Amelogenesis imperfecta: Next-generation sequencing sheds light on Witkop's classification

Area of Science:

• Genetics
• Oral Biology
• Rare Diseases

Background:

• Amelogenesis imperfecta (AI) is a group of rare genetic disorders affecting tooth enamel development, with diverse clinical presentations and inheritance patterns.
• Existing classifications, like Witkop's, categorize AI based on enamel phenotype (hypoplastic, hypomineralized, hypomature) and inheritance mode.
• Over 70 causative genes are known, but the molecular etiology remains unclear for many AI cases.

Purpose of the Study:

• To determine the molecular etiology of amelogenesis imperfecta (AI) in a heterogeneous patient cohort using next-generation sequencing (NGS).
• To enhance the diagnosis and disease management strategies for individuals with AI.
• To identify novel genetic variants and understand their role in AI pathogenesis.

Main Methods:

• A cohort of patients with isolated or syndromic AI underwent phenotyping using the D4/phenodent protocol.
• Molecular diagnosis was performed using the GenoDENT NGS panel, which analyzes 567 genes simultaneously.
• Genetic variants were classified, and diagnoses were validated; exome sequencing was used for panel-negative cases.

Main Results:

• The GenoDENT NGS panel achieved a 60% diagnostic rate in the studied cohort of 111 families (221 individuals).
• Genetic diagnoses were validated for 81% of cases, with 47 newly reported pathogenic or likely pathogenic variants identified.
• Key genes identified included MMP20 and FAM83H for isolated AI, and FAM20A and LTBP3 for syndromic AI.

Conclusions:

• The NGS GenoDENT panel is a validated, cost-efficient tool for diagnosing AI and uncovering its molecular mechanisms.
• Identifying variants in syndromic AI genes has significantly improved patient care and overall management.
• Elucidating the genetic basis of AI provides deeper insights into Witkop's classification system and AI pathogenesis.