Identification of rare variants causing urea cycle disorders: A clinical, genetic, and biophysical study.
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ABSTRACT:
SUBMITTER: Liu F
PROVIDER: S-EPMC8051738 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundThe incidence, prevalence, and molecular epidemiology of urea cycle disorders (UCDs) in Argentina remain underexplored. The present study is the first to thoroughly assess the clinical and molecular profiles of UCD patients examined at a single reference center in Argentina.ResultsForty-nine UCD cases were collected. About half (26/49, 53%) manifested neonatally with classical presentation and had a high mortality (25/26, 96%). Ornithine transcarbamylase deficiency (OTCD) was the most common UCD (26 patients). Argininosuccinate synthetase deficiency (ASSD) was detected in 19 cases, while argininosuccinate lyase deficiency (ASLD) was diagnosed in 4 cases. Molecular genetic analysis revealed 8 private OTC mutations and two large deletion/duplication events in the OTC gene. Most mutations in the ASS1 and ASL genes were recurrent missense changes, and four alterations were novel. The clinical outcome of our UCD cohort was poor, with an overall mortality of 57% (28/49 cases), and a 28% (6/21) disability rate among the survivors.ConclusionsMost patients in our case series showed severe neonatal onset, with high morbidity/mortality. We detected in total 19 mutations, most of them recurrent and of high frequency worldwide. Noteworthy, we highlight the presence of a geographic cluster with high prevalence of a point mutation in the ASS1 gene. This study suggests that these disorders may be more frequent than commonly assumed, and stresses the need for increased awareness amongst health professionals and greater availability of diagnostic tools for accurate identification, early diagnosis, and timely treatment.
| S-EPMC6700778 | biostudies-literature
Project description:BackgroundThe urea cycle plays a key role in preventing the accumulation of toxic nitrogenous waste products, including two essential enzymes: ornithine transcarbamylase (OTC) and argininosuccinate lyase (ASL). Ornithine transcarbamylase deficiency (OTCD) results from mutations in the OTC. Meanwhile, argininosuccinate lyase deficiency (ASLD) is caused by mutations in the ASL.MethodsBlood tandem mass spectrometric analysis and urea organic acidemia screening were performed on five Chinese cases, including three OTCD and two ASLD patients. Next-generation sequencing was then used to make a definite diagnosis, and the related variants were validated by Sanger sequencing.ResultsThe five patients exhibited severe clinical symptoms, with abnormal biochemical analysis and amino acids profile. Genetic analysis revealed two variants [c.77G>A (p.Arg26Gln); c.116G>T (p.Gly39Val)] in the OTC, as well as two variants [c.1311T>G (p.Tyr437*); c.961T>A (p.Tyr321Asn)] in the ASL. Conservation analysis showed that the amino acids of the two novel mutations were highly conserved in different species and were predicted to be possibly damaging with several in silico prediction programs. 3D-modeling analysis indicated that the two novel missense variants might result in modest distortions of the OTC and ASL protein structures, respectively.ConclusionsTwo novel variants expand the mutational spectrums of the OTC and ASL. All the results may contribute to a better understanding of the clinical course and genetic characteristics of patients with urea cycle disorders.
| S-EPMC7336749 | biostudies-literature
Project description:BACKGROUND:Urea cycle disorders (UCDs) are inherited metabolic disorders that present with hyperammonemia, and cause significant mortality and morbidity in infants and children. These disorders are not well reported in the Indian population, due to lack of a thorough study of the clinical and molecular profile. RESULTS:We present data from two major metabolic centres in India, including 123 cases of various UCDs. The majority of them (72/123, 58%) presented in the neonatal period (before 30 days of age) with 88% on or before day 7 of life (classical presentation), and had a high mortality (64/72, 88%). Citrullinemia type 1 was the most common UCD, observed in 61/123 patients. Ornithine transcarbamylase (OTC) deficiency was the next most common, seen in 24 cases. Argininosuccinic aciduria was diagnosed in 20 cases. Deficiencies of arginase, N-acetylglutamate synthase, carbamoyl phosphate synthetase, citrin, and lysinuric protein intolerance were also observed. Molecular genetic analysis revealed two common ASS1 mutations: c.470G?>?A (p.Arg157His) and c.1168G?>?A (p.Gly390Arg) (36 of 55 tested patients). In addition, few recurrent point mutations in ASL gene, and a deletion of the whole OTC gene were also noted. A total of 24 novel mutations were observed in the various genes studied. We observed a poor clinical outcome with an overall all time mortality of 63% (70/110 cases with a known follow-up), and disability in 70% (28/40) among the survivors. Prenatal diagnosis was performed in 30 pregnancies in 25 families, including one pre-implantation genetic diagnosis. CONCLUSIONS:We report the occurrence of UCDs in India and the spectrum that may be different from the rest of the world. Citrullinemia type 1 was the most common UCD observed in the cohort. Increasing awareness amongst clinicians will improve outcomes through early diagnosis and timely treatment. Genetic diagnosis in the proband will enable prenatal/pre-implantation diagnosis in subsequent pregnancies.
| S-EPMC6167905 | biostudies-literature
Project description:ImportanceClinical exome sequencing (CES) is rapidly becoming a common molecular diagnostic test for individuals with rare genetic disorders.ObjectiveTo report on initial clinical indications for CES referrals and molecular diagnostic rates for different indications and for different test types.Design, setting, and participantsClinical exome sequencing was performed on 814 consecutive patients with undiagnosed, suspected genetic conditions at the University of California, Los Angeles, Clinical Genomics Center between January 2012 and August 2014. Clinical exome sequencing was conducted as trio-CES (both parents and their affected child sequenced simultaneously) to effectively detect de novo and compound heterozygous variants or as proband-CES (only the affected individual sequenced) when parental samples were not available.Main outcomes and measuresClinical indications for CES requests, molecular diagnostic rates of CES overall and for phenotypic subgroups, and differences in molecular diagnostic rates between trio-CES and proband-CES.ResultsOf the 814 cases, the overall molecular diagnosis rate was 26% (213 of 814; 95% CI, 23%-29%). The molecular diagnosis rate for trio-CES was 31% (127 of 410 cases; 95% CI, 27%-36%) and 22% (74 of 338 cases; 95% CI, 18%-27%) for proband-CES. In cases of developmental delay in children (<5 years, n = 138), the molecular diagnosis rate was 41% (45 of 109; 95% CI, 32%-51%) for trio-CES cases and 9% (2 of 23, 95% CI, 1%-28%) for proband-CES cases. The significantly higher diagnostic yield (P value = .002; odds ratio, 7.4 [95% CI, 1.6-33.1]) of trio-CES was due to the identification of de novo and compound heterozygous variants.Conclusions and relevanceIn this sample of patients with undiagnosed, suspected genetic conditions, trio-CES was associated with higher molecular diagnostic yield than proband-CES or traditional molecular diagnostic methods. Additional studies designed to validate these findings and to explore the effect of this approach on clinical and economic outcomes are warranted.
| S-EPMC4278636 | biostudies-literature
Project description:Family-based designs are increasingly being used for identification of rare variants in complex disorders. This paper addresses two questions related to the utility of these designs. First, under what circumstances are rare disease-related variants expected to cosegregate with disease in families? Second, under what circumstances is a disease-variant association expected to be greater in studies restricted to familial cases than in studies of unselected cases? To investigate these questions, we developed a probability model of disease causation involving two loci. To address cosegregation, we examined the probability that an affected first-degree relative of a variant-carrying proband would also carry the variant. We find that this probability increases with increasing odds ratio (OR) for the variant, but declines with increasing sibling recurrence risk ratio (λs). For example, under reasonable assumptions, the 15q13.3 microdeletion in idiopathic generalized epilepsy, with an OR estimate of 68 in large case-control studies, is expected to be present in >95% of affected first-degree relatives of variant-carrying probands. However, for a variant with OR=5, the probability an affected relative has the variant ranges from 82% (when λs=2) to 58% (when λs=50). We also find that restriction of a study to familial cases does not necessarily increase a rare variant's association with disease, especially if λs is high and the variant contributes little to overall disease familial aggregation. These findings provide guidance for the design of family-based studies of rare variants in complex disorders.
| S-EPMC3598309 | biostudies-other
Project description:BACKGROUND:To improve our understanding of urea cycle disorders (UCDs) prospectively followed by two North American (NA) and European (EU) patient cohorts. AIMS:Description of the NA and EU patient samples and investigation of the prospects of combined and comparative analyses for individuals with UCDs. METHODS:Retrieval and comparison of the data from 1095 individuals (NA: 620, EU: 475) from two electronic databases. RESULTS:The proportion of females with ornithine transcarbamylase deficiency (fOTC-D), particularly those being asymptomatic (asfOTC-D), was higher in the NA than in the EU sample. Exclusion of asfOTC-D resulted in similar distributions in both samples. The mean age at first symptoms was higher in NA than in EU patients with late onset (LO), but similar for those with early (≤ 28 days) onset (EO) of symptoms. Also, the mean age at diagnosis and diagnostic delay for EO and LO patients were similar in the NA and EU cohorts. In most patients (including fOTC-D), diagnosis was made after the onset of symptoms (59.9%) or by high-risk family screening (24.7%), and less often by newborn screening (8.9%) and prenatal testing (3.7%). Analysis of clinical phenotypes revealed that EO patients presented with more symptoms than LO individuals, but that numbers of symptoms correlated with plasma ammonium concentrations in EO patients only. Liver transplantation was reported for 90 NA and 25 EU patients. CONCLUSIONS:Combined analysis of databases drawn from distinct populations opens the possibility to increase sample sizes for natural history questions, while comparative analysis utilizing differences in approach to treatment can evaluate therapeutic options and enhance long-term outcome studies.
| S-EPMC7329920 | biostudies-literature
Project description:BackgroundUrea cycle disorders (UCDs) are among the most common inborn errors of liver metabolism. As therapies for hyperammonemia associated with urea cycle dysfunction have improved, chronic complications, such as liver disease, have become increasingly apparent in individuals with UCDs. Liver disease in UCDs may be associated with hepatic inflammation, hepatic fibrosis, portal hypertension, liver cancer and even liver failure. However, except for monitoring serum aminotransferases, there are no clear guidelines for screening and/or monitoring individuals with UCDs for liver disease. Thus, we systematically evaluated the potential utility of several non-invasive biomarkers for liver fibrosis in UCDs.MethodsWe evaluated grey-scale ultrasonography, liver stiffness obtained from shear wave elastography (SWE), and various serum biomarkers for hepatic fibrosis and necroinflammation, in a cohort of 28 children and adults with various UCDs.ResultsOverall, we demonstrate a high burden of liver disease in our participants with 46% of participants having abnormal grey-scale ultrasound pattern of the liver parenchyma, and 52% of individuals having increased liver stiffness. The analysis of serum biomarkers revealed that 32% of participants had elevated FibroTest™ score, a marker for hepatic fibrosis, and 25% of participants had increased ActiTest™ score, a marker for necroinflammation. Interestingly, liver stiffness did not correlate with ultrasound appearance or FibroTest™.ConclusionOverall, our results demonstrate the high overall burden of liver disease in UCDs and highlights the need for further studies exploring new tools for identifying and monitoring individuals with UCDs who are at risk for this complication.Trial registrationThis study has been registered in ClinicalTrials.gov (NCT03721367).
| S-EPMC8195846 | biostudies-literature
Project description:The urea cycle generates arginine that is one of the major precursors for creatine biosynthesis. Here we evaluate levels of creatine and guanidinoacetate (the precursor in the synthesis of creatine) in plasma samples (ns = 207) of patients (np = 73) with different types of urea cycle disorders (ornithine transcarbamylase deficiency (ns = 22; np = 7), citrullinemia type 1 (ns = 60; np = 22), argininosuccinic aciduria (ns = 81; np = 31), arginase deficiency (ns = 44; np = 13)). The concentration of plasma guanidinoacetate positively correlated (p < 0.001, R2 = 0.64) with levels of arginine, but not with glycine in all patients with urea cycle defects, rising to levels above normal in most samples (34 out of 44) of patients with arginase deficiency. In contrast to patients with guanidinoacetate methyltransferase deficiency (a disorder of creatine synthesis characterized by elevated guanidinoacetate concentrations), creatine levels were normal (32 out of 44) or above normal (12 out of 44) in samples from patients with arginase deficiency. Creatine levels correlated significantly, but poorly (p < 0.01, R2 = 0.1) with guanidinoacetate levels and, despite being overall in the normal range in patients with all other urea cycle disorders, were occasionally below normal in some patients with argininosuccinic acid synthase and lyase deficiency. Creatine levels positively correlated with levels of methionine (p < 0.001, R2 = 0.16), the donor of the methyl group for creatine synthesis. The direct correlation of arginine levels with guanidinoacetate in patients with urea cycle disorders explains the increased concentration of guanidino compounds in arginase deficiency. Low creatine levels in some patients with other urea cycle defects might be explained by low protein intake (creatine is naturally present in meat) and relative or absolute intracellular arginine deficiency.
| S-EPMC8387902 | biostudies-literature
Project description:ObjectiveTo compare the clinical course and outcome of patients diagnosed with one of 4 neonatal-onset urea cycle disorders (UCDs): deficiency of carbamyl phosphate synthase 1 (CPSD), ornithine transcarbamylase (OTCD), argininosuccinate synthase (ASD), or argininosuccinate lyase (ALD).Study designClinical, biochemical, and neuropsychological data from 103 subjects with neonatal-onset UCDs were derived from the Longitudinal Study of Urea Cycle Disorders, an observational protocol of the Urea Cycle Disorders Consortium, one of the Rare Disease Clinical Research Networks.ResultsSome 88% of the subjects presented clinically by age 7 days. Peak ammonia level was 963 μM in patients with proximal UCDs (CPSD or OTCD), compared with 589 μM in ASD and 573 μM in ALD. Roughly 25% of subjects with CPSD or OTCD, 18% of those with ASD, and 67% of those with ALD had a "honeymoon period," defined as the time interval from discharge from initial admission to subsequent admission for hyperammonemia, greater than 1 year. The proportion of patients with a poor outcome (IQ/Developmental Quotient <70) was greatest in ALD (68%), followed by ASD (54%) and CPSD/OTCD (47%). This trend was not significant, but was observed in both patients aged <4 years and those aged ≥ 4 years. Poor cognitive outcome was not correlated with peak ammonia level or duration of initial admission.ConclusionNeurocognitive outcomes do not differ between patients with proximal UCDs and those with distal UCDs. Factors other than hyperammonemia may contribute to poor neurocognitive outcome in the distal UCDs.
| S-EPMC4440324 | biostudies-literature
Project description:Precise identification of causative variants from whole-genome sequencing data, including both coding and noncoding variants, is challenging. The Critical Assessment of Genome Interpretation 5 SickKids clinical genome challenge provided an opportunity to assess our ability to extract such information. Participants in the challenge were required to match each of the 24 whole-genome sequences to the correct phenotypic profile and to identify the disease class of each genome. These are all rare disease cases that have resisted genetic diagnosis in a state-of-the-art pipeline. The patients have a range of eye, neurological, and connective-tissue disorders. We used a gene-centric approach to address this problem, assigning each gene a multiphenotype-matching score. Mutations in the top-scoring genes for each phenotype profile were ranked on a 6-point scale of pathogenicity probability, resulting in an approximately equal number of top-ranked coding and noncoding candidate variants overall. We were able to assign the correct disease class for 12 cases and the correct genome to a clinical profile for five cases. The challenge assessor found genes in three of these five cases as likely appropriate. In the postsubmission phase, after careful screening of the genes in the correct genome, we identified additional potential diagnostic variants, a high proportion of which are noncoding.
| S-EPMC7182498 | biostudies-literature