The expanding phenotypic spectrum of verheij syndrome.

Verheij syndrome is a rare craniofacial spliceosomopathy presenting with craniofacial dysmorphism, multiple congenital anomalies and variable neurodevelopmental delay. It is caused by SNVs in PUF60 or interstitial deletions of the chromosome 8q24.3 region. PUF60 encodes a splicing factor which forms part of the spliceosome. To date, 27 patients with Verheij syndrome due to disease-causing PUF60 SNVs have been detailed substantively in peer-reviewed publications. Although the depth of their phenotyping has varied greatly, they exhibit marked phenotypic heterogeneity. We report five additional unrelated patients, including the first described patients of Khmer and Indian ethnicities and the eldest patient to date, with five heterozygous PUF60 variants identified through exome sequencing, four previously unreported. These included three frameshift (p.(Pro385Leufs*12), p.(Gly268Alafs*18) and p.(Met287Ilefs*5)), one missense (p.(Arg146Cys)) and one inframe deletion variant (p.(Ala150-Phe152del)). All patients underwent deep phenotyping identifying variable dysmorphism, growth delay, neurodevelopmental delay, and multiple congenital anomalies, including several unique features. Our adult patient is the only individual reported not to have had either neurodevelopmental delay or intellectual disability. In combining these detailed phenotypic data with the previously reported patients we further refine the known frequencies of features associated with Verheij syndrome. These include neurodevelopmental delay/Intellectual disability (97%), short stature (60%), limb anomalies (66%), axial skeletal anomalies (57%), cardiac anomalies (61%), brain malformation (57%), hearing loss (48%), colobomata (32%) and other ocular anomalies (61%). This case series, incorporating two patients from previously unreported ethnic backgrounds, further delineates the mutational spectrum and unpredictable pleiotropy of PUF60 pathogenic variants.