Somatic uniparental disomy with a rare EFL1 variant causes Shwachman-Diamond syndrome through dysregulating ribosomal protein synthesis

We present three unrelated Korean Shwachman-Diamond syndrome (SDS) patients that carry an incomplete but identical homozygous EFL1 p.Thr1069Ala variant due to a bone marrow-specific mosaic uniparental disomy (UPD) in chromosome 15. This rare variant is found in 0.017% of East Asians and is asymptomatic in a heterozygous status, but harbors a hypomorphic effect, leading to 80S assembly of ribosomal protein (RP) transcripts. We propose a novel somatically-induced pathogenesis mechanism and EFL1 dysfunction that eventually leads to aberrant translational control and ribosomopathy.