Three Offspring with Cri-du-Chat Syndrome from Phenotypically Normal Parents

Area of Science:

• Genetics
• Human Genetics
• Reproductive Genetics

Background:

• Cri-du-chat syndrome involves facial dysmorphism, intellectual disability, and congenital anomalies, often arising de novo.
• The genetic basis for recurrent cases in families with healthy parents remains incompletely understood.

Purpose of the Study:

• To investigate the underlying genetic cause of Cri-du-chat syndrome in three siblings born to unaffected parents.
• To determine if gonadal mosaicism is responsible for the recurrent transmission of the chromosomal abnormality.

Main Methods:

• Karyotyping and microarray analysis were performed on the affected siblings.
• Fluorescence in situ hybridization (FISH) was used to analyze chromosomal translocations.
• FISH and microarray analysis were conducted on parental samples, including sperm, to investigate mosaicism.

Main Results:

• The siblings presented with a 5p deletion and 19q duplication, indicative of an unbalanced translocation.
• Parental karyotypes were normal, suggesting the abnormality did not originate from inherited balanced translocations.
• FISH analysis of the father's sperm revealed a 5p deletion in 12.8% of cells, confirmed as mosaicism by microarray.

Conclusions:

• This is the first study to provide molecular evidence of paternal gonadal mosaicism for an unbalanced translocation causing Cri-du-chat syndrome.
• Paternal gonadal mosaicism should be considered in cases of recurrent de novo chromosomal abnormalities, including Cri-du-chat syndrome.
• Understanding gonadal mosaicism is critical for accurate genetic counseling and risk assessment in affected families.