Ethics in pre-ART genetics: a missed X-linked Menkes disease case

Area of Science:

• Clinical Genetics
• Reproductive Medicine
• Molecular Diagnostics

Background:

• Assisted reproductive technology (ART) has advanced significantly, with gamete donation becoming a standard procedure in fertility clinics.
• Major progress in genetic diagnostics enables rapid, affordable analysis of multiple genes or whole genomes, necessitating expertise in variant evaluation.

Observation:

• A case of Menkes disease is reported in infants born following ART, where genetic screening and variant scoring failed to identify an egg donor as a carrier.
• The identified pathogenic variant in the ATP7A gene was a single base pair deletion causing a frameshift and premature protein termination, predicted to result in severely diminished function.

Findings:

• The specific ATP7A gene variant, classified as likely pathogenic (class 4), should have been readily detectable by standard molecular genetic screening techniques.
• The failure to identify this pathogenic variant in the egg donor resulted in the birth of two male infants with the fatal X-linked disorder, Menkes disease.

Implications:

• This case underscores the critical importance of accurate and comprehensive genetic screening in gamete donors within ART programs to prevent severe inherited childhood disorders.
• It necessitates a review of current genetic diagnostic protocols, ethical considerations, and legal frameworks in ART to prevent such diagnostic errors and ensure patient safety.
• Highlights the need for robust quality management systems, such as ISO 15189 certification, in genetic testing laboratories to ensure reliable and accurate results for clinical decision-making.