The diverse pleiotropic effects of spliceosomal protein PUF60 : A case series of Verheij syndrome

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.

Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 98%

Section: Genetic Variantsmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Genetic Variantsmentioning

confidence: 99%

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

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Ansari

Ashraf

et al. 2023

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

Bach,

Miron,

Kurolap

et al. 2024

Klippel–Feil syndrome (KFS) has a genetically heterogeneous phenotype with six known genes, exhibiting both autosomal dominant and autosomal recessive inheritance patterns. PUF60 is a nucleic acid‐binding protein, which is involved in a number of nuclear processes, including pre‐mRNA splicing, apoptosis, and transcription regulation. Pathogenic variants in this gene have been described in Verheij syndrome due to either 8q24.3 microdeletion or PUF60 single‐nucleotide variants. PUF60‐associated conditions usually include intellectual disability, among other findings, some overlapping KFS; however, PUF60 is not classically referred to as a KFS gene. Here, we describe a 6‐year‐old female patient with clinically diagnosed KFS and normal cognition, who harbors a heterozygous de novo variant in the PUF60 gene (c.1179del, p.Ile394Serfs*7). This is a novel frameshift variant, which is predicted to result in a premature stop codon. Clinically, our patient demonstrates a pattern of malformations that matches reported cases of PUF60 variants; however, unlike most others, she has no clear learning difficulties. In light of these findings, we propose that PUF60 should be considered in the differential diagnosis of KFS and that normal cognition should not exclude its testing.

Diagnostic findings and yield of investigations for children with developmental regression

Furley,

Hunter,

Fahey

et al. 2024

Childhood conditions that feature developmental regression are poorly understood. Phenotype–genotype characterization and diagnostic yield data are needed to inform clinical decision‐making. The aim of this study was to report the conditions featuring developmental regression and assess diagnostic yields of investigations. A retrospective chart review of children presenting with developmental regression to a tertiary pediatric genetic clinic between 2018 and 2021 was performed. Of 99 children, 30% (n = 30) had intellectual disability (ID), 21% (n = 21) were autistic, 39% (n = 39) were autistic with ID, and 9% (n = 9) did not have ID or autism. Thirty‐two percent (n = 32) of children received a new diagnosis, including eight molecular findings not previously reported to feature developmental regression. Of the children investigated, exome sequencing (ES) provided the highest diagnostic yield (51.1%, n = 24/47), highest (63.6%, n = 14/22) for children with ID, 50% for autistic children with ID (n = 6/12) and children without autism or ID (n = 3/6), and 14.3% (n = 1/7) for autistic children without ID. We highlight the conditions that feature developmental regression and report on novel phenotypic expansions. The high diagnostic yield of ES, regardless of autism or ID diagnosis, indicates the presence of developmental regression as an opportunity to identify the cause, including for genetic differences not previously reported to include regression.