A novel deep intronic variant strongly associates with Alkaptonuria

Area of Science:

• Genetics
• Metabolic Disorders
• Rare Diseases

Background:

• Alkaptonuria (AKU) is an autosomal recessive disorder of tyrosine metabolism.
• AKU leads to ochronosis, arthropathy, and cardiac complications.
• The epidemiology and genetic landscape of AKU in East Asia remain largely uncharacterized.

Purpose of the Study:

• To investigate the epidemiology and molecular characteristics of alkaptonuria in East Asia.
• To identify and characterize novel mutations in the homogentisate 1,2-dioxygenase (HGD) gene in East Asian patients.
• To compare AKU patient data from East Asia with global populations.

Main Methods:

• Retrospective review of patients diagnosed with alkaptonuria between January 2010 and June 2020.
• Mutation analysis of the HGD gene in affected individuals.
• RNA sequencing to elucidate the functional impact of identified variants.
• Literature search to collate data on East Asian AKU patients.

Main Results:

• Three patients with alkaptonuria were identified in Taiwan.
• Four novel HGD variants (c.16-2063 A>C, p.(Thr196Ile), p.(Gly344AspfsTer25), and p.(Gly362Arg)) were found in six mutated alleles.
• The c.16-2063 A>C variant was shown to activate a cryptic exon, leading to protein truncation.
• Combined with literature data, 13 out of 18 mutated alleles in East Asian AKU patients were novel.

Conclusions:

• Alkaptonuria is a rare condition in Taiwan and East Asia.
• The genetic basis of AKU in this region is characterized by a high proportion of novel and private HGD mutations.
• Further research is needed to understand the full spectrum of HGD variants and their clinical implications in East Asia.