<i>PUF60</i>‐related developmental disorder: A case series and phenotypic analysis of 10 additional patients with monoallelic <i>PUF60</i> variants

<jats:title>Abstract</jats:title><jats:p><jats:italic>PUF60</jats:italic>‐related developmental disorder (also referred to as Verheij syndrome), resulting from haploinsufficiency of <jats:italic>PUF60</jats:italic>, is associated with multiple congenital anomalies affecting a wide range of body systems. These anomalies include ophthalmic coloboma, and congenital anomalies of the heart, kidney, and musculoskeletal system. Behavioral and intellectual difficulties are also observed. While less common than other features associated with <jats:italic>PUF60</jats:italic>‐related developmental disorder, for instance hearing impairment and short stature, identification of specific anomalies such as ophthalmic coloboma can aid with diagnostic identification given the limited spectrum of genes linked with this feature. We describe 10 patients with <jats:italic>PUF60</jats:italic> gene variants, bringing the total number reported in the literature, to varying levels of details, to 56 patients. Patients were recruited both via locally based exome sequencing from international sites and from the DDD study in the United Kingdom. Eight of the variants reported were novel <jats:italic>PUF60</jats:italic> variants. The addition of a further patient with a reported c449‐457del variant to the existing literature highlights this as a recurrent variant. One variant was inherited from an affected parent. This is the first example in the literature of an inherited variant resulting in <jats:italic>PUF60</jats:italic>‐related developmental disorder. Two patients (20%) were reported to have a renal anomaly consistent with 22% of cases in previously reported literature. Two patients received specialist endocrine treatment. More commonly observed were clinical features such as: cardiac anomalies (40%), ocular abnormalities (70%), intellectual disability (60%), and skeletal abnormalities (80%). Facial features did not demonstrate a recognizable gestalt. Of note, but remaining of unclear causality, we describe a single pediatric patient with pineoblastoma. We recommend that stature and pubertal progress should be monitored in <jats:italic>PUF60</jats:italic>‐related developmental disorder with a low threshold for endocrine investigations as hormone therapy may be indicated. Our study reports an inherited case with <jats:italic>PUF60</jats:italic>‐related developmental disorder which has important genetic counseling implications for families.</jats:p>

Grimes, H., Ansari, M., Ashraf, T., Cueto‐González, A. M., Calder, A., Day, M., Fernandez Alvarez, P., Foster, A., Lahiri, N., Repetto, G. M., Scurr, I., Varghese, V., & Low, K. J. (2023). puf60 ‐related developmental disorder: A case series and phenotypic analysis of 10 additional patients with monoallelic puf60 variants. American Journal of Medical Genetics Part A, 191(10), 2610-2622. https://doi.org/10.1002/ajmg.a.63313