Type of mutations
Heterozygous pathogenic variants occur frequently de novo in the CLTC gene. The spectrum of pathogenic CLTC variants include nonsense, frameshift, missense, and splice site variants and in-frame deletions. Almost all CLTC variants described to date are private and are dispersed throughout the gene.
Pathogenic variants are detected by sequencing analysis of the CLTC gene.
Possible molecular diagnostic approaches to confirm the diagnosis in a proband include:
- Performing a multi-gene panel, which includes CLTC, if the clinical diagnosis of autosomal dominant mental retardation-56 is considered;
- or performing exome sequencing, if multiple differential diagnosis exist.
Parents’ clinical evaluation and targeted genetic testing of the identified variant in the CLTC gene is recommended to verify if the pathogenic variant identified in the proband was inherited or occurred de novo.
Suspected pathophysiologic mechanism
An individual’s phenotype seems to be partially associated with the type of variant in the CLTC gene.
Missense and other in-frame variants, possibly resulting in a dominant-negative effect, seem to be more often associated with a more severe phenotype, including severe ID, microcephaly, hypoplasia of the corpus callosum, and epilepsy. Truncating variants, such as nonsense and frameshift variants, likely resulting in a loss-of-function effect, seem to be more frequently associated with a milder phenotype (mild intellectual disability). Nevertheless, there were exceptions and other additional genetic and nongenetic factors may eventually further explain the variability in the severity of the phenotype observed in these two groups of individuals. The characterization of a larger cohort of individuals with pathogenic CLTC variants will be needed to further prove this hypothesis.