MFSD2A frameshift variant in Kerry Hill sheep with microcephaly

Area of Science:

• Veterinary Genetics
• Neurodevelopmental Disorders
• Animal Genomics

Background:

• Microcephaly is a rare neurodevelopmental disorder characterized by reduced head and brain size.
• This condition sporadically affects farm animals, presenting significant challenges in animal health and breeding.
• Previous research has linked MFSD2A gene variants to microcephaly in humans.

Purpose of the Study:

• To investigate the genetic cause of an early-onset neurodegenerative disorder in Kerry Hill sheep lambs.
• To identify the specific genetic variant responsible for microcephaly in affected lambs.
• To establish a potential animal model for human microcephaly research.

Main Methods:

• Genome sequencing of affected lambs and comparison with control genomes.
• Pedigree analysis to determine inheritance patterns.
• Bioinformatic analysis to identify causative genetic variants and predict their functional impact.

Main Results:

• A single private protein-changing frameshift variant (MFSD2A: c.285dupA, p.(Asp96fs*9)) was identified in affected lambs.
• This variant is predicted to cause a loss-of-function of the MFSD2A gene, truncating 80% of the protein.
• The inheritance pattern strongly suggested a monogenic autosomal recessive trait.

Conclusions:

• A recessively inherited form of microcephaly in sheep is caused by a loss-of-function variant in the MFSD2A gene.
• This study reports the first spontaneous MFSD2A variant in domestic animals, offering a valuable model for studying microcephaly.
• The findings contribute to understanding the role of MFSD2A in brain development and homeostasis across species.