Lessons from a pair of siblings with BPAN

Area of Science:

• Genetics
• Neuroscience
• Rare Diseases

Background:

• Neurodegeneration with brain iron accumulation (NBIA) is a group of inherited neurological disorders.
• Beta-propeller protein-associated neurodegeneration (BPAN) accounts for approximately 7% of NBIA cases, characterized by distinct clinical and imaging findings.
• BPAN is typically caused by heterozygous variants in the WDR45 gene, with a proposed X-linked dominant inheritance pattern and male lethality.

Observation:

• Whole-exome sequencing identified a novel in-frame deletion (c.161_163delTGG) in the WDR45 gene.
• This variant was found in a hemizygous state in a 20-year-old male with severe neurocognitive impairment and seizures.
• The patient's sister, who had intellectual disability, carried the variant heterozygously, and their mother was mosaic for the alteration.

Findings:

• The study demonstrates that inherited WDR45 variants can cause BPAN.
• Hemizygous WDR45 variants in males can be viable, but are associated with a more severe phenotype compared to heterozygous females.
• Siblings with germline WDR45 variants may exhibit more severe effects in males than females.

Implications:

• The findings challenge the proposed male lethality of germline WDR45 variants.
• This research highlights the importance of considering gonadal and germline mosaicism in BPAN inheritance.
• Parental testing for WDR45 variants is recommended for siblings diagnosed with BPAN, even in the presence of asymptomatic carriers.