Craniosynostosis, inner ear, and renal anomalies in a child with complete loss ofSPRY1(sprouty homolog 1) function

SPRY1encodes protein sprouty homolog 1 (Spry-1), a negative regulator of receptor tyrosine kinase signalling. Null mutant mice display kidney/urinary tract abnormalities and altered size of the skull; complete loss-of-function of Spry-1 in humans has not been reported.Analysis of whole-genome sequencing data from individuals with craniosynostosis enrolled in the 100,000 Genomes Project identified a likely pathogenic variant withinSPRY1. Reverse-transcriptase PCR and western blot analysis were used to investigate the effect of the variant onSPRY1mRNA and protein, in lymphoblastoid cell lines from the patient and both parents.A nonsense variant inSPRY1,encoding p.(Leu27*), was confirmed to be heterozygous in the unaffected parents and homozygous in the child. The child’s phenotype, which included sagittal craniosynostosis, subcutaneous cystic lesions overlying the lambdoid sutures, hearing loss associated with bilateral cochlear and vestibular dysplasia and a unilateral renal cyst, overlapped the features reported inSpry1−/−null mice. Functional studies supported escape from nonsense-mediated decay, but western blot analysis demonstrated complete absence of full-length protein in the affected child and a marked reduction in both parents.This is the first report of complete loss of Spry-1 function in humans, associated with abnormalities of the cranial sutures, inner ear, and kidneys.