A novel de novo pathogenic variant in TBL1XR1 as a new proposed cause of Pierpont syndrome

TBL1XR1, which encodes transducing β‐like 1 X‐linked receptor 1, is implicated in both Pierpont syndrome and intellectual developmental disorder, autosomal dominant‐41 (MRD‐41, OMIM #616944). While both conditions are autosomal dominant, variants associated with Pierpont syndrome are believed to behave in a dominant negative fashion, whereas those causing MRD‐41 result in haploinsufficiency. Here, we present a patient with a de novo novel variant in TBL1XR1 (c.977G > A,p.S326N) identified by trio exome sequencing. Though a different variant at this same residue has previously been associated with MRD‐41, our patient's presentation is suggestive of Pierpont syndrome. The patient's clinical phenotype, which includes short stature, developmental delay, dysmorphic craniofacial features, and plantar fat pads, more closely resembles that of known patients with Pierpont syndrome than MRD‐41. Furthermore, this missense variant is directly adjacent to one previously associated with Pierpont syndrome and exists in the same region as all variants associated with Pierpont, on the inner surface of a WD40 ring. We propose this variant is a newly identified cause of Pierpont syndrome.