Exome sequencing identified a de novo frameshift pathogenic variant of CTBP1 in an extremely rare case of HADDTS

Khamirani, Hossein Jafari; Zoghi, Sina; Sichani, Ali Saber; Dianatpour, Mehdi; Mohammadi, Sanaz; Tabei, Seyed Mohammad Bagher; Dastgheib, Seyed Alireza

doi:10.1007/s12041-021-01315-0

Cited by 6 publications

(10 citation statements)

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“… 3 Since then, a further 11 individuals have been reported in the literature with the same variant in CTBP1 , and one individual with a de novo frameshift pathogenic variant in CTBP1 (c.1315_1316delCA, p.Gln439ValfsTer84) with similar phenotypes (Table 2 ). 1 , 4 , 5 , 6 , 7 Of note, only one individual had a muscle biopsy demonstrating decreased mitochondrial respiratory enzymes activities in complex I and IV with additional patchy loss of COX activity and clumped SDH reactivity. 7 A further case reported persistently elevated serum lactate levels with muscle biopsy demonstrating features of muscular dystrophy but respiratory chain enzyme analysis was not reported.…”

Section: Discussionmentioning

confidence: 99%

“…CTBP1 is ubiquitously expressed in all tissues in vertebrates and plays critical roles in gene regulation during human development, with its importance for neurodevelopment being mediated via regulation of genes involved in neuron survival, growth, membrane excitability, synaptic transmission and plasticity 2 . Pathogenic variants in the CTBP1 gene have been previously reported to cause an early onset neurodevelopmental phenotype with associated decreased mitochondrial respiratory chain activities in a single case report 1,3–8 …”

Section: Introductionmentioning

confidence: 99%

“…2 Pathogenic variants in the CTBP1 gene have been previously reported to cause an early onset neurodevelopmental phenotype with associated decreased mitochondrial respiratory chain activities in a single case report. 1,[3][4][5][6][7][8] A variety of neurodevelopmental abnormalities are common manifestations of mitochondrial disorders and an increasing number of well-known genes associated with neurodevelopmental disorders show evidence of impaired mitochondrial function. [9][10][11] We present the second reported case of mitochondrial dysfunction in a 6-year-old girl with previously reported pathogenic heterozygous de novo missense variant in the CTBP1 gene.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mitochondrial respiratory chain dysfunction in a patient with a heterozygous de novo CTBP1 variant

et al. 2022

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The C‐terminal binding protein 1 (CTBP1) functions as a transcriptional corepressor in vertebrates and has been identified to have critical roles in nervous system growth and development. Pathogenic variants in the CTBP1 gene has been shown to cause hypotonia, ataxia, developmental delay and tooth enamel defect syndrome (HADDTS). There have only been 16 cases reported to date with heterozygous, pathogenic variants in CTBP1 manifesting with a neurodevelopmental phenotype. We report a further case of a pathogenic, heterozygous, de novo variant in CTBP1 identified by whole exome sequencing in a female with the typical phenotype of global developmental delay, hypotonia, cerebellar dysfunction and failure to thrive. Additionally, muscle biopsy demonstrates evidence of a respiratory chain defect, only previously reported once in the literature. This supports the role of CTBP1 in maintenance of normal mitochondrial activity and highlights the importance of considering secondary mitochondrial dysfunction in genes not directly involved in the mitochondrial respiratory chain.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mitochondrial respiratory chain dysfunction in a patient with a heterozygous de novo CTBP1 variant

et al. 2022

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“…We identify three case reports [11,13,14] and two case series reports [10,12]. All five studies identified variants by wholeexome sequencing (WES).…”

Section: Methodsmentioning

confidence: 99%

CTBP1 and CTBP2 mutations underpinning neurological disorders: a systematic review

et al. 2022

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C-terminal binding proteins (CtBP1/2) are transcriptional coregulators that play a significant role during vertebrate neurodevelopment. This systematic review aims to identify case reports with genetic variants in CTBP1 and CTBP2 associated with brain development syndromes.We screened different databases (PubMed, Scopus, Google Scholar, LILACS) by systematically searching journals and checking reference lists and citations of background papers. We found fourteen cases (10 males) from five papers carrying two pathogenic, heterozygous variants in the CTBP1 gene (13 individuals carried the missense mutation c.991C T, p.Arg342Trp, and one subject carrying the 2-base pair deletion c.1315_1316delCA, p.Gln439ValfsTer84). These mutations were de novo in 13 cases and one case of maternal germinal mosaicism. Two variants are in the same domain of the protein: Pro-Leu-Asp-Leu-Ser (PLDLS) C terminal. Patients with these mutations exhibit a phenotype with intellectual disability, HADDTS syndrome (hypotonia, ataxia, developmental delay, and tooth enamel defects), and cerebellar volume loss. We did not identify reported cases associated with homozygous mutations harbored in CTBP1. We did not identify any report of neurodevelopment phenotypes associated with heterozygous or homozygous CTBP2 mutations. Due to CTBP2/RIBEYE being a gene with dual function, identifying and interpreting the potential pathogenic variants is challenging.Further, homozygous mutations in the CTBP2 gene may be lethal. The mechanisms involved in the pathogenesis of neurodevelopment due to variants of these proteins have not yet been elucidated, despite some functional evidence. Further studies should be conducted to understand these transcription factors and their interaction with each other and their partners.

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Spastic paraplegia 51: phenotypic spectrum related to novel homozygous AP4E1 mutation

Manoochehri

Goodarzi

Tabei

2022

J Genet

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Exome sequencing identified a de novo frameshift pathogenic variant of CTBP1 in an extremely rare case of HADDTS

Cited by 6 publications

References 10 publications

Mitochondrial respiratory chain dysfunction in a patient with a heterozygous de novo CTBP1 variant

Mitochondrial respiratory chain dysfunction in a patient with a heterozygous de novo CTBP1 variant

CTBP1 and CTBP2 mutations underpinning neurological disorders: a systematic review

Spastic paraplegia 51: phenotypic spectrum related to novel homozygous AP4E1 mutation

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