Case Report: Severe neonatal lupus in an infant with homozygous NCF1 p.Arg90His variant and a der(14)t(4;14) translocation.

Neonatal lupus erythematosus (NLE) is a rare, passively acquired autoimmune disease. The manifestations of NLE are varied, and the outcomes of the majority of cases result in spontaneous resolution. However, severe cases are limited. Emerging evidence highlights the genetic heterogeneity of NLE. The missense variant p.Arg90His in NCF1 has been demonstrated to be associated with autoimmune diseases, including systemic lupus erythematosus. Chromosomal abnormalities manifest as developmental and growth delays and facial anomalies, among other phenotypic characteristics. Whether the co-occurrence of the missense variant p.Arg90His in NCF1 and der(14)t(4;14) translocation would raise critical questions about the individual remains a mystery. In this report, we first describe a female patient with NLE who is homozygous for the p.Arg90His mutation in the NCF1 gene and also exhibits a der(14)t(4;14) translocation. Whole exome sequencing (WES) identified a homozygous NCF1 missense variant of NM_000265.4:c.269G>A(p.Arg90His) in the proband. Sanger sequencing confined the variant and showed that both parents were heterozygous for this variant. G-banding karyotype showed a chromosome abnormality of 47,XX,+der(14)t(4;14)(p15.2;q11.1) in the proband and a balanced translocation of 46,XX,t(4;14)(p15.2;q11.1) in her mother. The patient exhibited a refractory hematologic disease as a characteristic feature and was treated with glucocorticoids. She displayed unique facial features, developmental delay, and growth retardation during follow-up. This case offers a practical example to elucidate the genotype-phenotype correlations between chromosomal abnormalities, the NCF1 variant, and the observed clinical manifestations. In addition, we propose that the homozygous NCF1 p.Arg90His variant acts as a potent genetic modifier, exacerbating the severity of the clinical manifestations of NLE, with a predominant impact on the hematologic system.