Maple syrup urine disease mutation spectrum in a cohort of 40 consanguineous patients and insilico analysis of novel mutations

Abiri, Maryam; Saei, Hassan; Eghbali, Mohammad; Karamzadeh, Razieh; Shirzadeh, Tina; Sharifi, Zohreh; Zeinali, Sirous

doi:10.1007/s11011-019-00435-y

Cited by 13 publications

(11 citation statements)

References 37 publications

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“…Variants of DBT gene were encountered in 11 patients (Table 4). Five patients (P23‐27) had a previously reported nonsense variant, p.R431*, due to a single base substitution (Abiri et al, 2019; Sun et al, 2020). Four patients (P28‐31) had a previously reported nonsense variant (p.E224*) (Fisher et al, 1993).…”

Section: Resultsmentioning

confidence: 99%

Genotype–phenotype correlation of 33 patients with maple syrup urine disease

Khalifa

Imtiaz

Ramzan

et al. 2020

American J of Med Genetics Pt A

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Maple syrup urine disease (MSUD) is a rare autosomal recessive inherited disorder due to defects in the branched-chain α-ketoacid dehydrogenase complex (BCKDC). MSUD varies in severity and its clinical spectrum is quite broad, ranging from mild to severe phenotypes. Thirty-three MSUD patients were recruited into this study for molecular genetic variant profiling and genotype-phenotype correlation. Except for one patient, all other patients presented with the classic neonatal form of the disease. Seventeen different variants were detected where nine were novel. The detected variants spanned across the entire BCKDHA, BCKDHB and DBT genes. All variants were in homozygous forms. The commonest alterations were nonsense and frameshift variants, followed by missense variants. For the prediction of variant's pathogenicity, we used molecular modeling and several in silico tools including SIFT, Polyphen2, Condel, and Provean. In addition, six other tools were used for the prediction of the conservation of the variants' sites including Eigen-PC, GERP++, SiPhy, PhastCons vertebrates and primates, and PhyloP100 rank scores. Herein, we presented a comprehensive characterization of a large cohort of patients with MSUD. The clinical severity of the variants' phenotypes was well correlated with the genotypes. The study underscores the importance of the use of in silico analysis of MSUD genotypes for the prediction of the clinical outcomes in patients with MSUD.

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Section: Resultsmentioning

confidence: 99%

Genotype–phenotype correlation of 33 patients with maple syrup urine disease

Khalifa

Imtiaz

Ramzan

et al. 2020

American J of Med Genetics Pt A

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“…In conditions for which the causative gene from the biochemical phenotype is poorly defined or in metabolic disorders that are not able to be biochemically sub-typed (e.g., peroxisomal biogenesis disorders), an NGS panel undertaking post hoc filtering for genes of interest (a 'panel') can be informative. An example is maple-syrup urine disease, which has multiple genes linked with an indistinguishable metabolite profile [49]. In practice, the choice of the underlying assay is often linked with workflow, since post hoc filtering allows for the creation of a virtual gene panel.…”

Section: Confirmatory Diagnostic Testingmentioning

confidence: 99%

Metabolomics to Improve the Diagnostic Efficiency of Inborn Errors of Metabolism

Mordaunt

Cox

Fuller

2020

IJMS

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Early diagnosis of inborn errors of metabolism (IEM)—a large group of congenital disorders—is critical, given that many respond well to targeted therapy. Newborn screening programs successfully capture a proportion of patients enabling early recognition and prompt initiation of therapy. For others, the heterogeneity in clinical presentation often confuses diagnosis with more common conditions. In the absence of family history and following clinical suspicion, the laboratory diagnosis typically begins with broad screening tests to circumscribe specialised metabolite and/or enzyme assays to identify the specific IEM. Confirmation of the biochemical diagnosis is usually achieved by identifying pathogenic genetic variants that will also enable cascade testing for family members. Unsurprisingly, this diagnostic trajectory is too often a protracted and lengthy process resulting in delays in diagnosis and, importantly, therapeutic intervention for these rare conditions is also postponed. Implementation of mass spectrometry technologies coupled with the expanding field of metabolomics is changing the landscape of diagnosing IEM as numerous metabolites, as well as enzymes, can now be measured collectively on a single mass spectrometry-based platform. As the biochemical consequences of impaired metabolism continue to be elucidated, the measurement of secondary metabolites common across groups of IEM will facilitate algorithms to further increase the efficiency of diagnosis.

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“…The BCKDHB gene may be a major variant type of MSUD in the Chinese population. Four of these were novel variants, one located in BCKDHA gene p. while the patient who had the same mutation showed classic phenotype in a previous report 29 .…”

Section: Gly→arg Ser→pro Lys→thrmentioning

confidence: 75%

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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Maple syrup urine disease mutation spectrum in a cohort of 40 consanguineous patients and insilico analysis of novel mutations

Cited by 13 publications

References 37 publications

Genotype–phenotype correlation of 33 patients with maple syrup urine disease

Genotype–phenotype correlation of 33 patients with maple syrup urine disease

Metabolomics to Improve the Diagnostic Efficiency of Inborn Errors of Metabolism

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

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