NKX2-1 Downstream Regulatory Structural Variants Explain a Substantial Proportion of Molecular Diagnoses in Patients With Benign Hereditary Chorea.

Regulatory structural variants downstream of NKX2-1 (deletions, complex rearrangements) reducing expression without disrupting the coding sequence; region with regulatory activity (open chromatin, H3K27ac).

Assessment of the spectrum and frequency of regulatory variants in NKX2-1-related disorders. Eight families (13 affected individuals) carried structural variants downstream of NKX2-1 without coding-sequence disruption: five deletions and three complex rearrangements. Neurological manifestations (chorea, myoclonus, ataxia) were universal, whereas the full triad appeared only with complex rearrangements. The shared deleted region showed open chromatin and H3K27ac peaks in fetal brain, lung and thyroid. These regulatory variants accounted for 27 % of NKX2-1-related diagnoses.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

A concrete reminder that missing diagnoses often hide outside the coding sequence: here, 27 % of NKX2-1-related cases are due to downstream regulatory SVs. The practical consequence is clear — include this regulatory region and systematic SV detection when coding variants are excluded. Consistent with the shift toward genome sequencing, where such regions become interpretable.

Analysis by Dr Thibaut Benquey