Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy

Area of Science:

• Genetics
• Molecular Biology
• Developmental Biology

Background:

• Embryonic development relies on precise DNA replication and cell division.
• Mutations in DNA repair/replication genes can cause neurodevelopmental disorders with microcephaly and chromosomal instability.

Purpose of the Study:

• To identify the genetic basis of a novel neurodevelopmental disorder characterized by microcephaly, short stature, cardiac abnormalities, and anemia.
• To elucidate the underlying molecular mechanisms contributing to the observed phenotype.

Main Methods:

• Genetic analysis to identify variants in patients with Atelís Syndrome.
• Cellular studies to characterize the chromosomal instability phenotype.
• Analysis of DNA replication stress and G-quadruplex replication.

Main Results:

• Biallelic variants in SLF2 and SMC5 genes were identified in 11 patients.
• Patient cells displayed segmented and dicentric chromosomes with mosaic variegated hyperploidy, termed Atelís Syndrome.
• Cells showed increased replication stress, impaired G-quadruplex replication, and loss of sister chromatid cohesion.

Conclusions:

• The study identifies SLF2 and SMC5 as crucial for genome stability during development.
• Defects in the RAD18-SLF1/2-SMC5/6 pathway contribute to Atelís Syndrome.
• This highlights a specific role for this pathway in preventing replication stress and maintaining chromosomal integrity.