Delineating the CTBP1-Related Phenotypic Spectrum: A Review of HADDTS and Atypical Variants

Abstract

Hypotonia, Ataxia, Developmental Delay, and Tooth Enamel Defect Syndrome (HADDTS; OMIM #617915) is an ultra-rare autosomal dominant disorder caused by predominantly de novo pathogenic variants in CTBP1, encoding a NAD(H)-dependent transcriptional corepressor. We reviewed all HADDTS cases reported from database inception to July 2026, searching PubMed/MEDLINE, Google Scholar, ClinVar, DECIPHER, OMIM, preprint servers, and the HADDTS Foundation, identifying 25 peer-reviewed cases from at least 11 countries; registries indicate at least 50 known individuals. Global developmental delay and language impairment were universal (25/25, 100%), followed by intellectual disability (24/25, 96%), hypotonia (22/25, 88%), ataxia and enamel defects (19/25, 76% each), cerebellar atrophy (18/25, 72%), feeding difficulties (15/25, 60%), myopathy (15/25, 60%), regression (10/25, 40%), oculomotor apraxia (7/25, 28%), scoliosis (6/25, 24%), respiratory chain dysfunction (5/25, 20%), skeletal anomalies (4/25, 16%), and seizures (2/25, 8%). The recurrent p.Arg342Trp (NM_001328.2; p.Arg331Trp, MANE Select NM_001012614.2) accounts for 84%, with severity from mild impairment to profound disability. In all four non-recurrent-variant carriers the canonical tetrad was incomplete; seizures and classifying skeletal anomalies occurred only in that group. Mutant CTBP1 acts dominant-negatively and heterodimerises with the essential paralog CTBP2, explaining the multisystem severity. HADDTS is a neurodevelopmental-mitochondrial overlap disorder; registries, mitochondrial evaluation, and allele-specific therapies are priorities.