Unexpectedly high levels of normally spliced transcripts from the pathogenic SLC10A7 alleles in a recessive form of skeletal dysplasia.

Bi-allelic loss-of-function (LoF) variants in SLC10A7 cause short stature, amelogenesis imperfecta, and skeletal dysplasia with scoliosis (SSASKS). Here, we report findings from an individual of Chinese ancestry with SSASKS carrying compound heterozygous splice-altering SLC10A7 variants: a previously reported pathogenic variant (NM_001029998.6:c.722-16A>G, paternal) and a de novo splice site variant (NM_001029998.6:c.472-1G>T, maternal). In silico predictions, minigene assays, and analyses of RNA and protein from the affected individual revealed that c.472-1G>T causes in-frame exon 7 skipping and c.722-16A>G induces out-of-frame exon 9 skipping. RNA sequencing of blood-derived cells showed that ∼32% residual SLC10A7 function in the affected individual, consistent with the 43% protein accumulation observed by western blot analysis of muscle tissue. These findings indicate that a previously presumed complete LoF allele instead results in partial LoF, prompting a refinement of the genotype-phenotype framework for SLC10A7-related SSASKS. This study highlights the challenges of predicting partial LoF effects, the value of RNA and protein analyses from affected individual-derived tissues, and the importance of distinguishing partial from complete LoF variants in the diagnosis and counseling of recessive disorders.