Genetic bases of craniosynostoses: An update

Area of Science:

• Genetics
• Developmental Biology
• Pediatric Medicine

Background:

• Craniosynostosis (CS) involves premature fusion of cranial sutures, resulting in abnormal skull shape and affecting 1:2,000-3,000 live births.
• Genetic factors account for 20% of CS cases, categorized as isolated (non-syndromic CS/NSCS) or part of syndromes (syndromic CS/SCS).
• Established syndromic CS (e.g., Crouzon, Apert) involve FGF receptors and TWIST pathways, but recent advances reveal broader genetic heterogeneity.

Purpose of the Study:

• To review molecular etiologies of syndromic and non-syndromic craniosynostosis over the last 15 years.
• To propose a systematic, multidisciplinary approach for genetic evaluation in CS patients.
• To develop a diagnostic flowchart to aid in the genetic assessment of craniosynostosis.

Main Methods:

• Literature review of molecular etiologies for syndromic CS (SCS) and non-syndromic CS (NSCS) reported in the past 15 years.
• Analysis of genetic diagnostic tools like whole exome and genome sequencing.
• Synthesis of findings to propose a structured diagnostic approach.

Main Results:

• Recent genetic studies highlight significant heterogeneity in CS, blurring lines between syndromic and non-syndromic forms.
• Advanced sequencing technologies have identified numerous genetic bases for CS.
• Genetic characterization aids in counseling regarding comorbidity and prognosis, but raises challenges with low-penetrance variants.

Conclusions:

• A systematic, multidisciplinary approach and a diagnostic flowchart are essential for effective genetic evaluation of CS.
• Tailored genetic testing strategies are needed, considering diagnostic yield, genetic counseling implications, and cost-effectiveness.
• Understanding the genetic basis of CS is crucial for accurate diagnosis, prognosis, and patient management.