A recurrent de novo CTBP1 mutation is associated with developmental delay, hypotonia, ataxia, and tooth enamel defects

Abstract

Exome sequencing is an effective way to identify genetic causes of etiologically heterogeneous conditions such as developmental delay and intellectual disabilities. Using exome sequencing, we have identified four patients with similar phenotypes of developmental delay, intellectual disability, failure to thrive, hypotonia, ataxia, and tooth enamel defects who all have the same de novo R331W missense variant in C-terminal binding protein 1 (CTBP1). CTBP1 is a transcriptional regulator critical for development by coordinating different regulatory pathways. The R331W variant found in these patients is within the C-terminal portion of the PLDLS (Pro-Leu-Asp-Leu-Ser) binding cleft, which is the domain through which CTBP1, interacts with chromatin-modifying enzymes and mediates chromatin-dependent gene repression pathways. This is the first report of mutations within CTBP1 in association with any human disease.

De novo CTBP1 variant is associated with decreased mitochondrial respiratory chain activities

“…Inspection of rare and novel heterozygous variants that were predicted to be damaging to protein function revealed a c.991C>T p.(Arg331Trp) missense change in CTBP1 (NM_001012614.1). Following the report of 4 patients sharing the identical heterozygous CTBP1 variant that arose de novo in each case, 8 Sanger sequencing with extracted blood DNA from our patient and her parents confirmed that the c.991C>T p.(Arg331Trp) variant had arisen de novo or 1 parent was low level mosaic ( figure, B ). The c.991C>T p.(Arg331Trp) variant was absent from our in-house exomes and external databases, affected a highly conserved residue, and was predicted to be deleterious by PolyPhen-2, SIFT, and Align GVGD ( figure, C ).…”

“…All 4 previously reported patients presented with comparable phenotypes of hypotonia, ataxia, severe developmental delay, intellectual disability, and problems with weight gain. 8 Similarly, our patient had generally low muscle tone, developmental regression, severe intellectual disability, and was nonambulatory. Cerebellar atrophy was also noted in our patient and 2 reported patients.…”

“…The original description of 4 patients with a recurrent de novo CTBP1 variant did not report respiratory chain defects in skeletal muscle, although one patient was investigated for “pathogenic mitochondrial mutations”. 8 As yet, it is unclear whether mitochondrial dysfunction contributes to the pathogenesis of this disorder or is a secondary consequence. Therefore, future studies of mitochondrial function and morphology in tissue from affected patients could provide further insights into the pathologic mechanisms involved.…”

“…Using WES, we identified a recurrent pathogenic de novo heterozygous CTBP1 variant previously associated with an early-onset neurologic disorder. 8 We highlight the challenges of variant prioritization in a patient who was initially suspected to have an autosomal recessive mitochondrial disorder.…”

Whole-exome sequencing on deceased fetuses with ultrasound anomalies: expanding our knowledge of genetic disease during fetal development

“…6,7 Additionally, WES has enabled the discovery of many new genotype-phenotype associations; for example, pathogenic variants in the TKT gene are found in individuals with short stature, developmental delay, and congenital heart defects; and pathogenic variants in the CTBP1 gene have been shown to cause developmental delay, hypotonia, ataxia, and tooth enamel defects. 8,9 Using WES in pediatric and adult populations, we previously demonstrated in a large clinical series an overall diagnostic yield of 28.8% with a range of 24% for singleton cases to 31% for trio-based analysis, which is comparable to other laboratories reporting yields of 22 to 26%. [10][11][12][13] Fetal specimens submitted for exome sequencing to investigate ultrasound anomalies comprise a unique phenotypic cohort.…”