Phenotypic spectrum of BLM‐ and RMI1‐related Bloom syndrome

Abstract

Bloom syndrome (BS) is an autosomal recessive disorder with characteristic clinical features of primary microcephaly, growth deficiency, cancer predisposition, and immunodeficiency. Here, we report the clinical and molecular findings of eight patients from six families diagnosed with BS. We identified causative pathogenic variants in all families including three different variants in BLM and one variant in RMI1. The homozygous c.581_582delTT;p.Phe194* and c.3164G>C;p.Cys1055Ser variants in BLM have already been reported in BS patients, while the c.572_573delGA;p.Arg191Lysfs*4 variant is novel. Additionally, we present the detailed clinical characteristics of two cases with BS in which we previously identified the biallelic loss‐of‐function variant c.1255_1259delAAGAA;p.Lys419Leufs*5 in RMI1. All BS patients had primary microcephaly, intrauterine growth delay, and short stature, presenting the phenotypic hallmarks of BS. However, skin lesions and upper airway infections were observed only in some of the patients. Overall, patients with pathogenic BLM variants had a more severe BS phenotype compared to patients carrying the pathogenic variants in RMI1, especially in terms of immunodeficiency, which should be considered as one of the most important phenotypic characteristics of BS.

Photodermatoses: what's new

“…Bloom syndrome is a rare autosomal recessive disorder with clinical features of primary microcephaly, growth deficiency, cancer predisposition, and immunodeficiency. In a study of eight patients presenting with Bloom syndrome, Gönenc et al detected one novel frameshift variant of BLM , two already known pathogenic variants of BLM , and one truncating variant in RMI1 [46]. Patients with pathogenic variants in the BLM gene showed more severe Bloom syndrome phenotypic characteristics in terms of photosensitivity, immunodeficiency, and infection rate than the patients carrying the RMI1 variant.…”

The BLM-TOP3A-RMI1-RMI2 proximity map reveals that RAD54L2 suppresses sister chromatid exchanges

“…Dissolution of dHJs by the BLM-TOP3A-RMI1-RMI2 (BTRR) complex is distinguished from dHJ resolution by structure-selective nucleases in that dissolution produces exclusively non-crossover products. As such, defects in BTRR components result in the canonical phenotype of BLM syndrome: increased sister chromatid exchanges (SCEs) (German et al , 1977; Martin et al , 2018; Gönenc et al , 2022; Hudson et al , 2016), increased loss of heterozygosity events (Yusa et al , 2004; Langlois et al , 1989; LaRocque et al , 2011), and increased risks of pleiotropic cancer (German, 1997; Ababou, 2021). Elevated SCEs are a broad indicator of genome instability and occur at random locations across the mammalian genome (Hamadeh et al, 2022) and in particular, in hotspots at common fragile sites (van Wietmarschen et al , 2018).…”