Phenotypic distinctions of BLM- and RMI1-associated Bloom syndrome

Abstract

AbstractBloom syndrome (BS) is an autosomal recessive disease with characteristic clinical features of primary microcephaly, growth deficiency, skin lesions, cancer predisposition, and immunodeficiency. Here, we report the clinical and molecular findings of eight patients from six families diagnosed with BS. We identified causative mutations in all families, three different homozygous mutations in BLM and one causative homozygous mutation in RMI1. The homozygous c.581_582delTT (p.Phe194*) and c.3164G>C (p.Cys1055Ser) mutations in BLM have already been reported in BS patients, while the c.572_573delGA (p.Arg191Lysfs*4) is novel. Interestingly, whole-exome sequencing revealed a homozygous loss-of-function mutation in RMI1 in two BS patients of a consanguineous Turkish family. All BS patients had primary microcephaly, intrauterine growth delay, and short stature, presenting the phenotypic hallmarks of BS. However, a narrow face, skin lesions, and upper airway infections were observed only in some of the patients. Overall, patients with homozygous BLM mutations had a more severe BS phenotype compared to patients carrying the homozygous RMI1 mutation, especially in terms of immunodeficiency and associated recurrent infections. Low-level immunoglobulins were observed in all BLM-mutated patients, emphasizing the immunodeficiency profile of the disease, which should be considered as an important phenotypic characteristic of BS, especially in the current Covid-19 pandemic era.