The prevalence and phenotypic range associated with biallelic PKDCC variants

Area of Science:

• Genetics and Developmental Biology
• Skeletal Dysplasia Research
• Human Molecular Genetics

Background:

• PKDCC is crucial for Hedgehog signaling, chondrogenesis, and skeletal development.
• Previous evidence linked biallelic PKDCC variants to rhizomelic limb shortening but was based on limited cases.
• Understanding PKDCC's role is vital for diagnosing skeletal dysplasias.

Purpose of the Study:

• To investigate the association between biallelic PKDCC variants and rhizomelic limb shortening.
• To expand the cohort of affected individuals for a comprehensive analysis.
• To determine the prevalence and clinical features associated with PKDCC variants.

Main Methods:

• Utilized data from the 100,000 Genomes Project.
• Performed exome sequencing and panel testing through international collaboration.
• Assembled a cohort of eight individuals from seven families with biallelic PKDCC variants.
• Conducted in silico structural modeling for variant assessment.
• Queried databases to estimate condition prevalence.

Main Results:

• Identified eight individuals with biallelic PKDCC variants, including frameshifts and a missense variant.
• Estimated the condition's prevalence between 1:127 and 1:721 in skeletal dysplasia cohorts.
• Observed predominantly upper limb involvement, micrognathia, hypertelorism, and hearing loss as common features.

Conclusions:

• Strengthened the etiological link between biallelic PKDCC inactivation and rhizomelic limb-shortening.
• The findings provide a foundation for improved clinical interpretation of PKDCC variants.
• This study enhances diagnostic capabilities for skeletal dysplasias related to PKDCC.