A novel compound heterozygous YY1AP1 variant in Grange syndrome: importance of early signs in preventing life-threatening vascular complications

BACKGROUND: Grange syndrome is an ultra-rare autosomal recessive disorder caused by biallelic loss-of-function variants in the YY1AP1 gene. It is clinically characterized by multisystem involvement, including vascular stenosis, brachysyndactyly, osteopenia, cardiac anomalies, and neurodevelopmental delay. METHODS: Our case was followed up in the Child and Adolescent Psychiatry clinic with the diagnosis of intellectual disability. Whole-exome sequencing (WES) was performed, and Sanger sequencing was used to confirm the identified variant and conduct familial segregation analysis. RESULTS: We report a 17-year-old Turkish female who presented with academic failure, speech delay, dysarthria, facial dysmorphism, and surgically corrected hand syndactyly. Notably, she exhibited no clinical signs of vascular stenosis or hypertension at the time of diagnosis. A novel compound heterozygous variant combination in YY1AP1 (NM_139119.3) was identified: c.1489_1492del (p.Glu636ProfsTer13), previously reported as pathogenic, and c.1637_1638del (p.Pro546ArgfsTer26), a novel frameshift variant. These variants were maternally and paternally inherited, respectively. CONCLUSION: This is the first reported case of Grange syndrome diagnosed based on neurodevelopmental and dysmorphic findings before the onset of vascular or hypertensive symptoms. Our findings highlight the importance of considering YY1AP1-related pathology in the differential diagnosis of intellectual disability and syndactyly, even in the absence of vascular features. Early genetic diagnosis enables clinical surveillance for life-threatening complications associated with this syndrome.