12q21 Interstitial Deletions Review of the Literature

chromosome 12

The segment 12q21 is relatively large (21.2 Mb) but contains only 60 genes. Such low gene density allows the evaluation of the potential role of each gene. Recently a 1.6 Mb critical region (CR) has been determined for rare 12q21 deletions’ most commonly described clinical features. Recalcati et al. reported 7 new patients to 1) analyze this new CR, specifically with candidate genes SYT1 and PPP1R12A, and 2) investigate the effect of genes outside this region. The studied group included 5 females and 2 males (aged from 4 to 16 years). All patients had some neurodevelopmental problems, most have dysmorphic features but as a rule did not have visceral defects (although two had atrial septal defects and one had a horseshoe kidney). CR obtained by the analysis of 12 previously reported patients with 12q21 deletions showed that this region included 4 genes: SYT1, PPP1R12A, PAWR, and OTOGL (with SYT1 and PPP1R12A being the major candidates).

The current clinical data finds SYT1 and PPP1R12A to be responsible for neurodevelopmental and for congenital defects/ dysmorphism seen in 12q21 deletions, respectively. In the group studied by Recalcati et al. patients 1, 2, and 3’s deletions confirm the CR and include these two genes. However the deletion in the patients 4, 5, 6, and 7 did not overlap with the CR region. The authors suggest that other genes such as TMTC2, SLC6A15, CEP290, TMTC3, and NTS may play a role in this neurological phenotype. Patient 4 and 6 also show interatrial defects, which has been presented in earlier literature. However, there is no data available that suggest mutations in this region are associated with cardiac defects. Moreover, Patients 5 and 6 are noted for their facial dysmorphisms and carry NTS and SLC6A15 deletions. Since this is also presented in Akilapa et al., the authors find supporting evidence for NTS and SLC6A15’s role in dysmorphism, such as wide mouth and broad nasal base. Finally, Patient 7 has been diagnosed with hearing loss and possesses a deletion of KITLG, similar to a patient in Kline et al., supporting the causative role of KITLG in the deafness phenotype some 12q21 patients have.

Recalcati et al. “12q21 Interstitial Deletions: Seven New Syndromic Cases Detected by Array-CGH and Review of the Literature”. “Genes”(Basel) 2022, v.13:780.

Chromosome Disorder Outreach Inc. medical geneticist and medical advisor Dr. Iosif Lurie M.D. Ph.D examines newly published research studies to locate the most important and relevant for our members. Synopses of these articles are then posted to our website’s research pages. For more information on any article please contact info@chromodisorder.org