Application of high-resolution array comparative genomic hybridization in children with unknown syndromic...

Area of Science:

• Genetics
• Neurodevelopmental Disorders
• Genomic Medicine

Background:

• Microcephaly presents as isolated or syndromic, often with neurological and congenital anomalies.
• Syndromic microcephaly cases can be phenotypically complex and require advanced diagnostic methods.
• Array-comparative genomic hybridization (array-CGH) is a powerful tool for investigating genetic causes of developmental disorders.

Purpose of the Study:

• To apply array-CGH for diagnosing clinically undefined syndromic microcephaly.
• To identify copy number variations (CNVs) in patients with syndromic microcephaly and negative standard karyotypes.
• To establish genotype-phenotype correlations in microcephaly cases.

Main Methods:

• Array-CGH analysis was performed on 53 undiagnosed patients with syndromic microcephaly.
• High-resolution Agilent arrays (4 × 180K and 1 × 244K) were utilized.
• Standard karyotype analysis was negative in 52 out of 53 cases prior to array-CGH.

Main Results:

• Copy number variations (CNVs) were detected in 25 out of 53 patients.
• CNVs ranged from 15 kb to 31.6 Mb in size.
• Causal CNVs for microcephaly were identified in 11 cases, with 7 more being probably causal; 16 cases revealed genes potentially linked to brain deficits.

Conclusions:

• Array-CGH is crucial for diagnosing syndromic microcephaly cases with unknown genetic causes.
• The technique facilitates the discovery of novel microdeletions and microduplications.
• Array-CGH enables precise genotype-phenotype correlation through accurate breakpoint definition.