Unexpected Inheritance Patterns in a Large Cohort of Patients with a Suspected Ciliopathy

Area of Science:

• Genetics
• Molecular Biology
• Rare Diseases

Background:

• Ciliopathies are genetic disorders stemming from cilia dysfunction, typically inherited in an autosomal recessive pattern.
• Rare inheritance exceptions like uniparental disomy (UPD) and de novo variants are documented but poorly understood in ciliopathies.
• Existing literature on UPD and de novo variants in ciliopathies is limited, necessitating further investigation.

Purpose of the Study:

• To investigate the prevalence of UPD and de novo variants in a large cohort of individuals with suspected ciliopathies.
• To review existing literature on UPD and de novo variants in the context of ciliopathies.
• To emphasize the clinical significance of identifying these rare genetic mechanisms for genetic counseling.

Main Methods:

• Analysis of 940 individuals (812 families) with suspected ciliopathies using Sanger sequencing, high-throughput sequencing, and/or SNP array.
• Literature review focusing on uniparental disomy (UPD) and de novo variants in ciliopathies.
• Detailed examination of a molecularly diagnosed cohort of 623 individuals (511 families) with ciliopathies, primarily Bardet-Biedl and Alström syndromes.

Main Results:

• Identified five instances of UPD, each revealing an inherited pathogenic variant.
• Detected five pathogenic variants of de novo origin, occurring in trans to another pathogenic variant.
• Reported 15 distinct pathogenic variants from these ten cases, including five novel variants.
• Demonstrated a notable prevalence of UPD and de novo variants in the studied ciliopathy cohort.

Conclusions:

• Uniparental disomy (UPD) and de novo variants occur more frequently in ciliopathies than previously assumed.
• Identifying these rare genetic events is critical for precise genetic diagnosis and effective family counseling.
• This research underscores the importance of considering non-canonical inheritance patterns in ciliopathy diagnostics.