Objective:

Describe a previously unreported heterozygous WDR45 missense variant, c.992G>A (p.Gly331Glu), identified during evaluation for suspected neurodegeneration in a patient with brain iron accumulation (NBIA/BPAN), and to define its clinical significance.

Background:

WDR45 encodes a β-propeller/WIPI protein; pathogenic variants cause X-linked dominant beta-propeller protein–associated neurodegeneration (BPAN), characterized by abnormal brain iron accumulation (NBIA) and progressive neurodegeneration. This c.992G>A WDR45 variant replaces a neutral, non-polar glycine with an acidic, polar glutamic acid at codon 331.

Design/Methods:

Genetic testing for NBIA was planned. Salivary DNA sample underwent hybridization-based target enrichment and Illumina sequencing. Targeted regions were sequenced at ≥50× depth; readings were aligned to GRCh37. Clinical genomic sequencing of an NBIA-relevant gene panel identified c.992G>A WDR45.

Results:

Case Summary: A 31-year-old female was referred to the neurology clinic with an abnormal brain MRI and history of progressive symptoms of stiffness in neck/back, limb paresthesias, gait instability, tremor, pre-syncope, syncope, autonomic and cognitive changes. She also mentioned nonspecific neurologic symptoms among family members. After evaluating her condition, she was clinically diagnosed with cervical dystonia. MRI imaging revealed hyperintensity on T2 and FLAIR in the Basal Ganglia with associated subtle susceptibilities on GRE consistent with the "eye of the tiger" sign. The clinical history, examination, and imaging were felt to be consistent with a progressive degenerative process, specifically neurodegeneration with brain iron accumulation.

Conclusions:

This may be the first case report of a clinically significant c.992G>A WDR45 variant associated with BPAN. It highlights the limitations of relying solely on genomic findings in suspected BPAN/NBIA cases. This variant is absent in the population databases, which suggests the necessity of combining MRI correlation (iron-sensitive sequences), segregation testing, and functional studies to interpret potential cases of BPAN/NBIA. Systematic reporting may enable future reclassification and support counseling, while avoiding management changes based solely on a Variant of Uncertain Significance.