Temtamy Syndrome via the C12orf57 Gene

Temtamy syndrome is a congenital neurological disorder characterized by intellectual disability and congenital anomalies. Major clinical features include global developmental delay and intellectual disability (100%), absent speech (74.5%), seizures (73.7%), autistic behavior (72.7%), generalized hypotonia (71.9%), facial dysmorphism (66.1%), and abnormal (hypoplasia, agenesis, dysplasia, or thick) corpus callosum (61.8%). Minor features include ocular anomalies (46.4%), delayed speech (37.5%), spasticity (35.1%), atrial septal defect (30.4%), abnormal thalamic size (38.5%), abnormal septum pellucidum (37.3%), abnormal white matter (37.3%), ventriculomegaly (35.3%), and abnormal anterior commissure (21.2%). Less common clinical features include microphthalmia (14.3%), coloboma (14.5%), ventricular septal defect (10.0%), and pulmonic stenosis (11.1%) (Alrakaf et al. 2018. PubMed ID: 29383837; Wang et al. 2020. PubMed ID: 31853307). The clinical features of Temtamy syndrome show considerable variability, even among affected family members (Li et al. 2007. PubMed ID: 17632789; Salih et al. 2013. PubMed ID: 23633300; Platzer et al. 2014. PubMed ID: 24798461).

Temtamy syndrome is extremely rare, with an estimated incidence of less than one in a million individuals worldwide. However, the identification of a founder variant in the causative gene, C12orf57, in 1.5% of patients with intellectual disability in a large Arab cohort indicates it is the most common cause of intellectual disability in Saudi Arabia (Anazi et al. 2017. PubMed ID: 27431290; Monies et al. 2017. PubMed ID: 28600779; Alrakaf et al. 2018. PubMed ID: 29383837).

Advantages of molecular testing for Temtamy syndrome via C12orf57 sequencing include molecular confirmation of diagnosis, differential diagnosis, and reproductive planning.

Temtamy syndrome is an autosomal recessive disorder caused by biallelic pathogenic variants in the C12orf57 gene. The majority of causative variants in C12orf57 are loss of function variants, including start loss, splicing donor/acceptor variants, premature protein termination, and frameshift variants (Alrakaf et al. 2018. PubMed ID: 29383837). As mentioned above, a founder variant, C12orf57 c.1A>G (p.Met1?), has been identified in individuals of Arabic descent. It is the most common reported pathogenic variant in C12orf57 (Salih et al. 2013. PubMed ID: 23633300; Akizu et al. 2013. PubMed ID: 23453666; Zahrani et al. 2013. PubMed ID: 23453665; Alrakaf et al. 2018. PubMed ID: 29383837). In gnomAD, the maximum minor allele frequency for the C12orf57 c.1A>G variant is 0.006% (Genome Aggregation Database).

C12orf57 has been cited as a nonessential gene for growth of human tissue culture cells (Online Gene Essentiality). Very little is known about the function of the protein encoded by C12orf57. Expression of C12orf57 is enriched in adult human lung tissue and human fetal brain (Akizu et al. 2013. PubMed ID: 23453666). It has been suggested that C12orf57 may play a role in eye and brain development based on the features observed in Temtamy syndrome patients (Zahrani et al. 2013. PubMed ID: 23453665).

The clinical sensitivity of this test is difficult to estimate because of the phenotypic overlap with other disorders featuring intellectual disability, brain malformations, and eye malformations. Other disorders with similar clinical features include Peters-Plus syndrome, Muscular Dystrophy-Dystroglycanopathy (also known as Walker-Warburg syndrome and muscle-eye-brain disease), Aicardi-Goutieres syndrome, Donnai-Barrow syndrome, and Baraitser-Winter syndrome.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the C12orf57 gene plus 10 bases flanking noncoding DNA in all available transcripts in addition to 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).