Combinations of exonic deletions and rare mutations lead to misdiagnosis of propionic acidemia

Wang, Handuo; Meng, Lanlan; Li, Wen; Du, Juan; Tan, Yue‐Qiu; Gong, Fei; Lu, Guangxiu; Lin, Ge; Zhang, Qianjun

doi:10.1016/j.cca.2019.12.021

Cited by 5 publications

(3 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Molecular genetics testing is a vital standard for the prenatal diagnosis of PA that requires the exclusion of maternal contamination to avoid false test results. However, due to the high genetic heterogeneity or novel variants whose clinical appearance is unknown, a genetic diagnosis of PA may lead to misdiagnosis [37], and the method depends upon availability of genetic information from the proband and parents. In some PA families, only one causative pathogenic variant was found in the proband, or a genetic testing was not performed, leading to the inability to make a precise prenatal diagnosis using genetic testing alone.…”

Section: Discussionmentioning

confidence: 99%

Biochemical and genetic approaches to the prenatal diagnosis of propionic acidemia in 78 pregnancies

Dai

Xiao

Zhang

et al. 2020

Orphanet J Rare Dis

View full text Add to dashboard Cite

Background Propionic acidemia (PA) is a serious metabolic disorder, and different approaches have been applied to its prenatal diagnosis. To evaluate the reliability and validity of a biochemical strategy in the prenatal diagnosis of PA, we conducted a retrospective study of our 11-year experiences at a single center. Methods We accumulated data from 78 pregnancies from 58 families referred to our center and provided prenatal diagnosis by directed genetic analysis and/or metabolite measurement using tandem mass spectrometry (MS/MS) and gas chromatography/mass spectrometry (GC/MS) of amniotic fluid (AF) samples. Results Sixty-five unaffected fetuses (83.33%) and 13 affected fetuses (16.67%) were confirmed in our study. The characteristic metabolites including propionylcarnitine (C3) level, C3/acetylcarnitine (C2) ratio and 2-methylcitric acid (2MCA) level in unaffected and affected groups showed significant differences (P < 0.0001), while the level of 3-hydroxypropionic acid (3HPA) showed no significant difference between the two groups (P > 0.05).Of the 78 pregnancies, 24 fetuses were found to have either one causative pathogenic variant or were without genetic information in the proband. Three of these fetuses had elevated AF levels of C3, C3/C2 ratio, and 2MCA and, thus, were determined to be affected, while the remaining fetuses were determined to be unaffected based on a normal AF metabolite profile. Our genetic and biochemical results were highly consistent with postnatal follow-up results on all unaffected fetuses. Conclusions We conclude that a biochemical approach can serve as a fast and convenient prenatal diagnostic method for pregnancies at an increased risk for PA, which could be used in conjunction with genetic testing for precise prenatal diagnosis of this disorder. In our analysis, the characteristic metabolites C3 level, C3/C2 ratio, and 2MCA level in AF supernatant were dependable biochemical markers for diagnosis, of which the C3/C2 ratio appears to be the most reliable biochemical marker for the prenatal diagnosis of PA.

show abstract

Section: Discussionmentioning

confidence: 99%

Biochemical and genetic approaches to the prenatal diagnosis of propionic acidemia in 78 pregnancies

Dai

Xiao

Zhang

et al. 2020

Orphanet J Rare Dis

View full text Add to dashboard Cite

show abstract

“…Sanger sequencing, quantitative polymerase chain reaction (qPCR), next generation sequencing (NGS) are employed to detect and identify the pathogenic mutations of biallelic sites in PCCA or PCCB genes. In special cases, additional technologies such as cDNA analysis, multiplex ligation-dependent probe amplification (MLPA), or long-read whole-genome sequencing may be necessary to improve the detection rates [ 36 ]. Splicing variants need to be confirmed at the mRNA level.…”

Section: Introductionmentioning

confidence: 99%

Prevalence of propionic acidemia in China

Zhang,

Peng,

Wang

et al. 2023

Orphanet J Rare Dis

View full text Add to dashboard Cite

Propionic acidemia (PA) is a rare autosomal recessive congenital disease caused by mutations in the PCCA or PCCB genes. Elevated propionylcarnitine, 2-methylcitric acid (2MCA), propionylglycine, glycine and 3-hydroxypropionate can be used to diagnose PA. Early-onset PA can lead to acute deterioration, metabolic acidosis, and hyperammonemia shortly after birth, which can result in high mortality and disability. Late-onset cases of PA have a more heterogeneous clinical spectra, including growth retardation, intellectual disability, seizures, basal ganglia lesions, pancreatitis, cardiomyopathy, arrhythmias, adaptive immune defects, rhabdomyolysis, optic atrophy, hearing loss, premature ovarian failure, and chronic kidney disease. Timely and accurate diagnosis and appropriate treatment are crucial to saving patients’ lives and improving their prognosis. Recently, the number of reported PA cases in China has increased due to advanced diagnostic techniques and increased research attention. However, an overview of PA prevalence in China is lacking. Therefore, this review provides an overview of recent advances in the pathogenesis, diagnostic strategies, and treatment of PA, including epidemiological data on PA in China. The most frequent variants among Chinese PA patients are c.2002G > A in PCCA and c.1301C > T in PCCB, which are often associated with severe clinical symptoms. At present, liver transplantation from a living (heterozygous parental) donor is a better option for treating PA in China, especially for those exhibiting a severe metabolic phenotype and/or end-organ dysfunction. However, a comprehensive risk–benefit analysis should be conducted as an integral part of the decision-making process. This review will provide valuable information for the medical care of Chinese patients with PA.

show abstract

“…There are several clinical reports of PA in Chinese population in recent years [10][11][12][13][14]. Although mutations are mainly found on the PCCA gene, no predominant mutations exist in Chinese PA patients [10].…”

Section: Introductionmentioning

confidence: 99%

A novel delins (c.773_819+47delinsAA) mutation of the PCCA gene associated with neonatal-onset propionic acidemia: a case report

Wang

et al. 2020

BMC Med Genet

View full text Add to dashboard Cite

Background: Propionic acidemia (PA)(OMIM#606054) is an inborn error of branched-chain amino acid metabolism, caused by defects in the propionyl-CoA carboxylase (PCC) enzyme which encoded by the PCCA and PCCB genes. Case presentation: Here we report a Chinese neonate diagnosed with suspected PA based on the clinical symptoms, gas chromatography-mass spectrometry (GC/MS), and brain imaging tests. Targeted next-generation sequencing (NGS) was performed on the proband. We detected only one heterozygous recurrent nonsense variant (c.937C > T, p.Arg313Ter) in the PCCA gene. When we manually checked the binary alignment map (BAM) diagram of PCCA gene, we found a heterozygous deletion chr13:100915039-100915132delinsAA (c.773_819 + 47delinsAA) (GRCh37.p13) inside the exon 10 in the PCCA gene. The results were validated by Sanger sequencing and qPCR method in the family: the variant (c.937C > T, p.Arg313Ter) was in the maternal allele, and the delins was in the paternal allele. When the mother was pregnant again, prenatal diagnosis was carried out through amniocentesis at 18 weeks gestation, the fetus carried neither of the two mutations. After birth, newborn screening was undertaken, the result was negative. Conclusions: We identified a recurrent c.937C > T and a novel c.773_819 + 47delinsAA mutations in the PCCA gene, which may be the genetic cause of the phenotype of this patient. Our findings expanded the spectrum of causative genotype-phenotype of the PCCA gene. For the cases, the NGS results revealed only a heterozygous mutation in autosomal recessive disease when the gene is associated with phenotypes, it is necessary to manually check the BAM diagram to improve the detection rate. Targeted NGS is an effective technique to detect the various genetic lesions responsible for the PA in one step. Genetic testing is essential for genetic counselling and prenatal diagnosis in the family to avoid birth defects.

show abstract

Combinations of exonic deletions and rare mutations lead to misdiagnosis of propionic acidemia

Cited by 5 publications

References 27 publications

Biochemical and genetic approaches to the prenatal diagnosis of propionic acidemia in 78 pregnancies

Biochemical and genetic approaches to the prenatal diagnosis of propionic acidemia in 78 pregnancies

Prevalence of propionic acidemia in China

A novel delins (c.773_819+47delinsAA) mutation of the PCCA gene associated with neonatal-onset propionic acidemia: a case report

Contact Info

Product

Resources

About