Haploinsufficiency of NKX2-1 is likely to contribute to developmental delay involving 14q13 microdeletions

Chromosome 14

Chromosome 14 ideogram

The gene NKX2-1, located at the segment q13 of chromosome 14 is highly expressed in the thyroid, lungs, and pituitary glands. Previous literature has shown that pathogenic variants and heterozygous deletions of NKX2-1 are associated with a complex phenotype involving choreoathetosis, respiratory problems, and hypothyroidism—a triad of symptoms called brain-lung-thyroid syndrome (BLTS). Patients with BLTS also have mildly delayed acquisition of motor milestones and delayed growth. In the authors’ literature review, they concluded that the comorbidity rate of developmental delay does not change significantly depending on whether a patient had a microdeletion involving NKX2-1 or a nucleotide variant of NKX2-1. Machida et al. identify 7 novel patients with 5 different 14q13 microdeletions ranging from 2.6 Mb to 5.2 Mb (all including the gene NKX2-1), and hope to elucidate how the haploinsufficiency of NKX2-1 contributes to the overall phenotype. Clinical manifestations included short stature (6/7), neonatal respiratory distress (5/7), hypothyroidism (5/7), and involuntary movements including ataxia (4/7). Isolated other findings included pulmonary artery bifurcation stenosis, anodontia and distinctive facial findings. The classic triad of BLTS was not always present in the current study, with only 50% of patients with deletions involving NKX2-1 developing BLTS, but almost all patients in the study showed mild-to-severe developmental delay (one patient had border developmental delay). The authors then hypothesize that the developmental delay seen may be attributed to other genes in the deleted genomic region. The authors highlight that there are neighboring genes to NKX2-1 with a higher expectation to be haploinsufficient. Of these genes, the most highly expressed gene in the brain, is RALGAPA1, which is previously considered to be related to developmental delay and epilepsy. However, literature showed that the RALGAPA1  gene is causing pathology only when both copies of the gene are damaged, but heterozygotes with a single loss-of-function variant show no symptoms. Thus, haploinsufficiency of RALGAPA1 is not likely to be related to the clinical symptoms observed in patients with 14q13 microdeletions, allowing for the authors to conclude that NKX2-1 haploinsufficiency is the most likely explanation for the developmental delay seen in patients.

“Intractable & Rare Diseases Research” 2024, v.13(1):36-41.






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