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

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.