Copy number variation as a genetic basis for heterotaxy and heterotaxy-spectrum congenital heart defects

Area of Science:

• Developmental Biology
• Human Genetics
• Genomics

Background:

• Genomic disorders and copy number variations (CNVs) are found in 15-25% of syndromic conditions.
• Heterotaxy, a multiple congenital anomaly syndrome, involves defects in left-right (L-R) organ asymmetry and is genetically heterogeneous.
• The prevalence of CNVs in isolated birth defects, particularly heterotaxy spectrum congenital heart defects (CHDs), requires further investigation.

Purpose of the Study:

• To identify novel genetic causes of heterotaxy by analyzing CNVs in patients with heterotaxy and related CHDs.
• To determine the diagnostic yield of array-based CNV analysis in this patient cohort.
• To explore the association between specific CNVs and clinical phenotypes within the heterotaxy spectrum.

Main Methods:

• Array-based genotyping was used to analyze CNVs in 225 patients with heterotaxy and heterotaxy-spectrum CHDs.
• Detailed phenotyping was performed on all patients.
• Morpholino loss-of-function experiments in Xenopus were conducted to assess the function of novel candidate genes.

Main Results:

• Clinically relevant CNVs were identified in approximately 20% of patients, including both known and novel candidate genes.
• A significant association was found between abdominal situs inversus and pathogenic/likely pathogenic CNVs.
• d-transposition of the great arteries showed a higher association with common CNVs. A rare deletion in ZIC3 and a potential role for PFKP were identified.

Conclusions:

• Array-based CNV analysis demonstrates a high diagnostic yield in patients with heterotaxy.
• CNV analysis is valuable for identifying novel genetic factors and biological pathways involved in human laterality.
• The findings highlight the genetic heterogeneity of heterotaxy and the importance of comprehensive genomic analysis.