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

Am J Med Genet A. 2019 Feb;179(2):295-299. doi: 10.1002/ajmg.a.60700. Epub 2018 Dec 17.


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.

Keywords: Grange syndrome; splice variant; vascular disease; whole exome sequencing.

Publication types

  • Case Reports

MeSH terms

  • Adolescent
  • Adult
  • Arterial Occlusive Diseases / genetics*
  • Arterial Occlusive Diseases / physiopathology
  • Bone and Bones / abnormalities*
  • Bone and Bones / physiopathology
  • Brachydactyly / genetics*
  • Brachydactyly / physiopathology
  • Cell Cycle Proteins / genetics*
  • Child
  • Exome Sequencing
  • Female
  • Genetic Predisposition to Disease*
  • Heart Defects, Congenital / genetics*
  • Heart Defects, Congenital / physiopathology
  • Humans
  • Hypertension / genetics*
  • Hypertension / physiopathology
  • Male
  • Middle Aged
  • Pedigree
  • Protein Isoforms / genetics
  • Syndactyly / genetics*
  • Syndactyly / physiopathology
  • Transcription Factors / genetics*


  • Cell Cycle Proteins
  • Protein Isoforms
  • Transcription Factors
  • YY1AP1 protein, human

Supplementary concepts

  • Arterial Occlusive Disease, Progressive, with Hypertension, Heart Defects, Bone Fragility, and Brachysyndactyly