A Novel YY1AP1 Variant in Grange Syndrome: Clinical and Molecular Findings in Eight Individuals With a Dual Molecular...

Grange syndrome is a rare early-onset multisystem disorder characterized by multifocal steno-occlusive arterial disease, bone fragility, congenital cardiac anomalies, skeletal manifestations, and intellectual disability, caused by biallelic loss-of-function variants in YY1AP1. We report eight affected individuals (six females, two males) from a single consanguineous family. Molecular analysis included exome sequencing in three patients (P1, P5, and P7) and targeted next-generation sequencing in one patient (P8), with Sanger sequencing performed for segregation analysis and parental carrier testing. A novel biallelic YY1AP1 variant (NM_001198903.1: c.2531_2532del; p.E844Gfs*34) was identified in all affected individuals. One patient, a 4-month-old female, harbored an additional novel biallelic pathogenic variant in CLMP (NM_024769.5: c.167dup; p.N56Kfs*2), consistent with a dual molecular diagnosis. The most common presenting feature was multiple fractures, observed in six patients. The mean age at first fracture was 3.6 ± 1.7 years, and the mean baseline bone mineral density (BMD) Z-score was -4.1 ± 1.6. Three patients received intravenous bisphosphonate therapy for at least 2 years, resulting in improvement of mean BMD Z-scores from -4.9 ± 1.9 to -2.4 ± 0.7. This study represents the first Grange syndrome cohort reported from Türkiye and expands the clinical spectrum by demonstrating marked phenotypic variability, multisystem involvement, and potential benefit of bisphosphonate therapy in patients with significant bone fragility.