PUF60 – Verheij Syndrome

PUF60 encodes an essential splicing factor that regulates RNA processing and is critically involved in normal human development. Variants in PUF60, particularly loss‑of‑function mutations, have been robustly linked to 8q24.3 microdeletion syndrome (Verheij syndrome), a multisystem disorder characterized by intellectual disability, abnormal facial shape, and growth delay (PMID:30352594). This association is supported by multiple independent case reports and series documenting de novo as well as rare inherited heterozygous variants that disrupt protein function.

Multiple case reports have identified a spectrum of pathogenic variants, including nonsense, frameshift, and splice‑site alterations. For instance, the de novo variant c.1357C>T (p.Gln453Ter) was identified in a Chinese Han patient and is representative of the mutational spectrum seen in affected individuals (PMID:30352594). In addition, further studies have reported frameshift mutations and in‐frame deletions with consistent clinical findings, reinforcing a haploinsufficiency mechanism under an autosomal dominant inheritance model.

Segregation analyses across several families reveal that while most variants arise de novo, there are instances of vertical transmission from an affected parent, further substantiating autosomal dominant inheritance. Extended pedigree analyses have demonstrated segregation of the variant with disease in additional affected relatives (PMID:32851780).

Large multi‐patient studies have expanded the phenotypic spectrum of PUF60‐related disorders. These studies consistently document core features such as intellectual disability, abnormal facial morphology, and developmental delays, in addition to a range of other congenital anomalies that include cardiac, ocular and skeletal defects. Such studies not only augment the clinical validity but also facilitate refined genotype–phenotype correlations.

The variant spectrum for PUF60 includes disruptive changes such as frameshift and nonsense mutations. The reported mutation c.1357C>T (p.Gln453Ter) serves as an illustrative example, highlighting the deleterious effect of premature truncation on protein function. Overall, the genetic evidence demonstrates a strong correlation between heterozygous loss‑of‑function variants and the clinical manifestations of Verheij syndrome.

Functional studies further bolster this association by demonstrating that PUF60 loss‑of‑function leads to aberrant splicing and altered expression profiles of downstream target genes. Experimental assays, including in vivo and in vitro splicing efficiency analyses, reveal that disruption of PUF60 dosage impairs correct transcript processing, thereby recapitulating the developmental anomalies observed in patients (PMID:24140112; PMID:28327570).

In conclusion, the combined genetic and functional evidence strongly supports the clinical validity of the association between PUF60 and Verheij syndrome. This robust corpus of data emphasizes that PUF60 loss‑of‑function is a key diagnostic marker for this disorder and underscores its value for genetic counseling and therapeutic decision‑making.

Key Take‑home: PUF60 variants represent a strong diagnostic indicator for Verheij syndrome, with significant implications for patient management and genetic counseling.

References

• BMC Medical Genomics • 2018 • Role of PUF60 gene in Verheij syndrome: a case report of the first Chinese Han patient with a de novo pathogenic variant and review of the literature PMID:30352594
• European Journal of Human Genetics • 2016 • Dominant variants in the splicing factor PUF60 cause a recognizable syndrome with intellectual disability, heart defects and short stature PMID:27804958
• American Journal of Human Genetics • 2013 • SCRIB and PUF60 are primary drivers of the multisystemic phenotypes of the 8q24.3 copy-number variant PMID:24140112
• European Journal of Human Genetics: EJHG • 2017 • PUF60 variants cause a syndrome of ID, short stature, microcephaly, coloboma, craniofacial, cardiac, renal and spinal features PMID:28327570

Evidence Based Scoring (AI generated)