Intellectual Disability via the TECR Gene

Intellectual Disability (ID) is a heterogeneous group of neurodevelopmental disorders, characterized by congenital limitation in intellectual functioning (intelligence quotient, IQ ≤70), and adaptive behavior. It is diagnosed in ~1–3% of the population before 18 years of age (American Association of Intellectual and Developmental Disabilities, AAIDD). Nonsyndromic ID is defined by the presence of intellectual disability as the sole clinical feature; however, often times the distinction between syndromic and nonsyndromic ID remains difficult due to the subtle signs of syndromic ID (Kaufman et al. 2010. PubMed ID: 21124998).

Deficiency of synaptic glycoprotein TECR impairs the synthesis of very long chain fatty acids, leading to a form of nonsyndromic ID, known as mental retardation 14 (MRT14). The clinical features of MRT14 may include (but may not limited to) developmental delay, speech and language delay, poor fine motor skills (intention tremor), minimal reading and writing skills, and narrow palate (Çalışkan et al. 2011. PubMed ID: 21212097).

MRT14 is an autosomal recessive disorder, caused by pathogenic variants in human trans-2,3-enoyl-CoA reductase gene (TECR). TECR maps to chromosome 19p13.12 and consists of 13 coding exons that translate a 308 amino acid polypeptide of TECR, a membrane protein with 6 transmembrane-domains, 3 luminal loops, and cytosolic N and C termini. TECR reduces trans-2,3-enoyl-CoA to saturated acyl-CoA, the final step of very long chain fatty acid synthesis; however, the protein may have additional function in the nervous system. To date, only one pathogenic missense variant has been reported. Using biochemical assays, Abe et al. has demonstrated that this variant affects optimal enzymatic activity, protein stability and thus impairs the synthesis of very long chain fatty acids, in turn, altering the sphingolipid profile (Abe et al. 2013. PubMed ID: 24220030).

This test is predicted to detect pathogenic variants in <0.1% of individuals with intellectual disability (ID). In this context, it is important to note that although pathological variants over 800 genes have been identified in individuals with ID, a genetic diagnosis is still lacking in most cases due to extreme clinical and genetic heterogeneity of the condition (Vissers et al. 2016. PubMed ID: 26503795). Analytical sensitivity should be high because all pathogenic variants reported within this gene to date are detectable by sequencing.

To date, no gross deletion/duplication involving TECR has been reported. We expect the clinical sensitivity of this test to be <0.1% of ID cases.

This test provides full coverage of all coding exons of the TECR gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).