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

Abstract

PUF60‐related developmental disorder (also referred to as Verheij syndrome), resulting from haploinsufficiency of PUF60, 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 PUF60‐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 PUF60 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 PUF60 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 PUF60‐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 PUF60‐related developmental disorder with a low threshold for endocrine investigations as hormone therapy may be indicated. Our study reports an inherited case with PUF60‐related developmental disorder which has important genetic counseling implications for families.

Novel Genetic and Phenotypic Expansion in Ameliorated PUF60-Related Disorders

“…Another key feature of classical Verheij syndrome is iris coloboma. Previous reports had already reported a lower frequency of coloboma [18]. Our cohort reiterates this finding with an absence of coloboma and instead reports the presence of several other ophthalmological phenotypes, such as transient blurred vision during viral infections.…”

“…We identified disorders in social, emotional, and behavioral development, including aggressive behavior with self-injuring in patients 1 and 3; attention deficits in patients 2 and 4; and stereotypies in patients 1, 3, and 5. Previous studies have reported only a few cases with temper tantrums and self-injuring behavior, and here, we observed a much higher frequency in our cohort [17,18]. We propose that, if considering all domains of neurodevelopmental disorders, this phenotype is a key feature in diagnosing even milder PUF60-related disorders, and we consider it the singular core feature in the re-classification of the spectrum of PUF60-related disorders (Table 2).…”

“…Seizures were one of the key features in the first description of classical Verheij syndrome and other reports [11,12,[16][17][18][23][24][25][26]. Only one patient in our cohort presented with a history of seizures until the age of two years, and remained seizure-free without any medication until the present age of 15 years.…”

“…Pathogenic heterozygous PUF60 variant (History of) neurodevelopmental disorder in speech, motor, intellectual, and/or social, emotional and behavioral development Brain malformations are present in a number of PUF60 variants in the literature [11,12,[16][17][18][19][20][21][22][23]. Only patient 3 presented with brain malformations, including corpus callosum dysgenesis and mesencephalon hypoplasia (Figure 2b).…”

PUF60 loss‐of‐function with normal cognition should be considered in the differential diagnosis of Klippel–Feil syndrome

“…The PUF60 gene encodes a splicing factor that plays a critical role in RNA splicing by recognizing 3′ splice sites and facilitating the recruitment of snRNP complexes (Hastings et al, 2007; Page‐McCaw et al, 1999). Pathogenic variants in this gene have been associated with Verheij syndrome, caused by either a 8q24.3 microdeletion (Dauber et al, 2013; Verheij et al, 2009; Wells et al, 2016) or heterozygous single‐nucleotide variants (El Chehadeh et al, 2016; Fennell et al, 2022; Grimes et al, 2023; Low et al, 2017; Yamada et al, 2020), manifesting with a distinct constellation of congenital malformations. These malformations classically include short stature, intellectual disability, dysmorphic facial features, coloboma, hearing impairment, and anomalies affecting the skeletal, cardiac, and renal systems.…”