DeCure for Intellectual developmental disorder, autosomal dominant 69

Three unrelated consanguineous families with biallelic homozygous variants in NSUN6 were identified in a 2023 study. Two variants were predicted loss-of-function; one mapped to the first exon and was expected to cause absence of NSUN6 via nonsense-mediated decay, the other mapped to the last exon and encoded a protein that did not fold correctly. A missense variant in the third family lost enzymatic activity and could not bind the methyl donor S-adenosyl-L-methionine. Affected individuals had developmental delay, intellectual disability, motor delay, and behavioural anomalies. Homozygous ablation of the NSUN6 ortholog in Drosophila caused locomotion and learning impairment. The authors concluded that biallelic pathogenic variants in NSUN6 cause one form of autosomal recessive intellectual disability.

A 2021 report described a patient with intellectual disability who carried a heterozygous nonsense c.40C>T (p.Arg14X) variant of the TRIP12 gene, which was de novo in origin and unrecorded in the Human Gene Mutation Database. The variant was predicted pathogenic under ACMG standards (PVS1+PS2+PP3). The patient was diagnosed with autosomal dominant intellectual disability due to this TRIP12 variant.

A 2025 study of a Pakistani family with consanguineous parents and a history of intellectual disability identified a homozygous c.1693T>C;p.(Tyr565His) variant in SLC6A17 by whole exome sequencing. The variant segregated with the phenotype in the extended family. The condition, mental retardation autosomal recessive 48 (MRT48), is a recessive syndromic disorder characterised by progressive tremors, speech impairment, and behavioural problems. The study broadened the genotypic spectrum of SLC6A17 variants.

A 2025 report described a female proband with a CHD8 variant of uncertain significance whose clinical presentation was consistent with intellectual developmental disorder with autism and macrocephaly (IDDAM) but included atypical features such as ptosis and hearing loss. Genome sequencing confirmed the variant was inherited from her father, who exhibited subtle features including traits consistent with attention-deficit/hyperactivity disorder. Pathogenicity was confirmed through EpiSign DNA methylation analysis, which demonstrated characteristic methylation patterns, and structural biology analysis predicting significant protein destabilisation. The authors emphasised the importance of considering parental inheritance in IDDAM diagnoses and suggested epigenetic and structural biology analyses as tools for reclassifying variants of uncertain significance. No drug treatment was tested or proposed in any of these abstracts. What remains missing for these genetic forms of intellectual disability is any clinical trial, any repurposing candidate, any preclinical drug testing, and any patient stratification beyond the molecular diagnosis itself.