Open AccessBiotinidase deficiency: Genotype-biochemical phenotype association in Brazilian patients
Author(s) -
Taciane Borsatto,
Fernanda SperbLudwig,
Samyra Espindola Lima,
Maria Raquel Santos Carvalho,
Pablo Augusto de Souza Fonseca,
José Simon Camelo,
Erlane Marques Ribeiro,
Paula Frassinetti Vasconcelos de Medeiros,
Charles Marques Lourenço,
Carolina Fischinger Moura de Souza,
Raquel Boy,
Têmis Maria Félix,
Camila Matzenbacher Bittar,
Louise Lapagesse de Camargo Pinto,
Eurico Camargo Neto,
Henk J. Blom,
Ida Vanessa Döederlein Schwartz
Publication year - 2017
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0177503
Subject(s) - biotinidase deficiency , phenotype , genotype , biology , genetics , genotype phenotype distinction , newborn screening , exon , gene , medicine
The association between the BTD genotype and biochemical phenotype [profound biotinidase deficiency (BD), partial BD or heterozygous activity] is not always consistent. This study aimed to investigate the genotype-biochemical phenotype association in patients with low biotinidase activity. Methods All exons, the 5'UTR and the promoter of the BTD gene were sequenced in 72 Brazilian individuals who exhibited low biotinidase activity. For each patient, the expected biochemical phenotype based on the known genotype was compared with the observed biochemical phenotype. Additional non-genetic factors that could affect the biotinidase activity were also analysed. Results Most individuals were identified by neonatal screening (n = 66/72). When consecutive results for the same patient were compared, age, prematurity and neonatal jaundice appeared to affect the level of biotinidase activity. The biochemical phenotype at the time of the second blood collection changed in 11/22 patients compared to results from the first sample. Three novel variants were found: c.1337T>C (p.L446P), c.1466A>G (p.N489S) and c.962G>A (p.W321*). Some patients with the same genotype presented different biochemical phenotypes. The expected and observed biochemical phenotypes agreed in 68.5% of cases (concordant patients). The non-coding variants c.-183G>A, c.-315A>G and c.-514C>T were present in heterozygosis in 5/17 discordant patients. In addition, c.-183G>A and c.-514C>T were also present in 10/37 concordant patients. Conclusions The variants found in the promoter region do not appear to have a strong impact on biotinidase activity. Since there is a disparity between the BTD genotype and biochemical phenotype, and biotinidase activity may be affected by both genetic and non-genetic factors, we suggest that the diagnosis of BD should be based on more than one measurement of plasma biotinidase activity. DNA analysis can be of additional relevance to differentiate between partial BD and heterozygosity.