Identification of six novel mutations in five infants with suspected maple syrup urine disease based on blood and urine metabolism screening

Yang, Chenxi; Linpeng, Siyuan; Cao, Jingli; Wu, Lingqian

doi:10.1016/j.gene.2019.04.086

Cited by 5 publications

(3 citation statements)

References 18 publications

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“…Hotspot mutations are not found in the remaining population [19][20][21] .There were few reports on MSUD gene mutations in the Chinese population [22][23][24] , and no significant hotspot mutations have been identified. In this study, a total of 13 gene variants (15.4% located in BCKDHA gene, 76.9% in BCKDHB gene, and 7.7% in DBT gene) were found in 16 alleles in 8 families, and the mutation frequency of the BCKDHB gene was the highest, which was consistent with the results of other studies [25][26][27] . The BCKDHB gene may be a major variant type of MSUD in the Chinese population.…”

Section: Gly→arg Ser→pro Lys→thrsupporting

confidence: 92%

Genetic analysis by targeted next-generation sequencing and novel variation identification of maple syrup urine disease

Fang¹,

Zhu²,

Yin³

et al. 2021

Preprint

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Maple syrup urine disease (MSUD) is a rare autosomal recessive disorder that affects the degradation of branched chain amino acids (BCAAs). Only a few cases of MSUD have been documented in Mainland China. In this report, 8 patients (4 girls and 4 boys) with MSUD from 8 unrelated Chinese families were diagnosed at the age of 9 days to 1 year and 8 months. All the coding regions and exon/intron boundaries of BCKDHA, BCDKHB, DBT, DLD genes were analyzed by targeted NGS in the 8 MSUD pedigrees. Targeted NGS revealed 2 pedigrees with MSUD Ia, 5 pedigrees with Ib, 1 pedigree with MSUD II. Totally, 13 variants were detected, including 2 variants (p.Ala216Val and p.Gly281Arg) in BCKDHA gene，10 variants (p.Gly95Ala, p.Ser171Pro, p.Phe175Leu, p.Arg183Trp, p.Lys222Thr, p.Arg285Ter，p.Arg111Ter，p.S184Pfs*46, p.Arg170Cys, p.I160Ffs*25) in BCKDHB gene, 1 variants (p.Arg431Ter) in DBT gene. In addition, 4 previously unidentified variants (p.Gly281Arg in BCKDHA gene, p.Ser171Pro, p.Gly95Ala and p.Lys222Thr in BCKDHB gene) were found. NGS plus Sanger sequencing detection is effective and accurate for making gene diagnosis. Computational structural modeling indicated that these novel variations might affect structural stability.

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Section: Gly→arg Ser→pro Lys→thrsupporting

confidence: 92%

Genetic analysis by targeted next-generation sequencing and novel variation identification of maple syrup urine disease

Fang¹,

Zhu²,

Yin³

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Hotspot mutations are not found in the remaining population 23 – 25 . There were no significant hotspot mutations have been identified in the Chinese population 26 – 32 . Variants c.331C>T and c.853C>T in BCKDHB gene may be relatively common in Chinese patients.…”

Section: Discussionmentioning

confidence: 91%

Genetic analysis by targeted next-generation sequencing and novel variation identification of maple syrup urine disease in Chinese Han population

Fang

Zhu

Yin

et al. 2021

Sci Rep

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Maple syrup urine disease (MSUD) is a rare autosomal recessive disorder that affects the degradation of branched chain amino acids (BCAAs). Only a few cases of MSUD have been documented in Mainland China. In this report, 8 patients (4 females and 4 males) with MSUD from 8 unrelated Chinese Han families were diagnosed at the age of 6 days to 4 months. All the coding regions and exon/intron boundaries of BCKDHA, BCDKHB, DBT and DLD genes were analyzed by targeted NGS in the 8 MSUD pedigrees. Targeted NGS revealed 2 pedigrees with MSUD Ia, 5 pedigrees with Ib, 1 pedigree with MSUD II. Totally, 13 variants were detected, including 2 variants (p.Ala216Val and p.Gly281Arg) in BCKDHA gene, 10 variants (p.Gly95Ala, p.Ser171Pro, p.Phe175Leu, p.Arg183Trp, p.Lys222Thr, p.Arg285Ter, p.Arg111Ter, p.S184Pfs*46, p.Arg170Cys, p.I160Ffs*25) in BCKDHB gene, 1 variant (p.Arg431Ter) in DBT gene. In addition, 4 previously unidentified variants (p.Gly281Arg in BCKDHA gene, p.Ser171Pro, p.Gly95Ala and p.Lys222Thr in BCKDHB gene) were identified. NGS plus Sanger sequencing detection is effective and accurate for gene diagnosis. Computational structural modeling indicated that these novel variations probably affect structural stability and considered as likely pathogenic variants.

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“…Therefore, this study inferred that the enzyme Frontiers in Genetics frontiersin.org activity of c.659C>T(p.A220V) mutation is less impaired. Among the reported cases, the four reported variations c.818C>T (p.T273I), c.1006G>A (p.G336S), c.331C>T (p.R111*), and c.550delT (p.S184Pfs*46) appeared in the form of compound heterozygous, these mutations would cause classic MSUD patients (Ali and Ngu, 2018;Li et al, 2018;Yang et al, 2019). These results indicated that the mentioned four reported mutations profoundly influenced the enzyme activity.…”

Section: Discussionmentioning

confidence: 78%

Identification of gene mutations in six Chinese patients with maple syrup urine disease

Mao²,

Yang³

et al. 2023

Front. Genet.

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Background: Maple syrup urine disease (MSUD) is a rare autosomal recessive amino acid metabolic disease. This study is to identify the pathogenic genetic factors of six cases of MUSD and evaluates the application value of high-throughput sequencing technology in the early diagnosis of MUSD.Methods: Clinical examination was carried out for patients and used blood tandem mass spectrometry (MS/MS), urine gas chromatography-mass spectrometry (GC/MS), and the application of high-throughput sequencing technology for detection. Validate candidate mutations by polymerase chain reaction (PCR)—Sanger sequencing technology. Bioinformatics software analyzed the variants’ pathogenicity. Using Swiss PDB Viewer software to predict the effect of mutation on the structure of BCKDHA and BCKDHB proteins.Result: A total of six MSUD patients were diagnosed, including four males and two females. Nine variants were found in three genes of six MSUD families by high-throughput sequencing, including four missense mutations: c.659C>T(p.A220V), c.818C>T(p.T273I), c.1134C>G(p.D378E), and c.1006G>A(p.G336S); two non-sense mutations: c.1291C>T(p.R431*) and c.331C>T(p.R111*); three deletion mutations: c.550delT (p.S184Pfs*46), c.718delC (p.P240Lfs*14), and c.795delG (p.N266Tfs*64). Sanger sequencing’s results were consistent with the high-throughput sequencing. The bioinformatics software revealed that the mutations were harmful, and the prediction results of Swiss PDB Viewer suggest that variation affects protein conformation.Conclusion: This study identified nine pathogenic variants in the BCKDHA, BCKDHB, and DBT genes in six MSUD families, including two novel pathogenic variants in the BCKDHB gene, which enriched the genetic mutational spectrum of the disease. High-throughput sequencing is essential for the MSUD’s differential diagnosis, early treatment, and prenatal diagnosis.

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Identification of six novel mutations in five infants with suspected maple syrup urine disease based on blood and urine metabolism screening

Cited by 5 publications

References 18 publications

Genetic analysis by targeted next-generation sequencing and novel variation identification of maple syrup urine disease

Genetic analysis by targeted next-generation sequencing and novel variation identification of maple syrup urine disease

Genetic analysis by targeted next-generation sequencing and novel variation identification of maple syrup urine disease in Chinese Han population

Identification of gene mutations in six Chinese patients with maple syrup urine disease

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