Germ cell mosaicism for AUTS2 exon 6 deletion

Area of Science:

• Genetics
• Neurodevelopmental Disorders
• Human Genetics

Background:

• Haploinsufficiency of the AUTS2 gene is linked to neurodevelopmental disorders and dysmorphic features.
• Over 50 cases of AUTS2 syndrome have been documented, primarily involving de novo deletions of AUTS2 exons.
• Eight previously reported patients had deletions specifically affecting exon 6 of AUTS2.

Observation:

• This study details two siblings with identical pathogenic 85 kb deletions in 7q11.22, encompassing AUTS2 exon 6, identified via SNP array analysis.
• Both siblings presented with characteristic AUTS2 syndrome symptoms, including intellectual impairment and behavioral issues, but exhibited significant phenotypic variability.
• Parental and sibling blood samples showed no evidence of the deletion, and cytogenetic analyses ruled out structural rearrangements in the parents.

Findings:

• SNP array analysis confirmed the same deletion in both siblings, while excluding it in their parents and healthy brother.
• Conventional karyotyping and FISH analyses did not reveal structural rearrangements in the parents' chromosomes at 7q11.22.
• Germ cell mosaicism is proposed as the most plausible explanation for the recurrence of this specific AUTS2 deletion in the siblings.

Implications:

• This is the first reported instance of germ cell mosaicism associated with AUTS2 syndrome.
• The findings provide further evidence for significant intrafamilial phenotypic variability within AUTS2 syndrome.
• This study expands the clinical understanding of the phenotypic spectrum in individuals with AUTS2 exon 6 deletions.