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Grange syndrome is an autosomal recessive condition characterized by arterial occlusions and hypertension. Syndactyly, brachydactyly, bone fragility, heart defects, and learning disabilities have also been reported. Loss‐of‐function variants in  YY1AP1  have only recently been associated with Grange syndrome.  YY1AP1  encodes for the transcription coactivator yin yang 1‐associated protein 1 which regulates smooth muscle cell proliferation and differentiation. We here report on three siblings with steno‐occlusive arterial disorder and syndactyly in two of them. Whole exome sequencing including near‐splice regions led to the identification of two intronic  YY1AP1  variants which were predicted to interfere with normal splicing. Sanger sequencing demonstrated compound‐heterozygosity in all affected siblings. RT‐PCR analyses confirmed skipping of exon 6 on one allele and exonization of 22 bp in intron 6 on the other. This is the first report of biallelic  YY1AP1  variants in noncoding regions and just the second family with multiple affected siblings. Therefore, our report further delineates the phenotypic spectrum of Grange syndrome.

Identification of pathogenic YY1AP1 splice variants in siblings with Grange syndrome by whole exome sequencing