Gene · 2026
Expanding the mutational spectrum of RAD50: a case report of Nijmegen breakage syndrome-like disorder in a Chinese child.
СтатьяКлинический случайНазвание и аннотация: Перевод в очереди
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Sun Hui, Yang Bingyu, Wang Fengyun, Xie Rongrong, Chen Ting, Chen Xiuli, Wang Xiaoyan, Chen Linqi, Wu Haiying
Аннотация
BACKGROUND: 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.
CASE PRESENTATION: 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.
GENETIC FINDINGS: 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*).
DIAGNOSIS AND TREATMENT: 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.
OUTCOME AND SIGNIFICANCE: 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.
CASE PRESENTATION: 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.
GENETIC FINDINGS: 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*).
DIAGNOSIS AND TREATMENT: 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.
OUTCOME AND SIGNIFICANCE: 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.