Towards Next-Generation Sequencing as a First-Tier Diagnostic Test for Fructose-1,6-Bisphosphatase Deficiency

Area of Science:

• Genetics
• Metabolic Disorders
• Genomic Technologies

Background:

• Inborn errors of metabolism are increasingly detected through newborn screening and genomic advances.
• Fructose-1,6-bisphosphatase deficiency (FBP1 deficiency) is an underdiagnosed, treatable autosomal recessive disorder with a good prognosis if detected early.
• Delayed diagnosis of FBP1 deficiency is common due to non-specific symptoms, particularly in consanguineous populations.

Purpose of the Study:

• To investigate the diagnostic utility of first-tier next-generation sequencing (NGS) for FBP1 deficiency.
• To explore the diagnostic pathway and outcomes of novel FBP1 deficiency cases.
• To highlight the effectiveness of NGS in identifying genetic variants and founder mutations.

Main Methods:

• Utilized first-tier exome sequencing for diagnosing three novel cases of FBP1 deficiency.
• Analyzed diagnostic pathways and clinical outcomes in a tertiary care setting.
• Characterized the molecular profile, including gene deletions and frameshift mutations in the FBP1 gene.

Main Results:

• Two patients were diagnosed rapidly via exome sequencing, showing excellent outcomes after 6 years.
• One patient experienced delayed diagnosis and subsequent neurological sequelae.
• Identified exon 2 deletion in the FBP1 gene (a founder mutation) in two patients and a frameshift mutation in the third.

Conclusions:

• First-tier NGS is a rapid, non-invasive method for early diagnosis and management of FBP1 deficiency.
• NGS effectively detects various disease-causing variants, including large deletions and founder mutations.
• Genomic profiling using NGS is crucial for managing FBP1 deficiency, especially in prevalent populations.