IMPE Abstracts

Pathogenic genetic variants in epigenetic regulatory proteins can cause overgrowth syndromes, such as Sotos syndrome due to mutations in NSD1 or Weaver syndrome due to mutations in EZH2. The identified genes encode DNA or histone methyltransferases, primarily serving as epigenetic writers. However, no overgrowth disorder has previously been described in a gene that acts primarily as an epigenetic reader. We studied a 13-year-old male patient with generalized overgrowth of prenatal onset. His birth weight and length were 5.85 kg (+4.3 SDS) and 62 cm (+4.8 SDS), respectively. His height growth was striking at > +4 SDS without a significantly advanced bone age, eventually requiring epiphysiodesis at age 13 to reduce his adult height. His timing of puberty was as expected. His biochemical studies, including IGF-1, were all negative. Karyotype, mutation analysis in NSD1 for Sotos syndrome, and chromosome 11p15 analysis (MLPA and methylation) for Beckwith-Wiedemann syndrome were normal. Furthermore, he had normal development and intelligence. His mother and maternal grandmother showed a significant height gain (+2 SDS gain) compared to their midparental height, suggesting an X-linked semi-dominant inheritance. Exome sequencing on the extended family identified a frameshift variant (NM_001012968.3, c.312_313AGdel) in Spindlin 4 (SPIN4), one of the epigenetic readers, with X-linked inheritance. Neither this variant nor any other loss-of-function variant in SPIN4 was present in a population database (gnomAD). In functional studies, we found evidence that SPIN4 binds specific histone modifications, promotes canonical WNT signaling, inhibits cell proliferation in vitro, and that the identified frameshift variant had lost all of these functions. Ablation of Spin4 in mice (either male or female) recapitulated the human phenotype with generalized overgrowth, including increased longitudinal bone growth. Growth plate analysis revealed increased cell proliferation in the proliferative zone and an increased number of progenitor chondrocytes in the resting zone. We also found evidence of decreased canonical Wnt signaling in growth plate chondrocytes, providing a potential explanation for the increased number of resting zone chondrocytes. In conclusion, our findings provide strong evidence that SPIN4 is an epigenetic reader that negatively regulates mammalian body growth and that loss of SPIN4 causes an overgrowth syndrome in humans, expanding our knowledge of the epigenetic regulation of human growth.