A new 308 A-G substitution in HBG2 in an acyanotic newborn: case report

BACKGROUND: Neonatal hypoxemia in absence of structural cardiopulmonary anomalies is a diagnostic challenge. Haemoglobin variants involving the gamma-globin gene are recognized causes of transient desaturation in the newborn period. We report a novel HBG2 mutation identified in a clinically stable, non-cyanotic neonate born to a mother with active SARS-CoV-2 infection, highlighting a previously unreported variant with potential functional consequences on haemoglobin-oxygen affinity. METHODS: A term female newborn was delivered vaginally to a 39-years-old mother with gestational diabetes, thrombocytopenia, and SARS-CoV-2 infection, confirmed by real-time PCR at the time of delivery. The infant exhibited no signs of respiratory distress and normal blood gas analysis, but pulse oximetry revealed persistent arterial oxygen saturation of 88% in room air. Supplemental oxygen therapy (FiO₂ 23%) was initiated, resulting in a gradual improvement in saturation levels. Clinical examination and imaging were unremarkable, in particular no cardiac disease was present on heart ultrasound. Laboratory findings showed normal hemoglobin, haematocrit, and erythrocyte morphology, with a slightly reduced reticulocyte count. RESULTS: Hemoglobin electrophoresis revealed elevated fetal hemoglobin (HbF) (56.6%) with the presence of an abnormal variant band. Molecular analysis identified a heterozygous missense variant in the HBG2 gene (NM_000184.3:c.308 A > G), classified as likely pathogenic according to ACMG/AMP guidelines. Additionally, a promoter region polymorphism (NM_000184.3:c.-211 C > T (rs7882144), associated with increased fetal hemoglobin expression, was detected. No other etiologies were identified. The clinical course was uneventful and oxygen saturation normalized by one month of age without further intervention. CONCLUSIONS: This case expands the known spectrum of neonatal hemoglobinopathies by describing a novel gamma-globin variant associated with transient hypoxemia. In the absence of methemoglobinemia, cyanosis, or structural abnormalities, a diagnosis of functional hemoglobinopathy was supported. While no causal relationship with maternal SARS-CoV-2 infection was established, this case raises questions about possible effects of maternal infection on fetal gene expression. Comprehensive diagnostic evaluation, including molecular analysis, is essential in cases of unexplained neonatal desaturation to avoid misdiagnosis and provide accurate prognostic and genetic counseling.