KLF1 variants identified in neonate with severe hemolytic anemia and pulmonary hypertensionGenetic testing helps identify a rare cause of severe anemia

Frontiers in Medicine Published October 13, 2026 DOI ↗ Editorial oversight: Dr. Sofia Müller, MD · Lifespan & Whole-Person Care

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Key Takeaway

Consider KLF1 testing in unexplained Coombs-negative neonatal hemolytic anemia with pulmonary hypertension.

This publication is a case report accompanied by a literature review, describing a single female neonate who presented with unexplained Coombs/DAT-negative severe hemolytic anemia, pulmonary hypertension, and atypical cholestasis. The authors identified pathogenic compound heterozygous variants in the KLF1 gene: c.519_525dup (p.Gly176ArgfsTer179) and c.1012C>A (p.Pro338Thr). The infant required red blood cell transfusions and mechanical ventilatory support. At 24 months of follow-up, the patient remained transfusion-dependent. No adverse events, serious adverse events, discontinuations, or tolerability data were reported. The authors note that the small sample size (a single case) is a limitation, and funding or conflicts of interest were not reported. The practice relevance proposed by the authors is that early genetic testing should be performed for neonates presenting with unexplained (Coombs/DAT-negative) severe hemolytic anemia, particularly when complicated by pulmonary hypertension and atypical cholestasis, to rule out KLF1-related diseases. The text links KLF1 variants to the clinical presentation of hemolytic anemia and pulmonary hypertension. Certainty is limited by the case report design and accompanying literature review, and the findings should not be overinterpreted as evidence from a large-scale clinical trial.

How this fits prior evidence

This case report extends prior coverage of genetic etiologies for neonatal hematologic and metabolic disorders. A systematic review previously established loss-of-function ABCG5/ABCG8 mutations as a firm cause of sitosterolemia, supporting genetic testing even in heterozygous carriers. Separately, a pilot trial reported that multi-directional home phototherapy reduced treatment time and increased bilirubin reduction rates compared to unidirectional devices in severe neonatal jaundice. The current report adds KLF1 variants as a potential consideration in unexplained Coombs/DAT-negative hemolytic anemia with pulmonary hypertension and atypical cholestasis, but the evidence remains anecdotal and does not confirm causality.

When a newborn baby shows signs of severe anemia and high blood pressure in the lungs, doctors must act quickly to find the cause. In one case, a baby girl was diagnosed with hemolytic anemia, a condition where red blood cells are destroyed too fast. This was complicated by pulmonary hypertension and a liver issue called cholestasis.

Testing revealed the baby had specific mutations in the KLF1 gene. This gene is important for blood cell development. Because of these mutations, the baby developed a condition where she required regular blood transfusions to survive.

While this was a single case report, it highlights a critical point for doctors. When a newborn has severe anemia that doesn't respond to typical treatments, testing for KLF1 variants can provide a clear answer. This helps doctors understand why the baby's body is struggling and allows for better management of her condition.

What this means for you:

Genetic testing for KLF1 can help doctors identify a specific cause for severe anemia in newborns.

Common questions

What is KLF1 and how does it affect babies?

KLF1 is a gene that helps the body produce healthy blood cells. When a baby has mutations in this gene, it can lead to hemolytic anemia, where red blood cells are destroyed too quickly. In this specific case, the baby also experienced pulmonary hypertension, which is high blood pressure in the lungs.

What symptoms were seen in the infant with this condition?

The infant showed signs of severe hemolytic anemia, pulmonary hypertension, and atypical cholestasis. Because of the KLF1 gene variants, the baby developed transfusion-dependent anemia, meaning she required regular blood transfusions to maintain her health.

Why is genetic testing important for newborns with anemia?

Early genetic testing is important when a newborn has severe anemia that is not caused by typical factors. Testing for KLF1 variants helps doctors rule out specific genetic diseases, especially when the baby also shows signs of lung issues or liver problems.

Study Details

Study typeSystematic review

EvidenceLevel 1

PublishedOct 2026

View Original Abstract ↓

ObjectiveTo investigate the clinical characteristics, genotypic profiles, and diagnostic/therapeutic strategies for congenital hemolytic anemia induced by compound heterozygous variants in the KLF1 gene.MethodsWe retrospectively analyzed the clinical data of a neonate who presented primarily with ultra-severe anemia, elevated direct bilirubin, and pulmonary hypertension. Whole-exome sequencing (WES) was utilized for variant identification, followed by a comprehensive review of literature.ResultsThe patient, a female neonate, developed severe anemia within 10 h of birth, accompanied by rapidly progressing hyperbilirubinemia (predominantly direct hyperbilirubinemia). Bedside echocardiography revealed a patent ductus arteriosus (PDA) and pulmonary hypertension. Trio-WES identified pathogenic compound heterozygous variants in the KLF1 gene: c.519_525dup (p.Gly176ArgfsTer179) and c.1012C > A (p.Pro338Thr). Following multiple red blood cell transfusions and mechanical ventilatory support, the infant's condition stabilized. During a 24-month follow-up, the patient exhibited transfusion-dependent anemia.ConclusionFor neonates presenting with unexplained (Coombs/DAT-negative) severe hemolytic anemia, particularly when complicated by pulmonary hypertension and atypical cholestasis, early genetic testing should be performed to rule out KLF1-related diseases.

KLF1 variants identified in neonate with severe hemolytic anemia and pulmonary hypertensionGenetic testing helps identify a rare cause of severe anemia

How this fits prior evidence

Common questions

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KLF1 variants identified in neonate with severe hemolytic anemia and pulmonary hypertensionGenetic testing helps identify a rare cause of severe anemia

How this fits prior evidence

Common questions

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