A high frequency and geographical distribution of MMACHC R132* mutation in children with cobalamin C defect

Kaur, Rajdeep; Attri, Savita Verma; Saini, Arushi Gahlot; Sankhyan, Naveen

doi:10.1007/s00726-021-02942-8

Cited by 8 publications

(3 citation statements)

References 44 publications

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“…The CGA (Arg) → TGA transitions are considered to be the most frequent nonsense mutations in the genome followed by CAG(Gln) → TAG transitions 29 . Therefore, GC rich regions have preponderance for hypermutability as described previously in model organisms 30 and various other diseases 31 , 32 . CpG-rich loci have been associated with germline single nucleotide variations 33 – 35 .…”

Section: Discussionmentioning

confidence: 56%

Unusual clinical manifestations and predominant stopgain ATM gene variants in a single centre cohort of ataxia telangiectasia from North India

Rawat

Tyagi

Chaudhary

et al. 2022

Sci Rep

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Germline ATM gene variations result in phenotypic heterogeneity characterized by a variable degree of disease severity. We retrospectively collected clinical, genetic, and immunological data of 26 cases with A-T. Clinical manifestations included oculocutaneous telangiectasia (100%), ataxia (100%), fever, loose stools or infection (67%), cerebellar atrophy (50%), nystagmus (8%), dysarthria (15.38%), and visual impairment (8%). Genetic analysis confirmed ATM gene variations in 16 unrelated cases. The most common type of variation was stopgain variants (56%). Immunoglobulin profile indicated reduced IgA, IgG, and IgM in 94%, 50%, and 20% cases, respectively. T cell lymphopenia was observed in 80% of cases among those investigated. Unusual presentations included an EBV-associated smooth muscle tumour located in the liver in one case and Hyper IgM syndrome-like presentation in two cases. Increased immunosenescence was observed in T-cell subsets (CD4+CD57+ and CD8+CD57+). T-cell receptor excision circles (TRECs) were reduced in 3/8 (37.50%) cases.

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Section: Discussionmentioning

confidence: 56%

Unusual clinical manifestations and predominant stopgain ATM gene variants in a single centre cohort of ataxia telangiectasia from North India

Rawat

Tyagi

Chaudhary

et al. 2022

Sci Rep

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“…Moreover, the application of the cSMART assay could be expanded to genetic disorders with a high incidence, thus helping with disease prevention and treatment, especially for metabolic diseases with serious consequences. Besides, from cblC type MMA, there are many genetic disorders with a high incidence and hotspot mutations in specific population, such as c.1006C > T mutation in CBS gene mutation of homocystinuria in Qatar (El-Said et al, 2006;Al-Dewik et al, 2019), and c.394C > T mutation in MMACHC gene cobalamin C defect in North India (Kaur et al, 2021). Recently, a prenatal multigene screening assay called PreSeek covering more than 30 genes has been applied in clinical service (Zhang et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Noninvasive Prenatal Testing of Methylmalonic Acidemia cblC Type Using the cSMART Assay for MMACHC Gene Mutations

Liang

Chen

et al. 2022

Front. Genet.

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Noninvasive prenatal testing (NIPT) for monogenic disorders has been developed in recent years; however, there are still significant technical and analytical challenges for clinical use. The clinical feasibility of NIPT for methylmalonic acidemia cblC type (cblC type MMA) was investigated using our circulating single-molecule amplification and re-sequencing technology (cSMART). Trios molecular diagnosis was performed in 29 cblC type MMA-affected children and their parents by traditional Sanger sequencing. In the second pregnancy, invasive prenatal diagnosis (IPD) of the pathogenic MMACHC gene was used to determine fetal genotypes, and NIPT was performed using a novel MMACHC gene–specific cSMART assay. Maternal–fetal genotypes were deduced based on the mutation ratio in maternal plasma DNA. Concordance of fetal genotypes between IPD and NIPT, and the sensitivity and specificity of NIPT were determined. After removing two cases with a low P value or reads, the concordance ratio for NIPT and IPD was 100.00% (27/27), and the sensitivity and specificity were 100.00% (54.07–100.00%) and 100.00% (83.89–100.00%), respectively. This study demonstrates that NIPT using the cSMART assay for cblC type MMA was accurate in detecting fetal genotypes. cSMART has a potential clinical application as a prenatal diagnosis and screening tool for carrier and low-risk genotypes of cblC type MMA and other monogenic diseases.

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“…Different substances such as chloramphenicol and gentamicin were investigated in cellular models of lysosomal storage diseases and methylmalonic aciduria but their use has not yet been extended to cblC disease ( Buck et al., 2009 ; Quoos Mayer et al., 2013 ). Mutations c.609G > A (p.W203Ter) and c.394C > T (p.Arg132Ter) with high prevalence in Chinese and Indian-Pakistani populations, respectively, cause stop codons within exon 4 and could be targets for stop codon readthrough approaches ( Kaur et al., 2021 ; Wang et al., 2019 ). Enzyme replacement therapy is not available for disorders of intracellular cobalamin metabolism so far.…”

Section: Clinical Overviewmentioning

confidence: 99%

Versatile enzymology and heterogeneous phenotypes in cobalamin complementation type C disease

et al. 2022

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A high frequency and geographical distribution of MMACHC R132* mutation in children with cobalamin C defect

Cited by 8 publications

References 44 publications

Unusual clinical manifestations and predominant stopgain ATM gene variants in a single centre cohort of ataxia telangiectasia from North India

Unusual clinical manifestations and predominant stopgain ATM gene variants in a single centre cohort of ataxia telangiectasia from North India

Noninvasive Prenatal Testing of Methylmalonic Acidemia cblC Type Using the cSMART Assay for MMACHC Gene Mutations

Versatile enzymology and heterogeneous phenotypes in cobalamin complementation type C disease

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