Genotype-biochemical phenotype analysis in newborns with biotinidase deficiency in Southeastern Anatolia

Biotinidase deficiency (BTD) is characterized by a wide range of genetic variants. However, the correlation between these variants and the biochemical phenotypes of BTD is not well-established due to the diversity of the BTD gene, the variable nature of biotinidase, and difficulties in measuring enzyme activity. This study aims to identify BTD gene variants in newborns screened for biotinidase deficiency in Southeastern Anatolia and to examine the correlation between these variants and biochemical phenotypes. BTD variant analysis and biotinidase enzyme (BT) activity measurements were performed on 711 newborns. Enzyme activity was measured using the colorimetric method. Biochemical phenotyping was categorized into three groups based on mean residual enzyme activity: profound (≤ 10%), partial (10.1–30%), and normal (> 30.1%). The pathogenicity of BTD gene variants was determined using BTD databases. The biochemical phenotypes were distributed as follows: a) profound: n = 22 (3%), b) partial: n = 95 (13.3%), and c) normal: n = 594 (83.7%). The mean enzyme activities (%) for these groups were 8.79 ± 1.87, 22.67 ± 4.55, and 97.98 ± 17.45, respectively. The most common alleles and their frequencies were p.D444H (n = 526) (37%), p.R157H (n = 172) (12.1%), and p.C33Ffster*36 (n = 73) (9%). The pathogenicity of the variants was as follows: pathogenic: 481 (33.8%), likely pathogenic: 4 (0.2%), and variant of uncertain significance (VUS): 538 (37.8%). In this large cohort in Southeastern Anatolia, the most common alleles were p.D444H, p.R157H, and p.C33Ffster*36 in BTD variants. The results indicate a low concordance between the biochemical phenotype and genotype in newborns with BTD. This study highlights the inadequacy of predicting the biochemical phenotype based solely on variant pathogenicity in biotinidase deficiency during the neonatal period.