Silico analysis of a novel mutation c.550delT in a Chinese patient with maple syrup urine disease

Li, Wenjie; Meng, Xianze; Wang, Weiqing; Lv, Jinfeng; Sun, Yingmei; Lv, Yanan; Wang, Caijuan; Wang, Hongqin; Wang, Mei; Song, Dongpo

doi:10.1002/ccr3.1774

Cited by 4 publications

(4 citation statements)

References 23 publications

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“…To date, more than 470 mutations associated with MSUD have been reported in Clinvar. There are approximately 38% of mutations occurring in the BCKDHB gene (Wenjie et al., 2018; Nellis & Danner, 2001; Theodoros et al., 2009) which has been described as the major gene causing MSUD, followed by BCKDHA gene and DBT gene (Peter et al., 2017). Although inheritance of MSUD adheres to a simple autosomal recessive pattern, mutations in each of the three BCKDH specific have been shown to cause MSUD (Nellis & Danner, 2001).…”

Section: Discussionmentioning

confidence: 99%

Identification of novel mutations in BCKDHB and DBT genes in Vietnamese patients with maple sirup urine disease

Nguyen

Nguyễn

et al. 2020

Molec Gen & Gen Med

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Background Maple sirup urine disease (MSUD) is an autosomal recessive inherited metabolic disorder. The disease‐causing mutations can affect the BCKDHA , BCKDHB , and DBT genes encoding for the E1α, E1β, and E2 subunits of the multienzyme branched‐chain α‐keto acid dehydrogenase (BCKDH) complex. In the present study, novel pathogenic variants in BCKDHB and DBT genes were identified in three Vietnamese families with MSUD. Methods Three newborn patients from three unrelated Vietnamese families were diagnosed with MSUD at the Metabolic Clinic, National Hospital of Pediatrics. Blood samples of 11 relatives from two generations of the three families diagnosed with MSUD were analyzed using exome and Sanger sequencing analyses. Results Novel pathogenic variants in BCKDHB (c.1103C>T, c.989A>G, and c.704G>A), and DBT (c.263_265delAAG) genes were identified in three pediatric patients with MSUD. Conclusions We have identified novel pathogenic variants in the MSUD‐related genes in the pedigree of the three patient's families. Our findings expand the mutational spectrum of MSUD and provide the scientific basis for genetic counseling for the patient's families.

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Section: Discussionmentioning

confidence: 99%

Identification of novel mutations in BCKDHB and DBT genes in Vietnamese patients with maple sirup urine disease

Nguyen

Nguyễn

et al. 2020

Molec Gen & Gen Med

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“…The BCKDHB gene c.538G > C was a common mutation found in Ashkenazi Jews 16 , and exon 5 of the BCKDHB gene may be a region of genetic variation and a hotspot region 17,18 . 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] .…”

Section: Gly→arg Ser→pro Lys→thrmentioning

confidence: 99%

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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“…The deficiency of BCKD causes the corresponding branched‐chain keto acids (BCKAs) formed by branched‐chain amino acid (BCAA) transaminase to be unable to oxidize dicarboxylic acid, resulting in the accumulation of BCAAs (including leucine, isoleucine, and valine), and BCKAs 2 . BCKD comprises three catalytic components: a branched‐chain α‐keto acid decarboxylase (E1) formed by two E1α and two E1β subunits, a dihydrolipoyl transacylase (E2), and a dihydrolipoamide dehydrogenase (E3), encoded by BCKDHA , BCKDHB , DBT , and DLD , respectively 3,4 . Based on clinical presentation onset age and residual BCKD complex activity, MSUD can be divided into four forms: classic, intermediate, intermittent, and thiamine responsive 5,6 .…”

Section: Introductionmentioning

confidence: 99%

“… 2 BCKD comprises three catalytic components: a branched‐chain α‐keto acid decarboxylase (E1) formed by two E1α and two E1β subunits, a dihydrolipoyl transacylase (E2), and a dihydrolipoamide dehydrogenase (E3), encoded by BCKDHA , BCKDHB , DBT , and DLD , respectively. 3 , 4 Based on clinical presentation onset age and residual BCKD complex activity, MSUD can be divided into four forms: classic, intermediate, intermittent, and thiamine responsive. 5 , 6 Patients with the classic phenotype of MSUD have <3% residual BCKD complex activity and a clinical onset typically in the first weeks of life.…”

Section: Introductionmentioning

confidence: 99%

Maple syrup urine disease due to a paracentric inversion of chr 19 that disrupts BCKDHA: A case report

et al. 2022

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Maple syrup urine disease (MSUD) is a rare autosomal recessive inherited disorder of branched‐chain amino acid metabolism caused by mutations in BCKDHA, BCKDHB, and DBT that encode the E1α, E1β, and E2 subunits of the branched‐chain α‐ketoacid dehydrogenase (BCKD) complex. Various MSUD‐causing variants have been described; however, no structural rearrangements in BCKDHA have been reported to cause the classic MSUD phenotype. Here, we describe the classic patient with MSUD with compound heterozygous pathogenic variants in BCKDHA: a missense variant (NM_000709.3:c.757G > A, NP_000700.1:p.Ala253Thr) and a paracentric inversion disrupting Intron 1 of BCKDHA, which was identified by whole‐genome sequencing and validated by fluorescence in situ hybridization. Using the sequence information of the breakpoint junction, we gained mechanistic insight into the development of this structural rearrangement. Furthermore, the establishment of junction‐specific polymerase chain reaction could facilitate identification of the variant in case carrier or future prenatal/preimplantation tests are necessary.

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Silico analysis of a novel mutation c.550delT in a Chinese patient with maple syrup urine disease

Cited by 4 publications

References 23 publications

Identification of novel mutations in BCKDHB and DBT genes in Vietnamese patients with maple sirup urine disease

Identification of novel mutations in BCKDHB and DBT genes in Vietnamese patients with maple sirup urine disease

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

Maple syrup urine disease due to a paracentric inversion of chr 19 that disrupts BCKDHA: A case report

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