proband was sequenced using a gene panel for inherited retinal disorders, and a single nucleotide polymorphism (SNP) array was conducted to detect the presence of deletions and uniparental disomy. Results:We identified a novel homozygous variant (c.524dupC, p.(Pro176ThrfsTer7)) in TULP1 resulting from maternal uniparental isodisomy of chromosome 6. The patient had clinical features consistent with biallelic pathogenic variants in TULP1, including congenital nystagmus, night blindness, non-recordable electroretinogram, mild myopia, and mild peripheral pigmentary changes in the fundus. Conclusions:This is the first report of uniparental disomy 6 and a homozygous variant in TULP1 associated with a rod-cone dystrophy. Molecular diagnosis of inherited retinal dystrophies is essential to inform the mode of transmission and clinical management, and to identify potential candidates for future gene-specific therapies.
| S-EPMC6066270 | biostudies-literature
Project description:BACKGROUND: Loss of function mutations in the genes encoding the pancreatic ?-cell ATP-sensitive potassium (KATP) channel are identified in approximately 80% of patients with diazoxide unresponsive hyperinsulinemic hypoglycemia (HH). For a small number of patients HH can occur as part of a multisystem disease such as Beckwith-Wiedemann syndrome (BWS). In approximately 20% of patients, BWS results from chromosome 11 paternal uniparental disomy (UPD), which causes dysregulation of imprinted growth regulation genes at 11p15.5. There is a considerable range in the clinical features and phenotypic severity associated with BWS which is likely to be due to somatic mosaicism. The cause of HH in these patients is not known. RESEARCH DESIGN AND METHODS: We undertook microsatellite analysis of 12 markers spanning chromosome 11p in two patients with severe HH and diffuse disease requiring a pancreatectomy. In both patients mutations in the K(ATP) channel genes had not been identified. RESULTS: We identified segmental paternal UPD in DNA extracted from pancreatic tissue in both patients. UPD was not observed in DNA extracted from the patient's leukocytes or buccal samples. In both cases the UPD encompassed the differentially methylated region at chromosome 11p15.5. Despite this neither patient had any further features of BWS. CONCLUSION: Paternal UPD of the chromosome 11p15.5 differentially methylated region limited to the pancreatic tissue may represent a novel cause of isolated diazoxide unresponsive HH. Loss of heterozygosity studies should therefore be considered in all patients with severe HH who have undergone pancreatic surgery when K(ATP) channel mutation(s) have not been identified.
| S-EPMC3356130 | biostudies-literature
Project description:BACKGROUND:The prenatal diagnosis of subjects with complete uniparental isodisomy of chromosome 4 (iUPD4) has rarely been reported and poses a great challenge for genetic counseling. In this study, a prenatal case with a high (1 in 58) risk of Down syndrome was diagnosed with iUPD4 by combined chromosomal microarray analysis (CMA), whole exome sequencing (WES) and ultrasound morphology scan. RESULTS:By CMA, a pathogenic copy number variant was not detected; however, a complete maternal iUPD4 was identified in this fetus after analyzing the parental genotype results. To detect potentially autosomal recessive variants, WES was performed. Two missense and two frameshift variants were identified but were predicted with uncertain significance; none of the mutations were definitively associated with congenital abnormality or inherited disease. In addition, a detailed ultrasound morphology scan did not identify any structural abnormalities, facial dysmorphisms or intrauterine growth restriction. The family history was unremarkable. The couple was counseled with the prenatal diagnostic results, and they opted to give birth to the child. No phenotypic abnormalities were observed in this child after the first year of life. CONCLUSION:This study provides further evidence that iUPD4 can result in a healthy live birth and demonstrates that the combined use of CMA, WES and ultrasound technology provides additional information for the prenatal diagnosis and clinical management of rare UPD events.
| S-EPMC4632482 | biostudies-literature
Project description:Uniparental disomy (UPD), which is the abnormal situation in which both copies of a chromosomal pair have been inherited from one parent, may cause clinical abnormalities by affecting genomic imprinting or causing autosomal recessive variation. Whole Exome Sequencing (WES) and chromosomal microarray analysis (CMA) are powerful technologies used to search for underlying causal variants. In the present study, WES was used to screen for candidate causal variants in the genome of a Chinese pediatric patient, who had been shown by CMA to have maternal uniparental isodisomy of chromosome 10. This was associated with numerous severe medical problems, including bilateral deafness, binocular blindness, stunted growth and leukoderma. A total of 13 rare homozygous variants of these genes were identified on chromosome 10. These included a classical splice variant in the HPS1 gene (c.398+5G>A), which causes Hermansky-Pudlak syndrome type 1 and may explain the patient's ocular and dermal disorders. In addition, six likely pathogenic genes on other chromosomes were found to be associated with the subject's ocular and aural disorders by phenotypic analysis. The results of the present study demonstrated that WES and CMA may be successfully combined in order to identify candidate causal genes. Furthermore, a connection between phenotype and genotype was established in this patient.
| S-EPMC4887894 | biostudies-literature
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.
| S-EPMC6687653 | biostudies-literature