Expanding the mutational spectrum of RAD50: a case report of Nijmegen breakage syndrome-like disorder in a Chinese child.

Nijmegen breakage syndrome-like disorder (NBSLD) is a rare chromosomal instability syndrome caused by biallelic pathogenic variants in RAD50, which is a key component of the MRE11-RAD50-NBS1 (MRN) complex involved in DNA double-strand break repair. Merely few cases have been reported worldwide, and its phenotypic spectrum remains incompletely defined. We report a 6-year-old Chinese boy, who presented with bilateral cryptorchidism, severe microcephaly, growth retardation, multiple café-au-lait macules, brachydactyly, and distinctive craniofacial features, including a sloping forehead, midface prominence, and receding mandible. Mild intellectual impairment was confirmed on formal neurocognitive testing. The immunological assessment revealed borderline lymphopenia without overt immunodeficiency. Whole-exome sequencing (WES) identified compound heterozygosity for two variants in RAD50 (NM_005732.3): a paternally inherited frameshift variant c.2165_2166insT (p.Lys722Asnfs*6) and a maternally inherited splice-site variant c.3752 + 4_3752 + 7dup. The minigene splicing assay revealed that the latter disrupts normal splicing, leading to partial intron retention and a premature stop codon (p.Ile1252*). Based on the clinical features and molecular confirmation, the patient was diagnosed with NBSLD. Allogeneic hematopoietic stem cell transplantation (HSCT) has been proposed as a potential therapeutic option for DNA damage repair disorders. However, it is not presently required for this patient, who is managed with regular surveillance. The present case expands the clinical and mutational spectrum of RAD50-associated NBSLD. It emphasizes the importance of combining clinical assessment, genomic analysis, and functional assays for the accurate diagnosis of rare chromosomal breakage disorders.