Inherited interstitial duplications of proximal 15q: genotype-phenotype correlations

Area of Science:

• Genetics
• Human Genetics
• Molecular Genetics

Background:

• Interstitial duplications of the proximal long arm of chromosome 15 (15q) are increasingly recognized genetic alterations.
• The Prader-Willi/Angelman critical region (PWACR) on chromosome 15 is a key locus for neurodevelopmental disorders.

Purpose of the Study:

• To investigate the cytogenetic, molecular cytogenetic, and molecular genetic characteristics of interstitial duplications of 15q in 20 unrelated patients.
• To determine the association between duplications, specifically those involving the PWACR, and clinical phenotypes, including developmental delay and speech difficulties.
• To explore the parental origin of these duplications and its potential impact on phenotype.

Main Methods:

• Cytogenetic analysis
• Molecular cytogenetic analysis using multiple probes, including those for the PWACR
• Molecular genetic analysis
• Comparative genomic hybridization (CGH)
• Family studies including parental and sibling samples

Main Results:

• Four out of 20 patients had interstitial duplications of 15q that included the PWACR, all presenting with developmental delay.
• These four patients inherited the duplication from their mothers; three of these mothers were also affected.
• Maternal inheritance of PWACR duplications was consistently associated with developmental delay and speech difficulties, but not with Prader-Willi syndrome or Angelman syndrome features.
• The remaining 16 patients had duplications not involving the PWACR; four of these had developmental delay.
• Comparative genomic hybridization suggested that duplicated material originated from proximal 15q outside the PWACR in two patients.
• Duplications were inherited from phenotypically normal parents in 14 families with equal frequency from mothers or fathers.

Conclusions:

• Interstitial duplications of 15q encompassing the PWACR are associated with developmental delay and speech impairment, particularly when maternally inherited.
• The use of PWACR-specific probes is crucial for distinguishing clinically significant duplications from those without apparent phenotypic consequence.
• These findings highlight the importance of parental origin in the phenotypic expression of 15q duplications.