Inherited SHQ1 mutations impair interaction with NAP57/dyskerin, a major target in dyskeratosis congenita

BACKGROUND: The inherited bone marrow failure syndrome dyskeratosis congenita (DC) is most frequently caused by mutations in DKC1 (MIM# 300126), the gene encoding NAP57 (aka dyskerin). The typically missense mutations modulate the interaction of NAP57 with its chaperone SHQ1, but no DC mutations have been identified in SHQ1 (MIM# 613663). Here, we report on two compound heterozygous mutations in SHQ1 in a patient with a severe neurological disorder including cerebellar degeneration. METHODS: The SHQ1 mutations were identified by patient exome sequencing. The impact of the mutations was assessed in pulldown assays with recombinant NAP57. RESULTS: The SHQ1 mutations were the only set of mutations consistent with an autosomal recessive mode of inheritance. The mutations map to the SHQ1‐NAP57 interface and impair the interaction of the recombinant SHQ1 variants with NAP57. CONCLUSION: Intrauterine growth retardation and the neurological phenotype of the patient are reminiscent of the severe clinical variant of DC, the Hoyeraal‐Hreidarsson syndrome (HH). Hence, SHQ1 screening may be warranted in patients with inherited bone marrow failure syndromes.