doi: 10.1111/ahg.12191 Short Communication Does the Novel KLF1 Gene Mutation Lead to a Delay in Fetal Hemoglobin Switch? Priya Hariharan 1 , Manju Gorivale 1 , Roshan Colah 1 , Kanjaksha Ghosh 2 and Anita Nadkarni 1∗ 1 Department of Haematogenetics, National Institute of Immunohaematology (ICMR), Parel, Mumbai, India 2 Blood Bank, Surat Raktadan Kendra & Research Centre, Surat, Gujarat, India Summary The Kruppel-like factor 1 (KLF1) gene is an essential transcription factor that is required for the proper maturation of the erythroid cells. Recent studies have reported that KLF1 variations are associated with increased fetal hemoglobin (HbF) levels. Here we report a novel KLF1 gene variation codon 211 A→G (c.632 A>G) in a family who was referred for hemoglobinopathy screening. Both parents were classical β -thalassemia trait (mother: HbA 2 4.1%, HbF 8.6%; father: HbA 2 5.5%, HbF 0.6%) codon 15 G→A heterozygous, and the child was β -thalassemia homozygous. Because the mother showed a high HbF level, the genetic determinants for raised HbF were screened. We detected a novel KLF1 gene variant in the mother and the child in the heterozygous state. The co-inheritance of this novel KLF1 variant might have increased the HbF levels in the mother and may have ameliorated the clinical manifestations of the 6-year-old untransfused β -thalassemia homozygous child. Identification of KLF1 gene variants may act as a novel target for increasing HbF levels in patients with β -hemoglobinopathies. Keywords: KLF1 mutation, raised HbF, India Introduction The fetal hemoglobin forms a predominant hemoglobin frac- tion in the fetus from 10 weeks of gestation until birth. How- ever, in a normal individual, the HbF levels are reduced to around <2% by 2 years of age. Genome-wide association studies have identified various major quantitative trait loci such as SNPs in HBSIL-MYB, BCL 11 A, and point mu- tations in the KLF1 gene accounting for about 20%–50% of the variations in HbF levels (Thein, 2008). Among these genes, KLF1 is an essential transcription factor that plays a key role in erythropoiesis by regulating the expression of a repertoire set of erythroid-specific target genes (Siatecka & Bieker, 2011). Borg et al. (2010) reported that mono allelic loss of the KLF1 gene partially suppresses the γ - to β -globin gene switch, thereby increasing the HbF levels in adults (Borg et al., 2010). Functional mutations leading to increased HbF levels are of remarkable interest, as this condition helps in the ∗ Corresponding author: Dr. ANITA NADKARNI (M.Sc., Ph.D.), Scientist E, National Institute of Immunohaematology, 13th Floor NMS Building, KEM Hospital Campus, Parel, Mumbai – 400012, India. Tel: 91-22-24138518/19; Fax: 91-22-24138521; E-mail: anitahnadkarni@yahoo.com amelioration of clinical phenotypes of β -hemoglobinopathies. In this paper, we report a novel KLF1 mutation codon 211 A→G (c.632 A>G) in a family with β -hemoglobinopathy showing a considerable increase in the HbF level, thus sup- porting the role of KLF1 in hemoglobin switching. Materials and Methods The study was approved by the institutional ethics committee, and written consent was taken from all the family members before collecting blood samples. Basic hematological param- eters were performed using an automated counter (Sysmex KX-21, Kobe, Japan). HbA 2 and HbF levels were measured using cation exchange HPLC on the Variant Hemoglobin Testing System (Bio-Rad Laboratories, Hercules, USA). Ge- nomic DNA was extracted by the conventional phenol chlo- roform method, from peripheral blood leukocytes. β -globin gene analysis was performed using the Covalent Reverse Dot Blot (CRDB) technique (Colah et al., 1997). KLF1 gene analysis was also carried out by DNA sequencing (Singleton et al., 2008). BCL 11 A genotyping was carried out by real-time genotyping TaqMan assay (Stefania et al., 2011). To further assess the effect of mutation on the protein function, bioinformatic softwares were used. Annals of Human Genetics (2017) 00,1–4 1 C  2017 John Wiley & Sons Ltd/University College London