X-linked Menkes disease: first documented report of germ-line mosaicism

Area of Science:

• Genetics
• Molecular Biology
• Pediatric Neurology

Background:

• Menkes disease is a rare X-linked neurodevelopmental disorder caused by mutations in the ATP7A gene.
• Germ-line mosaicism, where a parent carries a mutation in a subset of their germ cells, can complicate genetic diagnosis and counseling.
• This study investigated a three-generation family with suspected germ-line mosaicism in the maternal grandmother.

Purpose of the Study:

• To investigate the genetic basis of Menkes disease in a three-generation family.
• To determine if germ-line mosaicism in the maternal grandmother could explain the inheritance pattern.
• To assess the implications of germ-line mosaicism for genetic counseling in Menkes disease.

Main Methods:

• Biochemical analysis for Menkes disease diagnosis.
• DNA analysis, including Southern blot and haplotype analysis using intragenic markers of the ATP7A gene.
• Carrier analysis of the mother and genetic testing of the maternal grandmother.

Main Results:

• The index patient was diagnosed with Menkes disease due to a partial ATP7A gene deletion (EX11_EX23del).
• The mother was confirmed as a carrier, but the grandmother's somatic cells showed no deletion.
• Haplotype analysis revealed the grandmother transmitted three distinct ATP7A haplotypes, including the deletion, supporting germ-line mosaicism.

Conclusions:

• The inheritance pattern of Menkes disease in this family is best explained by extensive germ-line mosaicism in the maternal grandmother.
• Germ-line mosaicism presents diagnostic challenges and has significant implications for genetic counseling in Menkes disease families.
• Accurate genetic testing and counseling are crucial for families with suspected germ-line mosaicism.