Three Mexican Families with ß thalassemia intermedia with different molecular basis.

Beta thalassemia (ß-thal) is a frequent monogenic disease, is clinically and molecularly heterogeneous. This study described molecular and laboratory findings for three Mexican patients with ß-thal intermedia phenotype and their relatives. Three Mexican families were studied for presenting ß-thal intermedia, ARMS-PCR and Gap-PCR were performed to screen for common mutations, Sanger sequencing for rare or new alleles, and MLPA for identifying deletions and or duplications. In all three families we observed, in heterozygote condition, the mutation c.118C > T (p.Gln39*) also known as codon 39(C > T) in the ß globin gene (HBB) associated with a novel molecular defect: a new duplication of the alpha globin gene cluster, a new deletion that includes the loss of exon 3 of HBB and finally a novel mutation in the 3'UTR of HBB (HBB: c.*132C > A). We report three Mexican families with beta thalassemia intermedia due to different molecular basis; a new single nucleotide mutation involving the last nucleotide of the ß-globin chain transcript; and two possible new DNA rearrangements, an α cluster duplication, and a partial ß gene deletion.

Variants in genetic modifiers of ß-thalassemia can help to predict the major or intermedia type of the disease.

A cohort of 106 patients included in the French National Registry for Thalassemia were genotyped for 5 genetic modifiers of severity: i) ß-thalassemia mutations; (ii) the XmnI SNP; (iii) the -3.7 kb α-thal deletion; (iv) the tag-SNP rs 11886868 in BCL11A exon 2; and (v) the tag-SNP rs9399137 in the HBSB1L-cMYB inter-region. Multivariate analysis was performed to study the risk of thalassemia Intermedia phenotype associated with the different combinations of alleles. The presence or absence of the favorable alleles could accurately predict the type of thalassemia in 83.2% of the cases. The percentage of correct predictions made from the ß-thalassemia mutations and the XmnI SNP alone were significantly improved by the adjustment with the 3 other modifiers; from 73.6% to 83.2% (P<0.001). In this study, we showed that predictions based on genetic modifiers can foresee the Major or Intermedia type of ß-thalassemia, even in cohorts of patients with various ß-globin genotypes.

Tetra-amelia and lung hypo/aplasia syndrome: new case report and review.

Tetra-amelia is a rare malformation that may be associated with other anomalies and is usually inherited in an autosomal recessive pattern. We describe a fetus, born to a nonconsanguineous couple, with tetra-amelia, bilateral cleft lip and palate and bilateral lung agenesis, without other anomalies. Karyotype was normal (46,XX) and premature centromere separation was excluded. No mutation was identified upon molecular analysis of WNT3, HS6ST1, and HS6ST3. We reviewed the literature and the differential diagnosis to clarify the clinical delineation of conditions associated with tetra-amelia. The present report describes the sixth family with this pattern of malformations and reinforces the evidence that the "tetra-amelia and lung hypo/aplasia syndrome" is a distinct autosomal recessive condition, with no identified gene thus far.