Developmental delay with hypotrophy associated with homozygous functionally relevant REV3L variant

Area of Science:

• Genetics
• Molecular Biology
• Human Disease

Background:

• REV3L encodes DNA polymerase zeta (Pol zeta), crucial for translesion synthesis (TLS) in DNA damage tolerance.
• Previously, only dominant REV3L mutations causing Moebius syndrome were known.
• The genetic basis for many developmental disorders remains elusive.

Purpose of the Study:

• To report a novel human disorder associated with a homozygous REV3L variant.
• To investigate the functional consequences of this REV3L variant using a yeast model.
• To differentiate this disorder from Moebius syndrome and establish its inheritance pattern.

Main Methods:

• Whole exome sequencing to identify the genetic variant.
• Functional analysis of the REV3L variant (T2753R) in a yeast model (introducing S1192R mutation).
• Assessment of UV sensitivity, nuclear DNA mutagenesis, and mitochondrial DNA mutagenesis in yeast.

Main Results:

• A homozygous REV3L variant (T2753R) was identified in a child with developmental delay, hypotrophy, and dysmorphic features.
• The equivalent yeast mutation (S1192R) retained residual TLS function but caused nuclear TLS dysfunction and mitochondrial instability.
• The yeast mutation led to increased UV sensitivity, decreased nuclear mutagenesis, and increased mitochondrial mutagenesis.

Conclusions:

• This is the first reported case of a recessive disorder associated with a REV3L variant.
• The identified variant causes a distinct clinical phenotype and follows autosomal recessive inheritance.
• The findings highlight the critical role of REV3L in human development and DNA repair.