Glossary

The proportion of DNA reads (or cells) in a sample that carry a particular variant. A mosaic variant typically shows an allele fraction below about 50%, reflecting that only some cells carry the change.

The cellular process by which clathrin-coated vesicles carry molecules from the cell surface into the cell's interior. In neurons, this pathway is essential for recycling synaptic vesicle membrane and neurotransmitter receptors after each nerve impulse. CLTC variants disrupt this recycling process, impairing synaptic function in the developing brain.

The US National Institutes of Health's public database of reported relationships between human genetic variants and health conditions. Clinical laboratories submit variant classifications (pathogenic, likely pathogenic, VUS, benign, etc.) to ClinVar as part of standard diagnostic reporting.

A genetic change that appeared for the first time in the affected individual — it was not inherited from either parent. The vast majority of CLTC-ID cases are de novo.

An effect where a faulty protein actively interferes with the function of the normal protein made from the other gene copy. In CLTC missense variants, the misshapen clathrin can join normal clathrin triskelions and disrupt the whole delivery network.

An insertion or deletion of a number of DNA letters that is not a multiple of three, shifting the downstream reading frame. This typically creates an abnormal amino acid sequence ending in a premature stop codon — effectively a truncating variant.

The Genome Aggregation Database — a large public resource aggregating exome and genome sequencing data from over 140,000 individuals. gnomAD is used to assess how constrained a gene is (intolerant to loss-of-function variants) and whether a variant has been observed in the general population.

A condition where one working copy of a gene is not enough to maintain normal function. In CLTC-ID, loss-of-function variants leave cells with roughly half the normal amount of working clathrin heavy chain.

Describing a gene or variant where one working copy is not sufficient for normal function. Loss-of-function CLTC variants (splice-site, frameshift, nonsense) leave the cell haploinsufficient for clathrin heavy chain.

Having two different versions of a gene — in CLTC-ID, one copy carries the variant and the other copy is typical. Most CLTC-ID individuals are heterozygous.

A variant classified as probably disease-causing based on current evidence, but where the evidence does not yet meet the higher certainty bar for a full 'pathogenic' designation. Likely pathogenic and pathogenic variants are both considered clinically actionable under ACMG/AMP guidelines.

A gnomAD constraint metric quantifying how far below the expected number of loss-of-function variants a gene falls in the general population. CLTC has a LOEUF of 0.12 — placing it among the most constrained genes in the genome — indicating extreme intolerance to loss-of-function variants.

Shorthand for loss-of-function — a class of variant that reduces or eliminates a gene's protein output. In CLTC, LoF variants (splice-site, frameshift, nonsense) cause haploinsufficiency: the affected gene copy makes little or no working clathrin heavy chain.

A class of variant that reduces or eliminates a gene's protein output. In CLTC, splice-site, frameshift, and nonsense variants are all loss-of-function changes — the affected gene copy makes little or no working clathrin heavy chain.

A single DNA letter change that swaps one protein building block (amino acid) for a different one. The protein still gets built end-to-end but may be misshapen and, in CLTC, can exert a dominant-negative effect on the normal protein.

A variant present in only some of the body's cells, not all of them. This happens when the change occurs after the egg is fertilised. Mosaic cases often have a milder presentation than non-mosaic cases.

A genetic change classified as disease-causing based on established evidence criteria (ACMG/AMP guidelines), including population frequency, computational predictions, functional data, and clinical case evidence. A 'pathogenic' classification indicates the variant is sufficient to explain the health condition associated with the gene.

The proportion of individuals who carry a pathogenic variant and go on to develop the associated condition. CLTC loss-of-function variants appear to have high penetrance for intellectual disability and developmental delay, though the full phenotypic spectrum is still being characterised.

A gnomAD constraint score from 0 to 1 measuring how intolerant a gene is to loss-of-function variants. A pLI of 1.00 — as observed for CLTC — indicates the most extreme constraint category: no loss-of-function variants are seen in the general population, reflecting that even a single non-functional copy is strongly selected against.

The precise join points in a gene where non-coding sections are cut out and coding sections are joined together during RNA processing. A variant at a splice site can cause exons to be skipped or extra sequence to be included, usually disrupting the protein.

A variant at the precise junction in a gene where non-coding intron sequences are removed and coding exon sequences are joined during RNA processing. Splice-site variants can cause exon skipping or intron retention, typically disrupting the protein. In CLTC, splice-site variants are loss-of-function changes that cause haploinsufficiency.

Genetic testing performed on a child and both parents together. This allows the lab to determine whether a variant is de novo (new in the child) or inherited, which affects the recurrence risk for future pregnancies.

Any variant that prematurely terminates protein production — including nonsense variants (premature stop codons), frameshift variants (insertions or deletions), and certain splice-site changes. Truncating CLTC variants typically cause haploinsufficiency by preventing the affected gene copy from making a functional protein.

A grouping of genetic variants by their molecular mechanism — for example, loss-of-function (including frameshift, nonsense, and splice-site) versus missense versus structural. Variant class is a key determinant of pathomechanism and often predicts genotype-phenotype correlations, as seen in CLTC-ID where missense variants tend to cause more severe epilepsy than truncating variants.

A variant whose relationship to disease has not been established with sufficient evidence to classify it as pathogenic or benign. VUS classifications are provisional — additional functional data, case reports, or co-segregation evidence can reclassify them over time.