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

Abstract

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.

Figure 1

(a) Pedigree of the nonconsanguineous family with Grange syndrome. Filled symbols = individuals with verified steno‐occlusive arterial lesions. Whole‐exome sequenced probands are marked with orange circles. (b–d) Photographs of hands and feet of II:2. Syndactyly corrections (left hand: III‐V; right hand: III‐IV) had been performed in early childhood. (e–g) Digital subtraction angiography (DSA) of II:1. Left common carotid artery (CCA) in frontal (e) and lateral (f) view, right CCA in lateral view (g). Occlusion of the ICA shortly distal to the carotid bifurcation (f, white arrow). Unusually thickened ascending pharyngeal artery (e, black arrow) with a network of collaterals to the cavernous portion of the ICA via the thickened meningohypophyseal trunk (MHT, f, black asterisk) as well as via the inferolateral trunk (ILT, f, white asterisk) fed by branches of the middle meningeal artery (MMA, f, white open arrow) and the internal maxillary artery (IMA, f, black open arrow). Similar findings on the right side with severe stenosis of the ICA in the cervical portion (g, white arrow) and a very similar collateral pattern compared to the left ICA. (h) Confirmation of the predicted splice defects by RT‐PCR for all affected children (2–4), their father (1) and mother (5). Lanes 6 + 7: control samples, lane 8: blank; lane 9: size marker. pE6 = c.997+23T>G allele with exonization of 22 intronic bp. ΔE6 = c.826‐1G>A allele with skipping of exon 6. E = exon